Purpose of This PDQ Summary
Overview
General Information
History
Laboratory/Animal/Preclinical Studies

Effects of Newcastle Disease Virus on Human Cancer Cells NDV and Cancer Immunotherapy

Human/Clinical Studies

Immunotherapy with Oncolysates Immunotherapy with Whole Cell Vaccines Infection of Patients with NDV (including strain MTH-68)

Adverse Effects
Overall Level of Evidence for Newcastle Disease Virus
Changes to This Summary (04/24/2008)
More Information

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of Newcastle disease virus as a treatment for cancer. The summary is reviewed regularly and updated as necessary by the PDQ Cancer Complementary and Alternative Medicine Editorial Board ¹.

Information about the following is included in this summary:

• A brief history of Newcastle disease virus research.
• The results of clinical studies of Newcastle disease virus.
• Possible side effects of Newcastle disease virus.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level of evidence designation. These designations are intended to help the readers assess the strength of the evidence supporting the use of specific interventions or treatment strategies. The PDQ Cancer Complementary and Alternative Medicine Editorial Board uses a formal evidence ranking system ² in developing its level of evidence designations. These designations should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version ³, which is written in less technical language.

Overview

This complementary and alternative medicine (CAM) information summary provides an overview of the use of Newcastle disease virus (NDV) as a treatment for cancer. The summary includes a brief history of NDV research, a review of laboratory and animal studies, the results of clinical trials, and possible side effects of NDV-based therapy. Several different strains of NDV will be discussed in the summary, including the Hungarian strain MTH (More Than Hope)-68. Information presented in some sections of the summary can also be found in tables located at the end of those sections.

This summary contains the following key information:

• NDV is usually thought to be an avian (i.e., bird) virus, but it also infects humans. Although NDV causes a potentially fatal, noncancerous disease (Newcastle disease) in birds, it causes only minor illness in humans.



• NDV appears to replicate (i.e., reproduce) substantially better in human cancer cells than it does in most normal human cells.



• Individual strains of NDV are classified as lytic or nonlytic. Viruses of both strain types can kill cancer cells, but lytic strains have the potential to do this more quickly because they damage the plasma membrane of infected cells. Nonlytic strains appear to kill by interfering with cell metabolism.



• Lytic strains of NDV have been studied in humans for their ability to kill cancer cells directly, but viruses of both strain types have been used to make vaccines in an attempt to stimulate the immune system to fight cancer.



• NDV-based anticancer therapy has been reported to be of benefit in more than a dozen clinical studies, but the results of these studies must be considered inconclusive because the study designs were weak and the study reports were generally incomplete.

Many of the medical and scientific terms used in the summary are hypertext linked (at first use in each section) to the NCI Dictionary ⁴, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window. All linked terms and their corresponding definitions will appear in a glossary in the printable version of the summary.

Reference citations in some PDQ CAM information summaries may include links to external Web sites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the Web sites, or of any treatment or product, by the PDQ Cancer CAM Editorial Board or the National Cancer Institute.

General Information

Information presented in this section about the use of Newcastle disease virus (NDV) in the treatment of human cancer is summarized in a table located at the end of the section.

NDV is a paramyxovirus that causes Newcastle disease in a wide variety of birds (most notably, in chickens). Reviewed in [1-4] This often fatal disease is characterized by inflammation of respiratory tract and of either the brain or the gastrointestinal tract. Reviewed in [1-3,5,6] NDV can also infect humans, but, in humans, it is generally not very virulent, causing only mild flu-like symptoms or conjunctivitis and/or laryngitis. Reviewed in [1,3,7-15] The perception that NDV can replicate up to 10,000 times better in human cancer cells than in most normal human cells [13,16-20] Reviewed in [2,7-11,14,21-24] has prompted much interest in this virus as a potential anticancer agent. NDV has been labeled as a complementary and alternative medicine treatment because it is widely believed to be nontoxic; Reviewed in [15] however, this virus has been studied extensively by the conventional medical community.

The genetic material of NDV is RNA rather than DNA. Reviewed in [1,4,14,19,24-28] As with other types of viruses, essentially all of NDV’s replication cycle takes place inside infected cells, which are also known as host cells. Reviewed in [14,19,27,29] During a replication cycle, new virus proteins and copies of the NDV genetic material (i.e., genome) are made in the host cell’s cytoplasm. NDV is also an enveloped virus, which means that progeny virus particles are released from infected cells by budding off from them. Reviewed in [19,27,30] In this process, single copies of the NDV genome become wrapped in an outer coat (i.e., an envelope) that is made from a small piece of the host cell’s plasma membrane. Generally, the NDV outer coat contains only virus proteins that have been specifically inserted into the host cell's plasma membrane; Reviewed in [19,25,29,30] however, some host cell proteins may be included as well. Reviewed in [31,32] Two specific virus proteins, hemagglutinin-neuraminidase and the fusion protein, are the main NDV proteins found in the outer coat of isolated virus particles. Reviewed in [4,19,25,27]

There are many different strains of NDV, and they have been classified as either lytic or nonlytic for human cells. Lytic strains and nonlytic strains both appear to replicate much more efficiently in human cancer cells than they do in most normal human cells,[13,16-21] Reviewed in [14,33] and viruses of both strain types have been investigated as potential anticancer agents. One major difference between lytic strains and nonlytic strains is that lytic strains are able to make infectious progeny virus particles in human cells, whereas nonlytic strains are not. Reviewed in [14,19,25-27,34] This difference is due to the ability of lytic strains to produce activated hemagglutinin-neuraminidase and fusion protein molecules in the outer coat of progeny viruses in human cells. The progeny virus particles made by nonlytic strains contain inactive versions of these molecules. Activated hemagglutinin-neuraminidase and fusion protein molecules are required for NDV to enter a cell to replicate. Initial binding of NDV to a host cell takes place through the interaction of hemagglutinin-neuraminidase molecules in the virus coat with sialic-acid –containing molecules (i.e., gangliosides) on the surface of the cell. It is important to note, however, that nonlytic strains of NDV can make infectious progeny viruses in some types of nonhuman cells (e.g., chicken embryo cells), Reviewed in [14,19,25,26,33] thereby allowing these strains to be maintained.

Another major difference between lytic strains and nonlytic strains is that, although they both have the potential to kill infected cells, the mechanisms by which they accomplish this result are different. The production of infectious progeny virus particles by lytic strains gives them the ability to kill host cells fairly quickly. The budding of progeny viruses that contain activated hemagglutinin-neuraminidase and fusion protein molecules in their outer coats causes the plasma membrane of NDV-infected cells to fuse with the plasma membrane of adjacent cells, leading to the production of large, inviable fused cells known as syncytia.[13] Reviewed in [14,19,27] The more efficiently a lytic strain can replicate inside a host cell, the more quickly it can kill that cell. The preferential killing of cancer cells by a lytic virus is known as oncolysis; thus, lytic strains of NDV are also called oncolytic strains. In contrast, nonlytic strains of NDV kill infected cells more slowly, with death apparently the result of viral disruption of normal host cell metabolism.[35] Reviewed in [33]

As indicated previously, both lytic strains and nonlytic strains have been investigated for their anticancer potential. In fact, the major differences between the 2 strain types have been exploited to develop 3 different approaches to cancer therapy:

1. The infection of cancer patients with a lytic strain of NDV.
2. The use of oncolysates, i.e., preparations containing plasma membrane fragments from NDV-infected cancer calls, as anticancer vaccines.
3. The use of intact cancer cells infected with a nonlytic strain of NDV as whole cell vaccines.

One proposed advantage of the first approach is that virus replication may allow the spread of cytotoxic viruses to every cancer cell in the body; Reviewed in [9,31] however, the production of virus-neutralizing antibodies by the immune system might limit this possibility. Reviewed in [7,9,14,27] The rationale for the second and third approaches is that tumor-specific antigens (i.e., proteins or other molecules that are generally located in the plasma membrane of cancer cells and that are either unique to cancer cells or much more abundant in them) may be better recognized by the immune system if they are associated with virus antigens (i.e., virus proteins that have been inserted into the plasma membrane of host cells). Reviewed in [9,13,14,25,29,31,36-42] If this enhanced recognition takes place, then it may increase the chance that cancer cells, whether they are virus infected or not, will be recognized as foreign by the immune system and be destroyed. Reviewed in [9,13,25,41,42]

The principal developers of the third approach have stated that whole cell vaccines can stimulate the immune system better than oncolysates, Reviewed in [19,25,26,34,35,37,40,43-45] and that cells infected with a nonlytic strain of NDV will remain intact in the body long enough to generate these more effective immune responses.[35] Reviewed in [33] It should be noted that the cancer cells used in the third approach are treated with enough gamma radiation to prevent further cell division, but not enough to cause cell death, either before or after they are infected with the nonlytic virus.[43,44,46-52] Reviewed in [14] This precaution ensures that patients are not given a vaccine that contains actively proliferating cancer cells.

Either a patient’s own cancer cells (i.e., autologous cells) or cells from another patient with the same type of cancer (i.e., allogeneic cells) can be used to make oncolysates and whole cell vaccines. It is important to note that immune system responses similar to those obtained with oncolysates and whole cell vaccines may occur in patients infected with a lytic strain of NDV and that these responses would be expected to contribute to any observed anticancer effect.

To conduct human studies with viruses, vaccines, or other biological materials in the United States, researchers must file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA). Biological materials and drugs have been held to similar safety and effectiveness standards since 1972. In an IND application, researchers must provide safety and toxicity data from laboratory and animal studies to justify the dose, the route, and the schedule of administration to be used in the proposed clinical studies. Among the safety issues to be addressed, researchers must demonstrate an absence of harmful contaminants. Most human studies of NDV as an anticancer agent have taken place outside the United States; therefore, they have not required an IND. At present, at least 1 group of U.S. investigators has filed an IND application to study NDV as an anticancer treatment.[53] It should be noted that the FDA has not approved the use of NDV to treat any medical condition.

The NDV strains that have been evaluated most widely for the treatment of cancer are 73-T, MTH-68, and Ulster.[1,7,12,36,39,43,44,46-52,54-67] Reviewed in [23,45,68] Strain 73-T is lytic, and Ulster is nonlytic. Strain MTH-68 has not been classified, but it is assumed to be lytic.[1,7,60] Reviewed in [23,69,70] All 3 strains have shown little or no evidence of neurotropism (i.e., an ability to replicate efficiently in normal nerve cells or normal neural tissue).

In animal studies, NDV infection has been accomplished by intratumoral,[10,11,13,24,25] Reviewed in [33] intraperitoneal,[24,25,71] Reviewed in [33] intravenous,[33] intramuscular,[37] or subcutaneous [37] injection. NDV-infected, whole cell vaccines have been given to animals by intraperitoneal,[40] intradermal,[41] Reviewed in [33] or subcutaneous injection, Reviewed in [33] or by a combination of subcutaneous and intramuscular injection.[37,72]

In human studies, NDV oncolysates have been administered by subcutaneous [12,36,39,54,57,59,61-64] or intradermal [56,58] injection. NDV-infected, whole cell vaccines have been administered by intradermal injection only.[43,44,46-52,65-67] In cases where patients have been infected with a lytic strain of NDV, intratumoral,[21] intravenous,[1,53,60,73] or intramuscular [55] injection has been used, as well as inhalation [1,7] and direct injection into the colon (i.e., via a colostomy opening).[1] In some instances, cytokine treatment has been combined with NDV therapy.[39,46,47,50,56,58,59,64]

References

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48. Bohle W, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in colorectal cancer patients with virus-modified autologous tumor-cell vaccine. First clinical results with tumor-cell vaccines modified with live but avirulent Newcastle disease virus. Cancer 66 (7): 1517-23, 1990.  [PUBMED Abstract]
    
    
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50. Pomer S, Schirrmacher V, Thiele R, et al.: Tumor response and 4 year survival data of patients with advanced renal cell carcinoma treated with autologous tumor vaccine and subcutaneous r-IL-2 and IFN-alpha2b. Int J Oncol 6: 947-54, 1995. 
    
    
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History

The first published report to establish a link between infection with a virus and the regression of cancer appeared in 1912. Reviewed in [1-6] This report described a woman whose cervical cancer improved following treatment to prevent rabies. The woman had been bitten by a dog, and she was subsequently injected with a vaccine made of attenuated (i.e., weakened) rabies virus. Over the next 60 years, many other viruses, including Newcastle disease virus (NDV), were shown to have anticancer potential.[7-12] Reviewed in [1,3-6,13-24] The first report of positive results using NDV as a treatment for human cancer was published in 1964.[9] By that time, attenuated strains of NDV had been used for almost 2 decades to prevent Newcastle disease in birds, and the inability of this virus to cause serious illness in humans had been established.

As indicated previously (General Information ⁷ section), cells infected with NDV can be killed directly by the virus or indirectly through an immune system response to the infection. The immune system uses a variety of approaches to kill virus-infected cells, including attack by cytotoxic cells (i.e., natural killer cells and/or cytotoxic T cells); attack by antivirus antibodies, which are made by B cells; and the release of cytokines. Reviewed in [2,6,15,18,22,25-27]

Cytokines can be directly cytotoxic to virus-infected cells (e.g., tumor necrosis factor [TNF] -alpha Reviewed in [14,15,20]). In addition, they can stimulate increases in the activity and/or numbers of specific types of immune system cells (e.g., interferon -alpha, interferon-gamma, and TNF-alpha Reviewed in [2,28-30]).

As also indicated previously (General Information ⁷ section), if the immune system is responding to virus-infected cancer cells (or fragments of cancer cells), then better recognition of tumor-specific antigens may occur, and an increased ability to kill uninfected cancer cells may be acquired. Reviewed in [15,18,19,23,25,29,31-36] The immune system would use the same approaches to kill uninfected cancer cells that it uses to kill virus-infected cells. For example, it has been shown that TNF-alpha is directly cytotoxic to some, but not all, cancer cells, whereas normal cells are not harmed by this cytokine.[37-40]

Understanding Cancer Series: The Immune System ⁸.

References

1. Nelson NJ: Scientific interest in Newcastle disease virus is reviving. J Natl Cancer Inst 91 (20): 1708-10, 1999.  [PUBMED Abstract]
   
   
2. Csatary LK, Eckhardt S, Bukosza I, et al.: Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect Prev 17 (6): 619-27, 1993.  [PUBMED Abstract]
   
   
3. Nemunaitis J: Oncolytic viruses yesterday and today. J Oncol Manag 8 (5): 14-24, 1999. 
   
   
4. Webb HE, Smith CE: Viruses in the treatment of cancer. Lancet 1 (7658): 1206-8, 1970.  [PUBMED Abstract]
   
   
5. Ahlert T, Schirrmacher V: Isolation of a human melanoma adapted Newcastle disease virus mutant with highly selective replication patterns. Cancer Res 50 (18): 5962-8, 1990.  [PUBMED Abstract]
   
   
6. Sinkovics J, Horvath J: New developments in the virus therapy of cancer: a historical review. Intervirology 36 (4): 193-214, 1993.  [PUBMED Abstract]
   
   
7. Cassel WA, Garrett RE: Newcastle disease virus as an antineoplastic agent. Cancer 18: 863-8, 1965. 
   
   
8. Eaton MD, Heller JA, Scala AR: Enhancement of lymphoma cell immunogenicity by infection with nononcogenic virus. Cancer Res 33 (12): 3293-8, 1973.  [PUBMED Abstract]
   
   
9. Wheelock EF, Dingle JH: Observations on the repeated administration of viruses to a patient with acute leukemia. A preliminary report. N Engl J Med 271(13): 645-51, 1964. 
   
   
10. Flanagan AD, Love R, Tesar W: Propagation of Newcastle disease virus in Ehrlich ascites cells in vitro and in vivo. Proc Soc Exp Biol Med 90: 82-6, 1955. 
    
    
11. Sinkovics JG, Howe CD: Superinfection of tumors with viruses. Experientia 25 (7): 733-4, 1969.  [PUBMED Abstract]
    
    
12. Eaton MD, Levinthal JD, Scala AR: Contribution of antiviral immunity to oncolysis by Newcastle disease virus in a murine lymphoma. J Natl Cancer Inst 39 (6): 1089-97, 1967.  [PUBMED Abstract]
    
    
13. Csatary LK, Moss RW, Beuth J, et al.: Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 19 (1B): 635-8, 1999 Jan-Feb.  [PUBMED Abstract]
    
    
14. Kenney S, Pagano JS: Viruses as oncolytic agents: a new age for "therapeutic" viruses? J Natl Cancer Inst 86 (16): 1185-6, 1994.  [PUBMED Abstract]
    
    
15. Kirn DH, McCormick F: Replicating viruses as selective cancer therapeutics. Mol Med Today 2 (12): 519-27, 1996.  [PUBMED Abstract]
    
    
16. Lorence RM, Reichard KW, Katubig BB, et al.: Complete regression of human neuroblastoma xenografts in athymic mice after local Newcastle disease virus therapy. J Natl Cancer Inst 86 (16): 1228-33, 1994.  [PUBMED Abstract]
    
    
17. Lorence RM, Katubig BB, Reichard KW, et al.: Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Res 54 (23): 6017-21, 1994.  [PUBMED Abstract]
    
    
18. Reichard KW, Lorence RM, Cascino CJ, et al.: Newcastle disease virus selectively kills human tumor cells. J Surg Res 52 (5): 448-53, 1992.  [PUBMED Abstract]
    
    
19. Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998.  [PUBMED Abstract]
    
    
20. Lorence RM, Rood PA, Kelley KW: Newcastle disease virus as an antineoplastic agent: induction of tumor necrosis factor-alpha and augmentation of its cytotoxicity. J Natl Cancer Inst 80 (16): 1305-12, 1988.  [PUBMED Abstract]
    
    
21. Schirrmacher V, Haas C, Bonifer R, et al.: Human tumor cell modification by virus infection: an efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther 6 (1): 63-73, 1999.  [PUBMED Abstract]
    
    
22. Sinkovics JG, Horvath JC: Newcastle disease virus (NDV): brief history of its oncolytic strains. J Clin Virol 16 (1): 1-15, 2000.  [PUBMED Abstract]
    
    
23. Shoham J, Hirsch R, Zakay-Rones Z, et al.: Augmentation of tumor cell immunogenicity by viruses--an approach to specific immunotherapy of cancer. Nat Immun Cell Growth Regul 9 (3): 165-72, 1990.  [PUBMED Abstract]
    
    
24. Csatary LK: Viruses in the treatment of cancer. Lancet 2 (7728): 825, 1971.  [PUBMED Abstract]
    
    
25. Schirrmacher V, Ahlert T, Heicappell R, et al.: Successful application of non-oncogenic viruses for antimetastatic cancer immunotherapy. Cancer Rev 5: 19-49, 1986. 
    
    
26. Cooper NR, Nemerow GR: The role of antibody and complement in the control of viral infections. J Invest Dermatol 83 (1 Suppl): 121s-127s, 1984.  [PUBMED Abstract]
    
    
27. Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. New York, NY: Garland Publishing, 1994. 
    
    
28. Zorn U, Dallmann I, Grosse J, et al.: Induction of cytokines and cytotoxicity against tumor cells by Newcastle disease virus. Cancer Biother 9 (3): 225-35, 1994 Fall.  [PUBMED Abstract]
    
    
29. DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers, 1997. 
    
    
30. von Hoegen P, Zawatzky R, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. III. Potentiation of tumor-specific cytolytic T cell activity via induction of interferon-alpha/beta. Cell Immunol 126 (1): 80-90, 1990.  [PUBMED Abstract]
    
    
31. Haas C, Ertel C, Gerhards R, et al.: Introduction of adhesive and costimulatory immune functions into tumor cells by infection with Newcastle Disease Virus. Int J Oncol 13 (6): 1105-15, 1998.  [PUBMED Abstract]
    
    
32. Cassel WA, Murray DR: A ten-year follow-up on stage II malignant melanoma patients treated postsurgically with Newcastle disease virus oncolysate. Med Oncol Tumor Pharmacother 9 (4): 169-71, 1992.  [PUBMED Abstract]
    
    
33. Heicappell R, Schirrmacher V, von Hoegen P, et al.: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. I. Parameters for optimal therapeutic effects. Int J Cancer 37 (4): 569-77, 1986.  [PUBMED Abstract]
    
    
34. Zorn U, Duensing S, Langkopf F, et al.: Active specific immunotherapy of renal cell carcinoma: cellular and humoral immune responses. Cancer Biother Radiopharm 12 (3): 157-65, 1997.  [PUBMED Abstract]
    
    
35. Plaksin D, Porgador A, Vadai E, et al.: Effective anti-metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with Newcastle disease virus (NDV). Int J Cancer 59 (6): 796-801, 1994.  [PUBMED Abstract]
    
    
36. Bier H, Armonat G, Bier J, et al.: Postoperative active-specific immunotherapy of lymph node micrometastasis in a guinea pig tumor model. ORL J Otorhinolaryngol Relat Spec 51 (4): 197-205, 1989.  [PUBMED Abstract]
    
    
37. Helson L, Green S, Carswell E, et al.: Effect of tumour necrosis factor on cultured human melanoma cells. Nature 258 (5537): 731-2, 1975.  [PUBMED Abstract]
    
    
38. Haranaka K, Satomi N: Cytotoxic activity of tumor necrosis factor (TNF) on human cancer cells in vitro. Jpn J Exp Med 51 (3): 191-4, 1981.  [PUBMED Abstract]
    
    
39. Sugarman BJ, Aggarwal BB, Hass PE, et al.: Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science 230 (4728): 943-5, 1985.  [PUBMED Abstract]
    
    
40. Fransen L, Van der Heyden J, Ruysschaert R, et al.: Recombinant tumor necrosis factor: its effect and its synergism with interferon-gamma on a variety of normal and transformed human cell lines. Eur J Cancer Clin Oncol 22 (4): 419-26, 1986.  [PUBMED Abstract]
    
    

Laboratory/Animal/Preclinical Studies

Effects of Newcastle Disease Virus on Human Cancer Cells

The ability of Newcastle disease virus (NDV) to replicate efficiently in human cancer cells has been demonstrated in both laboratory studies and animal studies.[1-12] Reviewed in [13,14] Several of these studies have provided much of the evidence that lytic strains of NDV are also oncolytic.[3-6,8-10,12] Reviewed in [13]

Strain 73-T, which is lytic, has been shown to kill the following types of human cancer cells in vitro : fibrosarcoma, osteosarcoma, neuroblastoma, bladder carcinoma, cervical carcinoma, melanoma, Wilms tumor, and myeloid leukemia;[3,6,8,9] however, this strain did not kill human B-cell lymphoma (i.e., Burkitt lymphoma) cells in vitro.[8] In addition, strain 73-T did not kill normal, proliferating human white blood cells or normal human skin fibroblasts in vitro,[3,6,8] but it killed normal human lung fibroblasts in vitro at the same rate that it killed cancer cells.[8]

Lytic strain Roakin has been reported to kill human B-cell lymphoma and human T-cell lymphoma (i.e., Hodgkin lymphoma) cells in vitro four to five times faster than it kills normal, resting human white blood cells.[4,5] This strain, however, has also been reported to kill normal, proliferating human white blood cells in vitro, though at a lower rate than it kills cancer cells.[4]

Lytic strain Italien (or Italian) has been shown to kill human squamous cell lung carcinoma, melanoma, breast carcinoma, and larynx carcinoma, but not cervical carcinoma, cells in vitro.[12] The replication efficiency of this strain in normal human cells was not tested.

Overall, these results show that there are some types of human cancer cells in which individual lytic strains of NDV do not replicate very well and that there are some types of normal human cells in which they replicate very efficiently. Nonetheless, these data and the absence of serious illness in individuals infected with NDV Reviewed in [1-3,10,13,15-21] are consistent with the view that NDV replicates much more efficiently in human cancer cells than it does in most types of normal human cells.

NDV strain Ulster, which is nonlytic, has also been shown to replicate efficiently in human cancer cells in vitro, including cells of the following types of human tumors: colorectal carcinoma, gastric carcinoma, pancreatic carcinoma, bladder carcinoma, breast carcinoma, ovarian carcinoma, renal cell carcinoma, lung carcinoma, larynx carcinoma, cervical carcinoma, glioblastoma, melanoma, B-cell lymphoma, and T-cell lymphoma.[7] This strain does not replicate very efficiently in resting or proliferating normal human white blood cells in vitro.[7] Other experiments have shown that NDV Ulster can kill infected cells,[22] Reviewed in [14] and it can replicate in human cancer cells whether they are actively proliferating or not.[7] Reviewed in [20]

The ability of lytic strains of NDV to kill human cancer cells in vivo has also been examined. In xenograft studies, human cancer cells were injected either subcutaneously or intradermally into athymic, nude mice (i.e., mice that do not reject tumor cells from other animals because they have a defective immune system), and tumors were allowed to form. NDV was injected directly into the tumors, and tumor growth and animal survival were monitored.

Intratumoral injection of strain 73-T was associated with complete tumor regression in 75% to 100% of mice bearing human fibrosarcoma, neuroblastoma, or cervical carcinoma tumors.[1-3,10] Intratumoral injection of 73-T was also associated with more than 80% tumor regression in 66% of mice bearing human synovial sarcoma tumors.[2] In addition, intratumoral injection of 73-T was associated with 68% to 96% inhibition of tumor growth in mice bearing human epidermoid, colon, lung, breast, or prostate carcinoma tumors.[10]

Intratumoral injection of strain Italien was associated with complete tumor regression in 100% of mice bearing human melanoma tumors. The growth of metastatic tumors in these animals, however, was not affected, suggesting that the virus was unable to disseminate widely throughout the body.[11] Reviewed in [14,20]

Replication of strain 73-T in the above-mentioned neuroblastoma xenografts was demonstrated by showing an increase in the amount of virus that could be recovered from tumor samples over time.[1] When this strain was injected into the thigh muscle of athymic, nude mice, the amount of virus that could be recovered decreased with time,[1] a finding consistent with the proposal that NDV replicates much more efficiently in cancer cells than in most normal cells.

In one study, mice bearing human neuroblastoma xenografts were given single intraperitoneal injections of strain 73-T, and 9 (75%) of 12 treated mice exhibited complete, durable tumor regressions.[10]

It is important to note that athymic, nude mice still make small numbers of T cells, and they produce interferons, natural killer cells, and macrophages. Reviewed in [11,23,24] The possibility that these residual components of the immune system, which may be activated by the presence of NDV, contributed to the antitumor effects observed in the xenograft studies cannot be ruled out.

Other laboratory and animal studies have shown that NDV and NDV-infected cancer cells can stimulate a variety of immune system responses that are essential to the successful immunotherapy of cancer.[6,8,22,25-37] Reviewed in [11,20,38-42] A few of these studies used human cells,[6,8,26,27,35] Reviewed in [20,39,42] but most used animal cells and animal tumor models.[6,8,22,25,27-34,36] Reviewed in [11,20,38-41]

Data from a 2004 pilot clinical trial of an NDV-modified autologous tumor vaccine in 20 patients with stage III or IV head and neck squamous cell carcinomas suggest that the vaccine strategy can stimulate human antitumor immune responses in a manner similar to those found in animal models and may significantly prolong 5-year survival rates in this patient population. The study demonstrated the feasibility and safety of the vaccine regimen: no major side effects were observed in any of the patients.[43]

Two in vitro studies have shown that infection of human immune system cells with NDV causes the cells to produce and release the cytokines interferon-alpha and tumor necrosis factor (TNF)-alpha.[6,8] In one of these studies,[6] it was shown further that infection of human cancer cells with NDV makes the cells more sensitive to the cytotoxic effects of TNF-alpha.

Additional in vitro studies have shown that NDV-infected human cancer cells are better at activating human cytotoxic T cells, helper T cells, and natural killer cells than uninfected cancer cells.[8,26,27] The NDV protein hemagglutinin-neuraminidase, which is present in the plasma membrane of virus-infected cells, appears to play a role in the enhancement of T cell activation. There is evidence that this protein makes infected cells more adhesive, thereby promoting the interaction between virus-infected cells and immune system cells.[27] Reviewed in [20]

Other laboratory studies have shown that the interaction between NDV-infected cancer cells and T cells can be improved if monoclonal antibodies that bind the hemagglutinin-neuraminidase protein on the cancer cells and either the CD3 protein or the CD28 protein on T cells (i.e., bispecific monoclonal antibodies) are also used.[26,35] Reviewed in [20,39,42] It has been reported that this improved interaction leads to better T cell activation.[26,35] Reviewed in [20,39,42] T cells exposed to NDV-infected human colon cancer cells and bispecific monoclonal antibodies showed not only an increased ability to kill the virus-infected cells but also an ability to inhibit the proliferation of uninfected colon cancer cells.[26,35] Reviewed in [20] On the basis of these and other in vitro findings, it has been proposed that vaccines consisting of NDV-infected cancer cells and bispecific monoclonal antibodies be tested in humans.[20,26,35,39,42]

As noted above, animal cells and animal tumor models have also been used to explore the immunotherapy potential of NDV. ESb, a mouse model of metastatic T-cell lymphoma has been employed in most of this work;[22,25,28,32-34,36,37] Reviewed in [11,20,38-42] however, additional experiments have utilized one or more of the following tumor models: mouse B16 melanoma,[30] mouse Lewis lung carcinoma,[29,32] mouse P815 mastocytoma,[32] mouse Ca 761-P93 mammary carcinoma,[32] and guinea pig L10 hepatocellular carcinoma.[31]

In one study,[32] it was shown that anticancer activity could be induced in mouse macrophages both in vitro and in vivo by infection with NDV strain Ulster. Similar activation of mouse macrophages in vitro was observed after infection with the NDV lytic strain Lasota. In this study, the activated macrophages showed cytotoxic activity toward ESb, P815 mastocytoma, and Ca 761-P93 mammary carcinoma cells in vitro. Other experiments demonstrated that much of the observed anticancer activity could be attributed to the production and release of TNF-alpha by the infected macrophages. In addition, the infected, activated macrophages showed anticancer activity in vivo when they were injected into mice bearing Ca 761-P93 mammary carcinoma or Lewis lung carcinoma tumors.[32]

In another study, Reviewed in [11] intratumoral injection of NDV strain Ulster into growing ESb tumors in immunocompetent mice led to a cessation of tumor growth and an absence of metastases in 42% of treated animals. In the remaining mice, tumor growth and metastatic spread continued at the same rate as in control animals. Reviewed in [11] Additional results from this study indicated that the anticancer effect in the responding animals was due primarily to the activation of T cells directed against a tumor-specific antigen on ESb cells rather than a virus antigen. Reviewed in [11]

Other studies with NDV Ulster and the ESb tumor model support the idea that virus proteins inserted in the plasma membrane of NDV-infected cancer cells may help the immune system recognize tumor-specific antigens better, potentially leading to an increased ability to kill uninfected cancer cells and virus-infected cells.[22,25,28,33,34,36] Reviewed in [11,20,38,40,41] At least four studies [22,25,34,36] Reviewed in [40,41] have shown that T cells isolated from mice that have growing ESb tumors can be activated in vitro by co-culture with NDV-infected ESb cells and that the resulting activated T cells possess an enhanced ability to kill uninfected ESb cells in vitro. In addition, two in vivo studies [28] Reviewed in [11] have shown that mice injected with NDV-infected, irradiated ESb cells are 30 to 250 times more resistant to later injection with proliferating ESb cells than mice that are initially injected with uninfected, irradiated ESb cells. Furthermore, at least two in vivo studies have demonstrated that vaccination of mice with NDV-infected, irradiated ESb cells after surgery to remove a growing ESb primary tumor can prevent the growth of metastatic tumors in approximately 50% of treated animals.[28,33] Reviewed in [11,38,40,41] When the surviving mice were subsequently injected with proliferating ESb cells, they all remained free of cancer, indicating that the NDV/tumor cell vaccine had conferred anticancer immunity.[28,33] Reviewed in [11,40,41] Similar results were obtained from in vivo studies that employed the mouse B16 melanoma model,[30] the mouse Lewis lung carcinoma model,[29] or the guinea pig L10 hepatocellular carcinoma model.[31]

One factor that may influence the effectiveness of NDV/tumor cell vaccines is overall tumor burden. Results obtained with the B16 mouse melanoma model suggest that these vaccines are less effective in individuals with advanced metastatic disease.[30]

References

1. Lorence RM, Reichard KW, Katubig BB, et al.: Complete regression of human neuroblastoma xenografts in athymic mice after local Newcastle disease virus therapy. J Natl Cancer Inst 86 (16): 1228-33, 1994.  [PUBMED Abstract]
   
   
2. Lorence RM, Katubig BB, Reichard KW, et al.: Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Res 54 (23): 6017-21, 1994.  [PUBMED Abstract]
   
   
3. Reichard KW, Lorence RM, Cascino CJ, et al.: Newcastle disease virus selectively kills human tumor cells. J Surg Res 52 (5): 448-53, 1992.  [PUBMED Abstract]
   
   
4. Bar-Eli N, Giloh H, Schlesinger M, et al.: Preferential cytotoxic effect of Newcastle disease virus on lymphoma cells. J Cancer Res Clin Oncol 122 (7): 409-15, 1996.  [PUBMED Abstract]
   
   
5. Tzadok-David Y, Metzkin-Eizenberg M, Zakay-Rones Z: The effect of a mesogenic and a lentogenic Newcastle disease virus strain on Burkitt lymphoma Daudi cells. J Cancer Res Clin Oncol 121 (3): 169-74, 1995.  [PUBMED Abstract]
   
   
6. Lorence RM, Rood PA, Kelley KW: Newcastle disease virus as an antineoplastic agent: induction of tumor necrosis factor-alpha and augmentation of its cytotoxicity. J Natl Cancer Inst 80 (16): 1305-12, 1988.  [PUBMED Abstract]
   
   
7. Schirrmacher V, Haas C, Bonifer R, et al.: Human tumor cell modification by virus infection: an efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther 6 (1): 63-73, 1999.  [PUBMED Abstract]
   
   
8. Zorn U, Dallmann I, Grosse J, et al.: Induction of cytokines and cytotoxicity against tumor cells by Newcastle disease virus. Cancer Biother 9 (3): 225-35, 1994 Fall.  [PUBMED Abstract]
   
   
9. Cassel WA, Garrett RE: Newcastle disease virus as an antineoplastic agent. Cancer 18: 863-8, 1965. 
   
   
10. Phuangsab A, Lorence RM, Reichard KW, et al.: Newcastle disease virus therapy of human tumor xenografts: antitumor effects of local or systemic administration. Cancer Lett 172 (1): 27-36, 2001.  [PUBMED Abstract]
    
    
11. Schirrmacher V, Ahlert T, Heicappell R, et al.: Successful application of non-oncogenic viruses for antimetastatic cancer immunotherapy. Cancer Rev 5: 19-49, 1986. 
    
    
12. Ahlert T, Schirrmacher V: Isolation of a human melanoma adapted Newcastle disease virus mutant with highly selective replication patterns. Cancer Res 50 (18): 5962-8, 1990.  [PUBMED Abstract]
    
    
13. Kirn DH, McCormick F: Replicating viruses as selective cancer therapeutics. Mol Med Today 2 (12): 519-27, 1996.  [PUBMED Abstract]
    
    
14. Schirrmacher V, Griesbach A, Ahlert T: Antitumor effects of Newcastle Disease Virus in vivo: local versus systemic effects. Int J Oncol 18 (5): 945-52, 2001.  [PUBMED Abstract]
    
    
15. Csatary LK, Moss RW, Beuth J, et al.: Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 19 (1B): 635-8, 1999 Jan-Feb.  [PUBMED Abstract]
    
    
16. Emergency Preparedness Information eXchange.: Foreign Animal Diseases: Newcastle Disease. Burnaby, B.C., Canada: Telematics Research Lab, Simon Fraser University, 2002. Available online. ⁶ Last accessed May 2, 2006. 
    
    
17. Csatary LK, Eckhardt S, Bukosza I, et al.: Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect Prev 17 (6): 619-27, 1993.  [PUBMED Abstract]
    
    
18. Kenney S, Pagano JS: Viruses as oncolytic agents: a new age for "therapeutic" viruses? J Natl Cancer Inst 86 (16): 1185-6, 1994.  [PUBMED Abstract]
    
    
19. Batliwalla FM, Bateman BA, Serrano D, et al.: A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T cell repertoire. Mol Med 4 (12): 783-94, 1998.  [PUBMED Abstract]
    
    
20. Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998.  [PUBMED Abstract]
    
    
21. Moss RW: Alternative pharmacological and biological treatments for cancer: ten promising approaches. J Naturopathic Med 6 (1): 23-32, 1996. 
    
    
22. Schirrmacher V, Jurianz K, Roth C, et al.: Tumor stimulator cell modification by infection with Newcastle Disease Virus: analysis of effects and mechanism in MLTC-CML cultures. Int J Oncol 14 (2): 205-15, 1999.  [PUBMED Abstract]
    
    
23. Kadish AS, Doyle AT, Steinhauer EH, et al.: Natural cytotoxicity and interferon production in human cancer: deficient natural killer activity and normal interferon production in patients with advanced disease. J Immunol 127 (5): 1817-22, 1981.  [PUBMED Abstract]
    
    
24. Budzynski W, Radzikowski C: Cytotoxic cells in immunodeficient athymic mice. Immunopharmacol Immunotoxicol 16 (3): 319-46, 1994.  [PUBMED Abstract]
    
    
25. Schirrmacher V, Haas C, Bonifer R, et al.: Virus potentiation of tumor vaccine T-cell stimulatory capacity requires cell surface binding but not infection. Clin Cancer Res 3 (7): 1135-48, 1997.  [PUBMED Abstract]
    
    
26. Haas C, Herold-Mende C, Gerhards R, et al.: An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules. Cancer Gene Ther 6 (3): 254-62, 1999 May-Jun.  [PUBMED Abstract]
    
    
27. Haas C, Ertel C, Gerhards R, et al.: Introduction of adhesive and costimulatory immune functions into tumor cells by infection with Newcastle Disease Virus. Int J Oncol 13 (6): 1105-15, 1998.  [PUBMED Abstract]
    
    
28. Heicappell R, Schirrmacher V, von Hoegen P, et al.: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. I. Parameters for optimal therapeutic effects. Int J Cancer 37 (4): 569-77, 1986.  [PUBMED Abstract]
    
    
29. Shoham J, Hirsch R, Zakay-Rones Z, et al.: Augmentation of tumor cell immunogenicity by viruses--an approach to specific immunotherapy of cancer. Nat Immun Cell Growth Regul 9 (3): 165-72, 1990.  [PUBMED Abstract]
    
    
30. Plaksin D, Porgador A, Vadai E, et al.: Effective anti-metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with Newcastle disease virus (NDV). Int J Cancer 59 (6): 796-801, 1994.  [PUBMED Abstract]
    
    
31. Bier H, Armonat G, Bier J, et al.: Postoperative active-specific immunotherapy of lymph node micrometastasis in a guinea pig tumor model. ORL J Otorhinolaryngol Relat Spec 51 (4): 197-205, 1989.  [PUBMED Abstract]
    
    
32. Schirrmacher V, Bai L, Umansky V, et al.: Newcastle disease virus activates macrophages for anti-tumor activity. Int J Oncol 16 (2): 363-73, 2000.  [PUBMED Abstract]
    
    
33. Schirrmacher V, Heicappell R: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. II. Establishment of specific systemic anti-tumor immunity. Clin Exp Metastasis 5 (2): 147-56, 1987 Apr-Jun.  [PUBMED Abstract]
    
    
34. von Hoegen P, Zawatzky R, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. III. Potentiation of tumor-specific cytolytic T cell activity via induction of interferon-alpha/beta. Cell Immunol 126 (1): 80-90, 1990.  [PUBMED Abstract]
    
    
35. Haas C, Strauss G, Moldenhauer G, et al.: Bispecific antibodies increase T-cell stimulatory capacity in vitro of human autologous virus-modified tumor vaccine. Clin Cancer Res 4 (3): 721-30, 1998.  [PUBMED Abstract]
    
    
36. Von Hoegen P, Weber E, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. Augmentation of the tumor-specific T cell response in the absence of an anti-viral response. Eur J Immunol 18 (8): 1159-66, 1988.  [PUBMED Abstract]
    
    
37. Schirrmacher V, Schild HJ, Gückel B, et al.: Tumour-specific CTL response requiring interactions of four different cell types and recognition of MHC class I and class II restricted tumour antigens. Immunol Cell Biol 71 ( Pt 4): 311-26, 1993.  [PUBMED Abstract]
    
    
38. Schirrmacher V: Active specific immunotherapy: a new modality of cancer treatment involving the patient's own immune system. Onkologie 16: 290-6, 1993. 
    
    
39. Haas C, Schirrmacher V: Immunogenicity increase of autologous tumor cell vaccines by virus infection and attachment of bispecific antibodies. Cancer Immunol Immunother 43 (3): 190-4, 1996.  [PUBMED Abstract]
    
    
40. Schirrmacher V, von Hoegen P, Heicappell R: Virus modified tumor cell vaccines for active specific immunotherapy of micrometastases: expansion and activation of tumor-specific T cells. Prog Clin Biol Res 288: 391-9, 1989.  [PUBMED Abstract]
    
    
41. Schirrmacher V, von Hoegen P, Heicappell R: Postoperative activation of tumor specific T cells by immunization with virus-modified tumor cells and effects on metastasis. Adv Exp Med Biol 233: 91-6, 1988.  [PUBMED Abstract]
    
    
42. Schirrmacher V, Haas C: Modification of cancer vaccines by virus infection and attachment of bispecific antibodies. In: Walden P, Trefzer U, Sterry W, et al., eds.: Gene Therapy of Cancer. New York, NY: Plenum Press, 1998, pp 251-7. 
    
    
43. Karcher J, Dyckhoff G, Beckhove P, et al.: Antitumor vaccination in patients with head and neck squamous cell carcinomas with autologous virus-modified tumor cells. Cancer Res 64 (21): 8057-61, 2004.  [PUBMED Abstract]
    
    

Human/Clinical Studies

The anticancer potential of Newcastle disease virus (NDV) has been investigated in clinical studies in the United States, Germany, and Hungary. These studies have evaluated the use of oncolysates,[1-12] Reviewed in [13] whole cell vaccines,[14-26] Reviewed in [13,27-29] and infection of patients with a lytic strain of the virus.[30-36] Reviewed in [13,37-39] Findings from most of the studies, almost all of which were phase I or phase II clinical trials, have been reported in English-language biomedical journals; however, some results,[24,25] including the only data (i.e., preliminary immunological findings) from a randomized clinical trial,[25] have been reported exclusively in German. Overall, the results of these studies must be considered inconclusive. Most studies enrolled only small numbers of patients, and historical control subjects, rather than actual control groups, were often used for outcome comparisons. In addition, the evaluation of many studies is made difficult by poor descriptions of study design and the incomplete reporting of clinical data.

The following information is summarized in a table ⁹ located at the end of this section.

The use of NDV oncolysates in patients with metastatic melanoma was evaluated in 4 clinical studies in the United States.[1,2,4,6,9-11] Reviewed in [13] Three of these studies—a phase I clinical trial [9,10] and 2 phase II clinical trials [1,2,4,11]—were conducted by the same group of investigators. In all 4 studies, NDV strain 73-T was used to prepare oncolysate vaccines.

In the phase I study,[9,10] 13 patients who had advanced disease and who had not responded to conventional therapy (surgery alone or surgery plus chemotherapy and/or radiation therapy) were treated subcutaneously once a week or once every other week with injections of NDV oncolysates prepared from either their own tumor cells (i.e., autologous vaccines) or cultured melanoma cell lines (i.e., allogeneic vaccines). Several patients received additional conventional therapy while undergoing NDV treatment. Blood samples collected during the study showed increases in T cell numbers and the cytotoxic activity of lymphocytes in most patients (the latter was measured against melanoma cells in vitro ),[9] but only 1 patient showed a complete response.[10] This patient, who was alive and apparently cancer-free at the end of the study period (a survival of more than 112 weeks), received 6 courses of chemotherapy while undergoing oncolysate treatment and had the least advanced disease of the patients studied. Minor responses in some skin and lymph node metastases were noted in several other patients, but no responses in visceral metastases were detected.

As indicated above, the researchers who conducted this phase I study also conducted 2 phase II studies. The phase II studies tested the ability of NDV oncolysates to delay the progression of melanoma from regional cancer to systemic disease.[1,2,4,11] The patients in these phase II studies had undergone surgery to remove the primary cancer as well as radical lymph node dissection because of the presence of palpable disease in regional lymph nodes.

The first phase II study involved 32 patients, 5 of whom had been treated previously with other types of immunotherapy.[1,2,4,11] Melanoma was detected in 1 to 3 regional lymph nodes in 84% of the patients, in 4 to 5 regional lymph nodes in 9% of the patients, and in 6 to 8 regional lymph nodes in 6% of the patients. The second phase II study was initiated 4 years after the start of the first one, and it involved 51 additional patients.[1,2,11] Among these latter patients, 66% had melanoma detected in 1 to 3 regional lymph nodes, 16% had melanoma detected in 4 to 5 regional lymph nodes, and 18% had melanoma detected in 6 or more regional lymph nodes.[1,2,11]

In both studies, the patients were given subcutaneous injections of NDV oncolysates once a week for 4 weeks, beginning 4 to 8 weeks after surgery, followed by more subcutaneous injections given every 2 weeks until 1 year after surgery, and then continued subcutaneous injections given at intervals that increased gradually to every 3 months over the course of a 5-year period. From years 5 through 15 after surgery, some patients received additional oncolysate injections, which were given at intervals varying in length from 3 months to 6 months. Four of the patients in the first study were treated with both autologous and allogeneic vaccines, whereas the remaining patients in that study and all of the patients in the second study were treated with allogeneic vaccines only. Five years after surgery, 72% of the patients in the first study and 63% of the patients in the second study were reported to be alive and free of detectable melanoma.[11] The corresponding survival value for historical control subjects who had palpable regional disease was approximately 17% (a value derived from the scientific literature).[11] Ten years after surgery, 69% of the patients in the first study and 59% of the patients in the second study were reported to be alive and free of detectable melanoma,[2] compared with survival values of 5% to 15% for historical control subjects who had palpable regional disease or 33% for historical control subjects who had either palpable regional disease or microscopic evidence of regional lymph node metastasis.[1,2] Fifteen years after surgery, overall survival values of 59% and 53% were reported for patients in the first and second studies, respectively, with 1 survivor in the first study experiencing metastatic disease.[1] In general, survival in these 2 studies did not seem to be influenced by the number of regional lymph nodes that were positive for cancer at the time of radical lymph node dissection, and the patients who received both autologous and allogeneic vaccines did not appear to fare any better than the patients who received allogeneic vaccines only.[1]

The fourth U.S. study of NDV oncolysates in patients with melanoma was also a phase II trial.[6] This trial, which was conducted by a different group of researchers, involved 24 patients who likewise had disease that had spread to regional lymph nodes. The patients in this trial were treated in a manner similar to that of the patients in the other 2 phase II trials. In this trial, however, only 37% of the patients remained disease free 5 years after surgery, disease-free survival percentage that did not differ substantially from the 30% disease-free survival estimated for a group of historical control subjects who had been treated at the same institution with surgery alone or surgery and another type of adjuvant therapy.[6]

In contrast to the evidence of benefit found in the other phase II trials, the absence of benefit for NDV oncolysates in this fourth clinical trial remains to be explained. It has been reported that different methods of oncolysate preparation were used by the 2 groups of investigators who conducted these studies.[39] The positive results obtained by the first research group, however, must be viewed with caution. Until these results are confirmed independently in larger, randomized clinical trials, they should be considered preliminary.

Two additional phase II studies of NDV oncolysates have been conducted in Germany. One study involved 208 patients with locally advanced renal cell carcinoma (i.e., large tumors and no regional lymph node metastasis or tumors of any size and 1 or 2 regional lymph nodes positive for cancer).[8,12] The second study involved 22 patients with either metastatic breast cancer or metastatic ovarian cancer.[5,7]

In the advanced renal cell carcinoma study,[8,12] strain 73-T was used to prepare autologous oncolysates that were given to patients by subcutaneous injection once a week for 8 to 10 weeks beginning 1 to 3 months after radical surgery (i.e., nephrectomy and regional lymph node dissection). Two cytokines, low-dose recombinant interleukin-2 and recombinant interferon -alpha, were added to the oncolysate vaccines. Among the 208 patients who entered this study, 203 were followed for a period of time that ranged from 6 months to 64 months from the date of surgery, and these patients were considered evaluable for response. Approximately 91% of the evaluable patients remained free of detectable cancer during follow-up; 9% showed signs of progressive disease. The median time to relapse was more than 21 months. Fifty-six of the evaluable patients had 23 months to 64 months of follow-up from the time of surgery, and approximately 18% of these individuals showed signs of progressive disease during follow-up. All relapses in this subset of 56 patients occurred within 34 months of surgery.

The researchers who conducted this study concluded that the results demonstrated improved disease-free survival for the study subjects in comparison with survival data published in the scientific literature for similar patients who were treated with surgery alone.[8,12] Because this study was uncontrolled, however, it is not clear whether the improvement in disease-free survival was due to chance alone, to oncolysate therapy alone, to cytokine therapy alone, or to the combination of oncolysate therapy and cytokine therapy.

The same research group conducted a parallel investigation in which immune system responses to combination oncolysate and cytokine therapy were measured in 38 patients who had advanced renal cell carcinoma.[3] In this parallel study, responses to NDV antigens (i.e., the production of anti-NDV antibodies) and transient increases in blood levels of the cytokines interferon-alpha, interferon-gamma, and tumor necrosis factor (TNF)-alpha were found, but responses thought to be important to effective antitumor immunity (i.e., the production of antibodies against tumor-specific antigens, increases in natural killer cell activity, and increases in blood levels of helper T cells [i.e., CD4 antigen–positive cells] and cytotoxic T cells [i.e., CD8 antigen–positive cells]) were not.[3]

The phase II study of NDV oncolysates in patients with metastatic breast or metastatic ovarian cancer was described by its investigators as a study of autologous, whole cell vaccines.[5,7] The lytic strain Italien, however, was used in this study, so it is likely that immune system responses in the treated patients were stimulated by cellular fragments rather than by intact cancer cells.

In the study, 22 patients were vaccinated by intradermal injection at least 3 times during a 6- to 8-week period that began 2 weeks after surgery to remove malignant cells (either primary tumor cells or metastatic tumor cells). The patients also received intravenous injections of cyclophosphamide, high-dose recombinant interleukin-2, and autologous lymphocytes that had been simulated in vitro by treatment with interleukin-2. The cyclophosphamide was administered to block the activity of a class of T cells (i.e., suppressor T cells) that might weaken the desired immune responses. On average, the patients were followed for a period of 23 months from the time of surgery. Nine patients were reported to have either a complete response or a partial response after vaccine therapy. Five patients had stable disease, and 8 had progressive disease. The average duration of response was 5 months, after which disease progression was again observed. Blood samples taken from the patients during therapy showed increases in the numbers of natural killer cells and increases in serum concentrations of the cytokines interferon-alpha and TNF-alpha, but these changes did not persist. No other immune system responses were detected. Because this was an uncontrolled study, it is unclear whether any of the observed clinical and/or immune system responses can be attributed to treatment with NDV oncolysates. Furthermore, because the lytic strain Italien was used in the study, the possibility that the observed tumor regressions were due, in part, to oncolysis cannot be ruled out.

The following information is summarized in a table ¹¹ located at the end of this section.

All clinical studies of NDV-infected, whole cell vaccines that have been reported in the scientific literature were conducted in Germany.[14-26] Reviewed in [13,27-29] Most of these studies involved patients with colorectal cancer,[14,15,18,19,21] breast cancer,[16,17,24] ovarian cancer,[16,17,22] or renal cell cancer.[20,25] The nonlytic strain NDV Ulster was used to prepare autologous tumor cell vaccines in all of the studies.

The use of NDV-infected, whole cell vaccines in patients with either locally advanced or metastatic colorectal carcinoma was examined in 1 phase I clinical trial and 2 phase II clinical trials.[14,15,18,19,21] The phase I trial helped establish the optimum number of tumor cells and the optimum amount of virus to use in the average patient to produce the best possible immune response. Immune responses were monitored by means of a skin test that measured the extent of inflammation and hardening of the skin at vaccination sites (i.e., delayed-type hypersensitivity responses). The exact number of patients treated in this trial cannot be determined because nonidentical patient populations were described in the 2 published study reports.[18,19] One report lists 16 patients: 2 with stage II disease, 4 with stage III disease, and 10 with stage IV disease.[18] The second report lists 20 patients: 12 with stage II disease and 8 with stage III disease.[19] It is also not clear whether findings from individual patients were reported twice, i.e., in both trial reports. Patients with metastatic disease were allowed to enter this trial only if they had a solitary metastatic tumor.

In the trial, NDV-infected, autologous whole cell vaccines were administered to patients by intradermal injection beginning 4 weeks after surgery to remove the primary tumor or the metastatic tumor. Each patient received a total of 5 vaccinations, 4 given at 10-day intervals and a final booster given approximately 23 weeks after surgery. One of the study reports [18] states that 75% of the patients (12 of 16) showed increased immune system reactivity against uninfected, autologous tumor cells during the vaccination program. These responses were monitored by injecting uninfected, irradiated tumor cells into the skin and looking for delayed-type hypersensitivity responses. Histologic examination of several vaccination sites during the trial showed the presence of infiltrating immune system cells. These infiltrating cells were composed primarily of helper T cells; some cytotoxic T cells were also present, but B cells (i.e., antibody-producing cells) were either scarce or absent.[18]

The 2 phase II trials looked for evidence of therapeutic benefit in patients who had either metastatic colorectal carcinoma [14,21] or locally advanced colorectal carcinoma.[15] The trial that involved patients with metastatic disease recruited 23 individuals whose colorectal cancer had recurred in the liver following treatment of their primary tumor or whose colorectal cancer and liver metastases were diagnosed at the same time.[14,21] After surgery to remove the primary tumor and/or the metastases, all patients appeared to be free of residual cancer. NDV-infected, autologous tumor cells were then administered by intradermal injection every 2 weeks beginning 2 weeks after surgery. The total number of vaccinations given to the patients in this trial, however, is not clear. One of the 2 trial reports indicates that each patient received 4 vaccinations and a booster, which was given approximately 23 weeks after surgery.[14] The second trial report [21] indicates that each patient received 5 vaccinations and a booster. No additional treatment (chemotherapy or radiation therapy) was allowed during the trial.

During 18 months of follow-up, 14 (61%) of the patients in this trial had relapses of their cancer, compared with relapses in 20 (87%) of 23 historical control subjects who were treated with surgery alone by the same surgeons at the same hospital. Although this difference in disease-free survival was statistically significant, there was no statistically significant difference in overall survival between the study subjects and the historical control subjects. The researchers also reported that, in general, the patients who had the strongest immune system responses against uninfected autologous tumor cells after vaccination had the longest disease-free survival times. It should be noted, however, that the reporting of patient responses against uninfected autologous tumor cells in this trial was inconsistent.[14,21] One trial report,[14] which described results after 12 months of follow-up, indicates that 11 of 23 patients showed increased immune system reactivity against uninfected autologous tumor cells during the vaccination program; whereas the second trial report,[21] which described results after 18 months of follow-up, indicates that only 9 of 23 patients showed increased reactivity against uninfected autologous tumor cells.

The phase II trial that involved patients with locally advanced colorectal carcinoma (i.e., large tumors and no regional lymph node metastasis or tumors of any size and regional lymph nodes that were positive for cancer) recruited 57 individuals.[15] Among these 57 patients, 48 were treated with NDV-infected, whole cell vaccines, and 9 were treated with vaccines composed of autologous tumor cells and the bacterium Bacillus Calmette Guerin (BCG), which also has been used as an immune system stimulator. Patients recruited for this trial were treated first with surgery and then were given a choice between participating in the trial or receiving chemotherapy. The individuals who chose to participate in the trial were injected intradermally with the appropriate autologous tumor cell vaccines every other week for a total of 6 weeks (i.e., 3 vaccinations per patient) beginning 6 to 8 weeks after surgery. The follow-up period ranged from 6 months to 43 months (median of 22 months), and disease-free survival and overall survival were estimated for the vaccinated patients and for 661 historical control subjects who were treated with surgery alone. Two years after surgery, overall survival for the patients who were treated with NDV-infected, autologous whole cell vaccines was 98%, compared with 67% overall survival for the patients who were treated with BCG tumor cell vaccines and 74% overall survival for the historical control subjects. The differences in survival between the NDV/tumor-cell–vaccinated group and the other 2 groups were statistically significant. Disease-free survival 2 years after surgery for the NDV/tumor-cell–treated patients was 72%. The researchers who conducted this trial also reported that overall survival for the NDV/tumor-cell–treated group was not substantially different from that of the group of patients (n = 15) who chose to be treated with chemotherapy rather than immunotherapy.[15]

Two additional phase II studies investigated the use of NDV-infected, autologous tumor cell vaccines in patients who had either ovarian cancer or renal cell cancer.[20,22] The ovarian cancer trial enrolled 82 patients, but only 39 were evaluable for response.[22] The published report of this trial, however, described clinical findings for just 24 evaluable patients who had stage III disease; results for the remaining evaluable patients (5 with stage I disease, 5 with stage II disease, and 5 with stage IV disease) were not presented. The patients in this trial were treated with surgery and 6 courses of chemotherapy in addition to 3 courses of intradermally administered immunotherapy, but details about the adjuvant treatments (e.g., what constituted a course of immunotherapy or what chemotherapy drugs were used in addition to cisplatin) were very limited. Among the 24 evaluable patients with reported clinical findings, 15 had a complete remission, 8 had a partial remission, and 1 had progressive disease. The median disease-free survival time for the patients who had a complete remission was 30 months. These results were described as very encouraging by the investigators who conducted the study, but the degree of benefit afforded by the immunotherapy in this uncontrolled study cannot be established. In common with other studies of NDV-infected tumor cell vaccines, histologic examination of individual vaccination sites revealed the presence of infiltrates consisting predominantly of helper T cells.[22]

The phase II trial of NDV-infected, autologous tumor cell vaccines in patients with renal cell cancer enrolled 40 individuals whose disease had spread from the kidney to at least 1 other organ.[20] The patients in this trial underwent surgery (i.e., radical nephrectomy) to remove the primary tumor and then were given intradermal injections of NDV-infected tumor cells at 3 weeks and 5 weeks after surgery. The patients were also given subcutaneous injections of low-dose recombinant interleukin-2 and recombinant interferon-alpha. Five patients had a complete response, and 6 had a partial response. After 4 years of follow-up, overall survival for these 11 responding patients was 100%. Among the remaining 29 patients, 12 had stable disease (median survival = 31 months) and 17 had progressive disease (median survival = 14 months). The researchers also reported a median survival time of 13 months for 36 historical control subjects who were treated with surgery and other types of adjuvant therapy (chemotherapy, radiation therapy, or hormonal therapy). The overall percentage of patients with either a complete response or a partial response in this uncontrolled study (i.e., 28%) is similar to that found in other studies in which comparable patients were treated with cytokine therapy but not vaccine therapy.[20] Therefore, it is not clear whether any of the apparent clinical benefit in this trial can be attributed to vaccination with NDV-infected tumor cells.

A fifth phase II clinical trial tested NDV-infected, autologous tumor cell vaccines in 43 patients who had various advanced cancers (16 ovarian, 22 breast, 1 cervical, 1 vaginal, 1 lung, and 1 chondrosarcoma) that had not responded to previous treatment.[17] The patients in this trial received intravenous injections of cyclophosphamide and epirubicin, subcutaneous injections of low-dose recombinant interleukin-2 and interferon-alpha, and intradermal injections of the tumor cell vaccines. The cyclophosphamide and epirubicin were administered to block the activity of suppressor T cells that might weaken the desired immune responses. The trial report provided no information about the treatments that had failed, the time intervals between the failure of the last treatment and the beginning of immunotherapy, or how many vaccinations each patient received. The researchers considered 31 of the 43 patients to be evaluable for response. Among the evaluable patients, 1 individual who had ovarian cancer had a complete response that lasted more than 2 months. The remaining evaluable patients had either partial responses (n = 11), stable disease (n = 10), or progressive disease (n = 9) following treatment. In view of the limited information given, no conclusions can be drawn from this uncontrolled study about the effectiveness of NDV-infected, autologous whole cell vaccines in this patient population.

One additional clinical study evaluated the effect of vaccine quality on the survival of patients who were treated with NDV-infected, autologous tumor cells.[16] In this retrospective study, survival was estimated separately for 3 groups of patients who had early breast cancer (n = 63), metastatic breast cancer (n = 27), or metastatic ovarian cancer (n = 31) and who had sufficient numbers of recovered tumor cells to allow at least 2 vaccinations. Most of the patients who had early breast cancer were treated after surgery with conventional adjuvant therapies (chemotherapy, radiation therapy, and/or hormonal therapy) in addition to vaccine therapy. The patients who had metastatic breast or ovarian cancer had failed to respond to conventional treatments before the start of vaccine therapy. In addition to receiving tumor cell vaccines, these latter patients were treated with oral indomethacin and cimetidine, intravenous cyclophosphamide and epirubicin, and subcutaneous low-dose recombinant interleukin-2 and interferon-alpha. The indomethacin, cimetidine, cyclophosphamide, and epirubicin were given in an attempt to prevent the suppression of desired immune system responses. The autologous vaccines were classified as either high quality or low quality on the basis of the following 2 parameters: the ratio of tumor cells to other types of cells and the percentage of live tumor cells. The median times from surgery to the start of immunotherapy were 13 days, 27 days, and 28 days for the patients who had early breast cancer, metastatic breast cancer, and metastatic ovarian cancer, respectively.

Overall survival 4 years after surgery was estimated to be 96% for the patients with early breast cancer who had received a high-quality vaccine (n = 32), compared with an overall survival of 68% for those who had received a low-quality vaccine (n = 31). For the patients with metastatic breast cancer, the median survival time was estimated to be 1.75 years from the start of immunotherapy for those who had received a high-quality vaccine (n = 13), compared with a median survival time of 0.75 years for those who had received a low-quality vaccine (n = 14) (median follow-up time = 1.4 years). For patients with metastatic ovarian cancer, the median survival time was estimated to be 1.16 years from the start of immunotherapy for those who had received a high-quality vaccine (n = 18), compared with a median survival time of 0.84 years for those who had received a low-quality vaccine (n = 13) (median follow-up time = 1.23 years). The only survival difference that was statistically significant was the one for the patients who had early breast cancer. The retrospective nature of this study and the small numbers of patients in each treatment group should be viewed as major weaknesses.

In 2 of the above-mentioned studies, the phase I colorectal cancer study [18,19] and the phase II ovarian cancer study,[22] histologic examination of several vaccination sites revealed the presence of infiltrating immune system cells. These infiltrating cells, however, consisted primarily of helper T cells (CD4 antigen–positive cells); cytotoxic T cells (CD8 antigen–positive cells) were present, but only as a minor component. In another study,[26] vaccination sites from 5 cancer patients (2 with colon cancer, 2 with melanoma, and 1 with ovarian cancer) also contained infiltrates of predominantly helper T cells. In fact, CD8 antigen–positive T cells could not be detected in the lymphocytes cultured from vaccination sites of 2 of these 5 patients.[26] Reviewed in [21] The presence of small numbers of cytotoxic T cells at vaccination sites may be an important factor to consider when evaluating the results of the whole cell vaccine trials because animal studies [40-43] Reviewed in [15,18,44-52] and human studies [1] have suggested that this class of T cells is required for effective, long-term anticancer immunity. It should also be noted that, in another study,[53] increases in natural killer cell activity were measured in blood samples from 2 patients with colorectal cancer who exhibited delayed-type hypersensitivity responses at vaccination sites, but cytotoxic T cells directed against tumor-specific antigens could not be detected. Overall, these results indicate that NDV-infected, autologous, whole cell vaccines may be able to stimulate natural killer cell activity, which may have contributed the clinical outcomes described above, but also that these vaccines may be ineffective in promoting at least 1 additional immune system response (i.e., the production of tumor-specific antigen-targeted cytotoxic T cells) thought to be important to establishing long-term anticancer immunity. Whether the inclusion of bispecific monoclonal antibodies (see Laboratory/Animal/Preclinical Studies ¹² section) in the whole cell vaccines will make them more effective remains to be determined.

The following information is summarized in a table ¹⁴ located at the end of this section.

To date, most research into the treatment of human cancer by infection of patients with NDV has been conducted in Hungary.[30,31,33,34] Reviewed in [13,37-39] The Hungarian research effort has been led by a single group of investigators who advocate the use of NDV strain MTH-68, which is presumed to be lytic. Findings from these investigations have been published in the form of an anecdotal report that briefly describes results for 3 patients who had metastatic disease;[33] a single case report about a child who had glioblastoma multiforme;[34] a report of a small case series that included 4 individuals with advanced cancer;[30] and a report of a placebo-controlled, phase II clinical trial that included 33 patients in the NDV treatment group and 26 patients in the placebo group.[31] The patients in the phase II trial had various advanced cancers.[31] According to the investigators, MTH-68 treatment was beneficial for the majority of these patients.

The 5 patients described in the case report and the small case series were reported to have had either a complete remission or a partial remission following NDV therapy.[30,34] Two of the patients in the case series had advanced colorectal cancer, another had melanoma, and the fourth had advanced Hodgkin disease.[30] These 5 patients were treated with NDV daily for periods of time that ranged from 1 month to 7 years. Inhalation and intravenous injection were the main routes of virus administration. One of the patients with colorectal cancer, however, was treated by means of intracolonic injection (i.e., via a colostomy opening) for 4 weeks. It is important to note that all 5 patients were treated with conventional therapy before the start of NDV therapy and that 4 of the 5 received conventional therapy either concurrently with NDV therapy or after it. Given the small number of patients, the absence of control subjects, and the overlapping treatments, it is difficult to draw conclusions about the effectiveness of NDV therapy from these small studies.

In the phase II trial,[31] NDV was administered by inhalation only 2 times a week for a period of 6 months. The 33 patients in the NDV treatment group had the following types of cancer: colorectal (n = 13), stomach (n = 6), kidney (n = 3), pancreatic (n = 3), lung (n = 1), breast (n = 1), ovarian (n = 1), melanoma (n = 1), bile duct (n = 1), gallbladder (n = 1), sarcoma (n = 1), and ependymoma (n = 1). The distribution of cancers among the 26 patients in the placebo group was as follows: colorectal (n = 5), stomach (n = 3), kidney (n = 6), lung (n = 1), breast (n = 1), melanoma (n = 7), bile duct (n = 1), sarcoma (n = 1), and bladder (n = 1). Twenty-four (73%) of the patients in the NDV treatment group had distant metastases when they were recruited into the trial, compared with 22 (85%) of the patients in the placebo group. Thirty-one (94%) of the patients in the NDV treatment group received some form of conventional therapy (surgery, chemotherapy, or radiation therapy) before the start of virus therapy; 9 (29%) of these patients were treated with more than 1 type of conventional therapy. All (100%) of the patients in the placebo group received conventional therapy before the start of virus therapy; 15 (58%) of these individuals were treated with more than 1 type of conventional therapy. The average age of the patients in the NDV treatment group was 62.6 years, compared with an average age of 55.4 years for the patients in the placebo group. The 2 groups, however, were well-balanced with respect to gender distribution (61% males and 39% females in each treatment group) and average performance status (1.39 for each group, based on the following scale: 0 = free from complaints, 1 = capable of easy work, 2 = less than 50% bed rest required, 3 = more than 50% bed rest required, 4 = 100% bedridden). Two complete responses and 6 partial responses were reported for patients in the NDV treatment group, whereas no responses were observed in the placebo group. In the NDV treatment group, 10 patients were reported to have stable disease, compared with just 2 patients in the placebo group. In addition, more patients in the NDV treatment group than in the placebo group reported subjective improvements in their quality of life. Twenty-two (67%) of the patients in the NDV treatment group survived at least 1 year, compared with 4 (15%) of the patients in the placebo group. The 2-year survival proportions were 21% and 0% for patients in the NDV treatment group and the placebo group, respectively.

This phase II trial had a number of weaknesses that could have influenced its outcome. The most important weakness is the fact that the patients were not randomly assigned to the 2 treatment groups. This lack of randomization raises the possibility of selection bias. In this regard, it is noteworthy that a larger percentage of patients in the NDV treatment group than in the placebo group received conventional therapy within the 3 months preceding the initiation of NDV therapy (82% versus 58%).[31] In fact, the average time between the completion of conventional therapy and the start of NDV therapy among the patients who had a either a complete response or a partial response was 1.8 months.[31] Therefore, the contribution of NDV therapy to the observed clinical outcomes is difficult to determine.

In a phase I trial that was conducted in the United States, another lytic NDV strain, PV701, was tested in patients with various advanced cancers.[36] In this trial, 79 patients whose tumors had not responded to conventional therapy were given intravenous injections of virus. Four different treatment regimens were evaluated as follows:

1. A single dose of NDV given once every 28 days (17 patients).
2. A single dose of NDV given 3 times during a 1-week period, repeated every 28 days (13 patients).
3. Three injections of NDV given during a 1-week period, with the first injection containing a lower dose of virus than the remaining 2, repeated every 28 days (37 patients).
4. Six injections of NDV given during a 2-week period, with the first injection containing a lower dose of virus than the remaining 5, repeated every 21 days (12 patients).

The researchers found that the use of lower initial doses of virus allowed the administration of higher subsequent doses. A complete response was reported for 1 patient, and partial tumor regression was observed in 8 patients. Thirteen patients had stable disease for periods of time that lasted from 4 months to more than 30 months. Five patients died during the trial: 4 due to progressive disease and 1 due, possibly, to a treatment-related complication (see Adverse Effects ¹⁵ section). Several patients experienced significant adverse side effects from NDV treatment, including fever, fatigue, dehydration, low blood pressure, shortness of breath, and hypoxia. Some patients who experienced these adverse effects required hospitalization. The researchers who conducted this trial have indicated that additional clinical studies are under way.

A major concern about the effectiveness of treating cancer patients by repeated administration of a lytic strain of NDV is the possibility that the immune system will produce virus-neutralizing antibodies. Virus-neutralizing antibodies would prevent NDV from reaching and infecting malignant cells, thereby blocking oncolysis. Impairment of NDV infection would also limit the ability of cytotoxic T cells that target virus antigens to kill virus-infected cancer cells. In addition, limiting the infection of cancer cells would lessen the likelihood that the immune system would become trained to better recognize tumor-specific antigens. The Hungarian investigators have shown that anti-NDV antibodies are produced in MTH-68-treated patients,[30] but they apparently have not determined whether these antibodies are virus-neutralizing. However, the recent observation that immune system tolerance to viruses can be induced by repeated oral administration of virus proteins suggests that the concern about virus-neutralizing antibodies may not be entirely warranted.[54] Reviewed in [55] It is conceivable that frequent inhalation (or injection) of NDV may lead to immune system tolerance of this virus. This possibility should be explored in future studies.

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10. Murray DR, Cassel WA, Torbin AH, et al.: Viral oncolysate in the management of malignant melanoma. II. Clinical studies. Cancer 40 (2): 680-6, 1977.  [PUBMED Abstract]
    
    
11. Cassel WA, Murray DR: Treatment of stage II malignant melanoma patients with a Newcastle disease virus oncolysate. Nat Immun Cell Growth Regul 7 (5-6): 351-2, 1988.  [PUBMED Abstract]
    
    
12. Kirchner HH, Anton P, Atzpodien J: Adjuvant treatment of locally advanced renal cancer with autologous virus-modified tumor vaccines. World J Urol 13 (3): 171-3, 1995.  [PUBMED Abstract]
    
    
13. Nemunaitis J: Oncolytic viruses yesterday and today. J Oncol Manag 8 (5): 14-24, 1999. 
    
    
14. Liebrich W, Schlag P, Manasterski M, et al.: In vitro and clinical characterisation of a Newcastle disease virus-modified autologous tumour cell vaccine for treatment of colorectal cancer patients. Eur J Cancer 27 (6): 703-10, 1991.  [PUBMED Abstract]
    
    
15. Ockert D, Schirrmacher V, Beck N, et al.: Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma. Clin Cancer Res 2 (1): 21-8, 1996.  [PUBMED Abstract]
    
    
16. Ahlert T, Sauerbrei W, Bastert G, et al.: Tumor-cell number and viability as quality and efficacy parameters of autologous virus-modified cancer vaccines in patients with breast or ovarian cancer. J Clin Oncol 15 (4): 1354-66, 1997.  [PUBMED Abstract]
    
    
17. Ahlert T: Tumor cell vaccination and IL-2 therapy. Hybridoma 12 (5): 549-52, 1993.  [PUBMED Abstract]
    
    
18. Bohle W, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in colorectal cancer patients with virus-modified autologous tumor-cell vaccine. First clinical results with tumor-cell vaccines modified with live but avirulent Newcastle disease virus. Cancer 66 (7): 1517-23, 1990.  [PUBMED Abstract]
    
    
19. Lehner B, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in curatively resected colorectal cancer patients with a virus-modified autologous tumor cell vaccine. Cancer Immunol Immunother 32 (3): 173-8, 1990.  [PUBMED Abstract]
    
    
20. Pomer S, Schirrmacher V, Thiele R, et al.: Tumor response and 4 year survival data of patients with advanced renal cell carcinoma treated with autologous tumor vaccine and subcutaneous r-IL-2 and IFN-alpha2b. Int J Oncol 6: 947-54, 1995. 
    
    
21. Schlag P, Manasterski M, Gerneth T, et al.: Active specific immunotherapy with Newcastle-disease-virus-modified autologous tumor cells following resection of liver metastases in colorectal cancer. First evaluation of clinical response of a phase II-trial. Cancer Immunol Immunother 35 (5): 325-30, 1992.  [PUBMED Abstract]
    
    
22. Möbus V, Horn S, Stöck M, et al.: Tumor cell vaccination for gynecological tumors. Hybridoma 12 (5): 543-7, 1993.  [PUBMED Abstract]
    
    
23. Proebstle TM, Staib G, Kaufmann R, et al.: Autologous active specific immunization (ASI) therapy for metastatic melanoma [abstract from Fifth World Conference on Cancers of the Skin]. Melanoma Res 3: A-133, 35, 1993. 
    
    
24. Schirrmacher V: [Anti-tumor vaccination] Zentralbl Chir 125 (Suppl 1): 33-6, 2000.  [PUBMED Abstract]
    
    
25. Pomer S, Thiele R, Staehler G, et al.: [Tumor vaccination in renal cell carcinoma with and without interleukin-2 (IL-2) as adjuvant. A clinical contribution to the development of effective active specific immunization] Urologe A 34 (3): 215-20, 1995.  [PUBMED Abstract]
    
    
26. Stoeck M, Marland-Noske C, Manasterski M, et al.: In vitro expansion and analysis of T lymphocyte microcultures obtained from the vaccination sites of cancer patients undergoing active specific immunization with autologous Newcastle-disease-virus-modified tumour cells. Cancer Immunol Immunother 37 (4): 240-4, 1993.  [PUBMED Abstract]
    
    
27. Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998.  [PUBMED Abstract]
    
    
28. Schirrmacher V: Active specific immunotherapy: a new modality of cancer treatment involving the patient's own immune system. Onkologie 16: 290-6, 1993. 
    
    
29. Schirrmacher V, Schlag P, Liebrich W, et al.: Specific immunotherapy of colorectal carcinoma with Newcastle-disease virus-modified autologous tumor cells prepared from resected liver metastasis. Ann N Y Acad Sci 690: 364-6, 1993.  [PUBMED Abstract]
    
    
30. Csatary LK, Moss RW, Beuth J, et al.: Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 19 (1B): 635-8, 1999 Jan-Feb.  [PUBMED Abstract]
    
    
31. Csatary LK, Eckhardt S, Bukosza I, et al.: Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect Prev 17 (6): 619-27, 1993.  [PUBMED Abstract]
    
    
32. Cassel WA, Garrett RE: Newcastle disease virus as an antineoplastic agent. Cancer 18: 863-8, 1965. 
    
    
33. Csatary LK: Viruses in the treatment of cancer. Lancet 2 (7728): 825, 1971.  [PUBMED Abstract]
    
    
34. Csatary LK, Bakács T: Use of Newcastle disease virus vaccine (MTH-68/H) in a patient with high-grade glioblastoma. JAMA 281 (17): 1588-9, 1999.  [PUBMED Abstract]
    
    
35. Wheelock EF, Dingle JH: Observations on the repeated administration of viruses to a patient with acute leukemia. A preliminary report. N Engl J Med 271(13): 645-51, 1964. 
    
    
36. Pecora AL, Rizvi N, Cohen GI, et al.: Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol 20 (9): 2251-66, 2002.  [PUBMED Abstract]
    
    
37. Nelson NJ: Scientific interest in Newcastle disease virus is reviving. J Natl Cancer Inst 91 (20): 1708-10, 1999.  [PUBMED Abstract]
    
    
38. Moss RW: Alternative pharmacological and biological treatments for cancer: ten promising approaches. J Naturopathic Med 6 (1): 23-32, 1996. 
    
    
39. Sinkovics J, Horvath J: New developments in the virus therapy of cancer: a historical review. Intervirology 36 (4): 193-214, 1993.  [PUBMED Abstract]
    
    
40. Plaksin D, Porgador A, Vadai E, et al.: Effective anti-metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with Newcastle disease virus (NDV). Int J Cancer 59 (6): 796-801, 1994.  [PUBMED Abstract]
    
    
41. Von Hoegen P, Weber E, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. Augmentation of the tumor-specific T cell response in the absence of an anti-viral response. Eur J Immunol 18 (8): 1159-66, 1988.  [PUBMED Abstract]
    
    
42. Schirrmacher V, Schild HJ, Gückel B, et al.: Tumour-specific CTL response requiring interactions of four different cell types and recognition of MHC class I and class II restricted tumour antigens. Immunol Cell Biol 71 ( Pt 4): 311-26, 1993.  [PUBMED Abstract]
    
    
43. Bosslet K, Schirrmacher V, Shantz G: Tumor metastases and cell-mediated immunity in a model system in DBA/2 mice. VI. Similar specificity patterns of protective anti-tumor immunity in vivo and of cytolytic T cells in vitro. Int J Cancer 24 (3): 303-13, 1979.  [PUBMED Abstract]
    
    
44. Schirrmacher V, Haas C, Bonifer R, et al.: Human tumor cell modification by virus infection: an efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther 6 (1): 63-73, 1999.  [PUBMED Abstract]
    
    
45. Schirrmacher V, Ahlert T, Heicappell R, et al.: Successful application of non-oncogenic viruses for antimetastatic cancer immunotherapy. Cancer Rev 5: 19-49, 1986. 
    
    
46. Schirrmacher V, Haas C, Bonifer R, et al.: Virus potentiation of tumor vaccine T-cell stimulatory capacity requires cell surface binding but not infection. Clin Cancer Res 3 (7): 1135-48, 1997.  [PUBMED Abstract]
    
    
47. Bier H, Armonat G, Bier J, et al.: Postoperative active-specific immunotherapy of lymph node micrometastasis in a guinea pig tumor model. ORL J Otorhinolaryngol Relat Spec 51 (4): 197-205, 1989.  [PUBMED Abstract]
    
    
48. Schirrmacher V, Heicappell R: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. II. Establishment of specific systemic anti-tumor immunity. Clin Exp Metastasis 5 (2): 147-56, 1987 Apr-Jun.  [PUBMED Abstract]
    
    
49. von Hoegen P, Zawatzky R, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. III. Potentiation of tumor-specific cytolytic T cell activity via induction of interferon-alpha/beta. Cell Immunol 126 (1): 80-90, 1990.  [PUBMED Abstract]
    
    
50. Schirrmacher V, von Hoegen P, Heicappell R: Virus modified tumor cell vaccines for active specific immunotherapy of micrometastases: expansion and activation of tumor-specific T cells. Prog Clin Biol Res 288: 391-9, 1989.  [PUBMED Abstract]
    
    
51. Schirrmacher V, von Hoegen P, Heicappell R: Postoperative activation of tumor specific T cells by immunization with virus-modified tumor cells and effects on metastasis. Adv Exp Med Biol 233: 91-6, 1988.  [PUBMED Abstract]
    
    
52. von Hoegen P, Heicappell R, Griesbach A, et al.: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. III. Postoperative activation of tumor-specific CTLP from mice with metastases requires stimulation with the specific antigen plus additional signals. Invasion Metastasis 9 (2): 117-33, 1989.  [PUBMED Abstract]
    
    
53. Patel BT, Lutz MB, Schlag P, et al.: An analysis of autologous T-cell anti-tumour responses in colon-carcinoma patients following active specific immunization (ASI). Int J Cancer 51 (6): 878-85, 1992.  [PUBMED Abstract]
    
    
54. Ilan Y, Sauter B, Chowdhury NR, et al.: Oral tolerization to adenoviral proteins permits repeated adenovirus-mediated gene therapy in rats with pre-existing immunity to adenoviruses. Hepatology 27 (5): 1368-76, 1998.  [PUBMED Abstract]
    
    
55. Ilan Y, Chowdhury JR: Induction of tolerance to hepatitis B virus: can we 'eat the disease' and live with the virus? Med Hypotheses 52 (6): 505-9, 1999.  [PUBMED Abstract]
    
    

Adverse Effects

The side effects associated with exposure to Newcastle disease virus (NDV) have generally been described as mild to moderate in severity. As noted previously (General Information ⁷ section), NDV has been reported to cause mild flu-like symptoms, conjunctivitis, and laryngitis in humans. Reviewed in [1-11]

The most commonly reported side effect after treatment of cancer patients with the virus alone is fever, which usually subsides within 24 hours.[3,12,13] In one study of infectious virus, localized adverse effects, such as inflammation and edema, were observed in the vicinity of some tumors.[13] These adverse effects may have contributed to the death of 1 patient.[13] Other adverse effects reported in this study included fatigue, low blood pressure, shortness of breath, and hypoxia. Some of these adverse effects were serious enough to require hospitalization.

Mild headache, mild fever on the day of vaccination, and itching, swelling, and erythema at injection sites are the most commonly reported side effects following injection of NDV-infected whole cell vaccines.[14-18]

The only adverse effect associated with administration of NDV oncolysate vaccines is inflammation at injection sites.[19-21]

Most of the flu-like symptoms, fever, and edema observed in studies in which cytokines were combined with NDV oncolysates or whole cell vaccines have been attributed to treatment with interleukin-2.[19-23]

References

1. Csatary LK, Moss RW, Beuth J, et al.: Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 19 (1B): 635-8, 1999 Jan-Feb.  [PUBMED Abstract]
   
   
2. Emergency Preparedness Information eXchange.: Foreign Animal Diseases: Newcastle Disease. Burnaby, B.C., Canada: Telematics Research Lab, Simon Fraser University, 2002. Available online. ⁶ Last accessed May 2, 2006. 
   
   
3. Csatary LK, Eckhardt S, Bukosza I, et al.: Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect Prev 17 (6): 619-27, 1993.  [PUBMED Abstract]
   
   
4. Kenney S, Pagano JS: Viruses as oncolytic agents: a new age for "therapeutic" viruses? J Natl Cancer Inst 86 (16): 1185-6, 1994.  [PUBMED Abstract]
   
   
5. Kirn DH, McCormick F: Replicating viruses as selective cancer therapeutics. Mol Med Today 2 (12): 519-27, 1996.  [PUBMED Abstract]
   
   
6. Lorence RM, Reichard KW, Katubig BB, et al.: Complete regression of human neuroblastoma xenografts in athymic mice after local Newcastle disease virus therapy. J Natl Cancer Inst 86 (16): 1228-33, 1994.  [PUBMED Abstract]
   
   
7. Lorence RM, Katubig BB, Reichard KW, et al.: Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Res 54 (23): 6017-21, 1994.  [PUBMED Abstract]
   
   
8. Batliwalla FM, Bateman BA, Serrano D, et al.: A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T cell repertoire. Mol Med 4 (12): 783-94, 1998.  [PUBMED Abstract]
   
   
9. Reichard KW, Lorence RM, Cascino CJ, et al.: Newcastle disease virus selectively kills human tumor cells. J Surg Res 52 (5): 448-53, 1992.  [PUBMED Abstract]
   
   
10. Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998.  [PUBMED Abstract]
    
    
11. Moss RW: Alternative pharmacological and biological treatments for cancer: ten promising approaches. J Naturopathic Med 6 (1): 23-32, 1996. 
    
    
12. Wheelock EF, Dingle JH: Observations on the repeated administration of viruses to a patient with acute leukemia. A preliminary report. N Engl J Med 271(13): 645-51, 1964. 
    
    
13. Pecora AL, Rizvi N, Cohen GI, et al.: Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol 20 (9): 2251-66, 2002.  [PUBMED Abstract]
    
    
14. Liebrich W, Schlag P, Manasterski M, et al.: In vitro and clinical characterisation of a Newcastle disease virus-modified autologous tumour cell vaccine for treatment of colorectal cancer patients. Eur J Cancer 27 (6): 703-10, 1991.  [PUBMED Abstract]
    
    
15. Ockert D, Schirrmacher V, Beck N, et al.: Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma. Clin Cancer Res 2 (1): 21-8, 1996.  [PUBMED Abstract]
    
    
16. Bohle W, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in colorectal cancer patients with virus-modified autologous tumor-cell vaccine. First clinical results with tumor-cell vaccines modified with live but avirulent Newcastle disease virus. Cancer 66 (7): 1517-23, 1990.  [PUBMED Abstract]
    
    
17. Lehner B, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in curatively resected colorectal cancer patients with a virus-modified autologous tumor cell vaccine. Cancer Immunol Immunother 32 (3): 173-8, 1990.  [PUBMED Abstract]
    
    
18. Schlag P, Manasterski M, Gerneth T, et al.: Active specific immunotherapy with Newcastle-disease-virus-modified autologous tumor cells following resection of liver metastases in colorectal cancer. First evaluation of clinical response of a phase II-trial. Cancer Immunol Immunother 35 (5): 325-30, 1992.  [PUBMED Abstract]
    
    
19. Mallmann P, Eis-Hubinger AM, Krebs D: Lymphokine-activated tumor-infiltrating lymphocytes and autologous tumor vaccine in breast and ovarian cancer. Onkologie 15: 490-6, 1992. 
    
    
20. Anton P, Kirchner H, Jonas U, et al.: Cytokines and tumor vaccination. Cancer Biother Radiopharm 11 (5): 315-8, 1996.  [PUBMED Abstract]
    
    
21. Kirchner HH, Anton P, Atzpodien J: Adjuvant treatment of locally advanced renal cancer with autologous virus-modified tumor vaccines. World J Urol 13 (3): 171-3, 1995.  [PUBMED Abstract]
    
    
22. Pomer S, Schirrmacher V, Thiele R, et al.: Tumor response and 4 year survival data of patients with advanced renal cell carcinoma treated with autologous tumor vaccine and subcutaneous r-IL-2 and IFN-alpha2b. Int J Oncol 6: 947-54, 1995. 
    
    
23. Mallmann P: Autologous tumor-cell vaccination and lymphokine-activated tumor-infiltrating lymphocytes (LAK-TIL). Hybridoma 12 (5): 559-66, 1993.  [PUBMED Abstract]
    
    

Overall Level of Evidence for Newcastle Disease Virus

In view of the evidence accumulated to date, no conclusions can be drawn about the effectiveness of using Newcastle disease virus in the treatment of cancer. Most reported clinical studies have involved few patients, and historical control subjects rather than actual control groups have often been used for outcome comparisons. Poor descriptions of study design and incomplete reporting of clinical data have hindered evaluation of many of the reported findings.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For additional information about levels of evidence analysis, refer to Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine ².

Changes to This Summary (04/24/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

More Information

Additional Information about CAM Therapies

• The National Center for Complementary and Alternative Medicine ¹⁸ (NCCAM).
• The National Cancer Institute Office of Cancer Complementary and Alternative Medicine ¹⁹ (OCCAM).
• CAM on PubMed ²⁰, a special subset of the PubMed scientific literature database created through a partnership between NCCAM and the National Library of Medicine.

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database ²¹

  Full description of the NCI PDQ database.

Other PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment ²²

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment ²³

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care ²⁴

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer) ²⁵

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention ²⁶

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics ²⁷

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine ²⁸

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Glossary Terms

Treatment given after the primary treatment to increase the chances of a cure. Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, or biological therapy.

An unwanted side effect of treatment.

Taken from different individuals of the same species. Also called allogenic.

An incomplete description of the medical and treatment history of one or more patients. Anecdotal reports may be published in places other than peer-reviewed, scientific journals.

A type of protein made by plasma cells (a type of white blood cell) in response to an antigen (foreign substance). Each antibody can bind to only one specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen.

A substance that causes the immune system to make a specific immune response.

A type of laboratory mouse that is hairless, lacks a normal thymus gland, and has a defective immune system because of a genetic mutation. Athymic nude mice are often used in cancer research because they do not reject tumor cells, from mice or other species.

Weakened or thinned. Attenuated strains of disease-causing bacteria and viruses are often used as vaccines. The weakened strains are used as vaccines because they stimulate a protective immune response while causing no disease or only mild disease in the person receiving the vaccine.

Taken from an individual's own tissues, cells, or DNA.

A type of immune cell that makes proteins called antibodies, which bind to microorganisms and other foreign substances, and help fight infections. A B cell is a type of white blood cell. Also called B lymphocyte.

A weakened form of the bacterium Mycobacterium bovis (bacillus Calmette-Guérin) that does not cause disease. Bacillus Calmette-Guérin is used in a solution to stimulate the immune system in the treatment of bladder cancer and as a vaccine to prevent tuberculosis. Also called BCG.

A large group of single-cell microorganisms. Some cause infections and disease in animals and humans. The singular of bacteria is bacterium.

A tube through which bile passes in and out of the liver.

Pertaining to biology or to life and living things. In medicine, refers to a substance made from a living organism or its products. Biologicals may be used to prevent, diagnose, treat or relieve of symptoms of a disease. For example, antibodies, interleukins, and vaccines are biologicals. Biological also refers to parents and children who are related by blood.

A monoclonal antibody that binds two different types of antigen. Bispecific monoclonal antibodies do not occur naturally; they must be made in the laboratory.

The organ that stores urine.

In medicine, refers to a vaccination given after a previous vaccination. A booster helps maintain or increase a protective immune response.

Glandular organ located on the chest. The breast is made up of connective tissue, fat, and breast tissue that contains the glands that can make milk. Also called mammary gland.

An aggressive (fast-growing) type of B-cell non-Hodgkin lymphoma that occurs most often in children and young adults. The disease may affect the jaw, central nervous system, bowel, kidneys, ovaries, or other organs. There are three main types of Burkitt lymphoma (sporadic, endemic, and immunodeficiency related). Sporadic Burkitt lymphoma occurs throughout the world, and endemic Burkitt lymphoma occurs in Africa. Immunodeficiency-related Burkitt lymphoma is most often seen in AIDS patients.

A term for diseases in which abnormal cells divide without control. Cancer cells can invade nearby tissues and can spread to other parts of the body through the blood and lymph systems. There are several main types of cancer. Carcinoma is cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system. Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord.

Cancer that begins in the skin or in tissues that line or cover internal organs.

A detailed report of the diagnosis, treatment, and follow-up of an individual patient. Case reports also contain some demographic information about the patient (for example, age, gender, ethnic origin).

A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment.

The individual unit that makes up the tissues of the body. All living things are made up of one or more cells.

Relating to the neck, or to the neck of any organ or structure. Cervical lymph nodes are located in the neck. Cervical cancer refers to cancer of the uterine cervix, which is the lower, narrow end (the “neck”) of the uterus.

Cancer that forms in tissues of the cervix (the organ connecting the uterus and vagina). It is usually a slow-growing cancer that may not have symptoms but can be found with regular Pap tests (a procedure in which cells are scraped from the cervix and looked at under a microscope).

Treatment with drugs that kill cancer cells.

A type of cancer that forms in bone cartilage. It usually starts in the pelvis (between the hip bones), the shoulder, the ribs, or at the ends of the long bones of the arms and legs. A rare type of chondrosarcoma called extraskeletal chondrosarcoma does not form in bone cartilage. Instead, it forms in the soft tissues of the upper part of the arms and legs. Chondrosarcoma can occur at any age but is more common in people older than 40 years. It is a type of bone cancer.

A drug usually used to treat stomach ulcers and heartburn. It is also commonly used in a regimen to prevent allergic reactions.

A drug used to treat many types of cancer. Cisplatin contains the metal platinum. It kills cancer cells by damaging their DNA and stopping them from dividing. Cisplatin is a type of alkylating agent.

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical trial.

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical study.

A mixture of two or more different kinds of cells that are grown together.

The longest part of the large intestine, which is a tube-like organ connected to the small intestine at one end and the anus at the other. The colon removes water and some nutrients and electrolytes from partially digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus.

Having to do with the colon or the rectum.

An opening into the colon from the outside of the body. A colostomy provides a new path for waste material to leave the body after part of the colon has been removed.

Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices generally are not considered standard medical approaches. Standard treatments go through a long and careful research process to prove they are safe and effective, but less is known about most types of CAM. CAM may include dietary supplements, megadose vitamins, herbal preparations, special teas, acupuncture, massage therapy, magnet therapy, spiritual healing, and meditation. Also called CAM.

The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. Also called complete response.

The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. Also called complete remission.

A treatment that is given at the same time as another.

A membrane that lines the inner surface of the eyelid and also covers the front part of the eye. Conjunctivitis is inflammation of the conjunctiva.

An animal in a study that does not receive the treatment being tested. Comparing the health of control animals with the health of treated animals allows researchers to evaluate the effects of a treatment more accurately.

In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works.

A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment.

A human, plant, or animal cell that has been adapted to grow in the laboratory. Cultured cells may be used to diagnose infections, to test new drugs, and in research.

Cells of a single type (human, animal, or plant) that have been adapted to grow continuously in the laboratory and are used in research.

An anticancer drug that belongs to the family of drugs called alkylating agents.

A substance that is made by cells of the immune system. Some cytokines can boost the immune response and others can suppress it. Cytokines can also be made in the laboratory by recombinant DNA technology and used in the treatment of various diseases, including cancer.

The fluid inside a cell but outside the cell's nucleus. Most chemical reactions in a cell take place in the cytoplasm.

Cell-killing.

A type of immune cell that can kill certain cells, including foreign cells, cancer cells, and cells infected with a virus. Cytotoxic T cells can be separated from other blood cells, grown in the laboratory, and then given to a patient to kill cancer cells. A cytotoxic T cell is a type of white blood cell and a type of lymphocyte. Also called cytotoxic T lymphocyte and killer T cell.

An inflammatory response that develops 24 to 72 hours after exposure to an antigen that the immune system recognizes as foreign. This type of immune response involves mainly T cells rather than antibodies (which are made by B cells). Also called DTH.

The length of time after treatment for a specific disease during which a patient survives with no sign of the disease. Disease-free survival may be used in a clinical study or trial to help measure how well a new treatment works.

The molecules inside cells that carry genetic information and pass it from one generation to the next. Also called deoxyribonucleic acid.

The amount of medicine taken, or radiation given, at one time.

Swelling caused by excess fluid in body tissues.

Early stage in the development of a plant or an animal. In vertebrate animals (have a backbone or spinal column), this stage lasts from shortly after fertilization until all major body parts appear. In particular, in humans, this stage lasts from about 2 weeks after fertilization until the end of the seventh or eighth week of pregnancy.

In clinical trials, an event or outcome that can be measured objectively to determine whether the intervention being studied is beneficial. The endpoints of a clinical trial are usually included in the study objectives. Some examples of endpoints are survival, improvements in quality of life, relief of symptoms, and disappearance of the tumor.

A virus that has an outer wrapping or envelope. This envelope comes from the infected cell, or host, in a process called "budding off." During the budding process, newly formed virus particles become "enveloped" or wrapped in an outer coat that is made from a small piece of the cell's plasma membrane. The envelope may play a role in helping a virus survive and infect other cells.

A type of brain tumor that begins in cells lining the spinal cord central canal (fluid-filled space down the center) or the ventricles (fluid-filled spaces of the brain). Ependymomas may also form in the choroid plexus (tissue in the ventricles that makes cerebrospinal fluid). Also called ependymal tumor.

Cancer that begins in squamous cells (thin, flat cells that look like fish scales). Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the lining of the respiratory and digestive tracts. Also called squamous cell carcinoma.

A drug used together with other drugs to treat early breast cancer that has spread to lymph nodes. It is also being studied in the treatment of other types of cancer. Epirubicin is a type of anthracycline antibiotic. Also called Ellence and epirubicin hydrochloride.

Redness of the skin.

Patients whose response to a treatment can be measured because enough information has been collected.

A condition marked by extreme tiredness and inability to function due lack of energy. Fatigue may be acute or chronic.

A connective tissue cell that makes and secretes collagen proteins.

A type of soft tissue sarcoma that begins in fibrous tissue, which holds bones, muscles, and other organs in place.

An agency in the U.S. federal government whose mission is to protect public health by making sure that food, cosmetics, and nutritional supplements are safe to use and truthfully labeled. The Food and Drug Administration also makes sure that drugs, medical devices, and equipment are safe and effective, and that blood for transfusions and transplant tissue are safe. Also called FDA.

A protein made from a fusion gene, which is created by joining parts of two different genes. Fusion genes may occur naturally in the body by transfer of DNA between chromosomes. For example, the BCR-ABL gene found in some types of leukemia is a fusion gene that makes the BCR-ABL fusion protein. Fusion genes and proteins can also be made in the laboratory by combining genes or parts of genes from the same or different organisms.

The pear-shaped organ found below the liver. Bile is concentrated and stored in the gallbladder.

A type of radiation therapy that uses gamma radiation. Gamma radiation is a type of high-energy radiation that is different from x-rays.

A complex molecule that contains both lipids (fats) and carbohydrates (sugars) and is found in the plasma (outer) membrane of many kinds of cells. Several different types of gangliosides have been identified.

Having to do with the stomach.

The stomach and intestines. The gastrointestinal tract is part of the digestive system, which also includes the salivary glands, mouth, esophagus, liver, pancreas, gallbladder, and rectum.

Inherited; having to do with information that is passed from parents to offspring through genes in sperm and egg cells.

The complete genetic material of an organism.

A fast-growing type of central nervous system tumor that forms from glial (supportive) tissue of the brain and spinal cord and has cells that look very different from normal cells. Glioblastoma usually occurs in adults and affects the brain more often than the spinal cord. Also called GBM, glioblastoma multiforme, and grade IV astrocytoma.

A fast-growing type of central nervous system tumor that forms from glial (supportive) tissue of the brain and spinal cord and has cells that look very different from normal cells. Glioblastoma multiforme usually occurs in adults and affects the brain more often than the spinal cord. Also called GBM, glioblastoma, and grade IV astrocytoma.

A type of immune cell that stimulates killer T cells, macrophages, and B cells to make immune responses. A helper T cell is a type of white blood cell and a type of lymphocyte. Also called CD4-positive T lymphocyte.

A protein found in the outer coat of paramyxoviruses. This protein helps virus particles bind to cells, making infection easier.

A type of adenocarcinoma, the most common type of liver tumor.

The examination of tissue specimens under a microscope.

An individual treated in the past and used in a comparison group when researchers analyze the results of a clinical study that had no control group. The use of a control, or comparison, group helps researchers determine the effects of a new treatment more accurately.

A cancer of the immune system that is marked by the presence of a type of cell called the Reed-Sternberg cell. The two major types of Hodgkin disease are classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. Symptoms include the painless enlargement of lymph nodes, spleen, or other immune tissue. Other symptoms include fever, weight loss, fatigue, or night sweats. Also called Hodgkin lymphoma.

Treatment that adds, blocks, or removes hormones. For certain conditions (such as diabetes or menopause), hormones are given to adjust low hormone levels. To slow or stop the growth of certain cancers (such as prostate and breast cancer), synthetic hormones or other drugs may be given to block the body’s natural hormones. Sometimes surgery is needed to remove the gland that makes a certain hormone. Also called endocrine therapy, hormone therapy, and hormone treatment.

Treatment that adds, blocks, or removes hormones. For certain conditions (such as diabetes or menopause), hormones are given to adjust low hormone levels. To slow or stop the growth of certain cancers (such as prostate and breast cancer), synthetic hormones or other drugs may be given to block the body’s natural hormones. Sometimes surgery is needed to remove the gland that makes a certain hormone. Also called endocrine therapy, hormonal therapy, and hormone treatment.

A cell that is infected by a virus or another type of microorganism.

A condition in which there is a decrease in the oxygen supply to a tissue. In cancer treatment, the level of hypoxia in a tumor may help predict the response of the tumor to the treatment.

The complex group of organs and cells that defends the body against infections and other diseases.

The failure of the immune system to respond to an antigen that previously caused an immune response.

Having the ability to produce a normal immune response.

Treatment to boost or restore the ability of the immune system to fight cancer, infections, and other diseases. Also used to lessen certain side effects that may be caused by some cancer treatments. Agents used in immunotherapy include monoclonal antibodies, growth factors, and vaccines. These agents may also have a direct antitumor effect. Also called biological response modifier therapy, biological therapy, biotherapy, and BRM therapy.

In the laboratory (outside the body). The opposite of in vivo (in the body).

In the body. The opposite of in vitro (outside the body or in the laboratory).

A drug that reduces pain, fever, swelling, and redness. It is also being used to reduce tumor-induced suppression of the immune system and to increase the effectiveness of anticancer drugs. It is a type of nonsteroidal anti-inflammatory drug (NSAID).

Invasion and multiplication of germs in the body. Infections can occur in any part of the body and can spread throughout the body. The germs may be bacteria, viruses, yeast, or fungi. They can cause a fever and other problems, depending on where the infection occurs. When the body’s natural defense system is strong, it can often fight the germs and prevent infection. Some cancer treatments can weaken the natural defense system.

Redness, swelling, pain, and/or a feeling of heat in an area of the body. This is a protective reaction to injury, disease, or irritation of the tissues.

In medicine, refers to the act of taking a substance into the body by breathing.

Use of a syringe and needle to push fluids or drugs into the body; often called a "shot."

A biological response modifier (a substance that can improve the body's natural response to infections and other diseases). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and -gamma. The body normally produces these substances. They are also made in the laboratory to treat cancer and other diseases.

One of a group of related proteins made by leukocytes (white blood cells) and other cells in the body. Interleukin-2 is made by a type of T lymphocyte. It increases the growth and activity of other T lymphocytes and B lymphocytes, and affects the development of the immune system. Aldesleukin (interleukin-2 made in the laboratory) is being used as a biological response modifier to boost the immune system in cancer therapy. Interleukin-2 is a type of cytokine. Also called IL-2.

Within the colon.

Within the skin. Also called intracutaneous.

Within or into muscle. Also called IM.

Within the peritoneal cavity (the area that contains the abdominal organs). Also called IP.

Within a tumor.

Into or within a vein. Intravenous usually refers to a way of giving a drug or other substance through a needle or tube inserted into a vein. Also called I.V..

Injection into a vein.

In clinical trials, refers to a drug (including a new drug, dose, combination, or route of administration) or procedure that has undergone basic laboratory testing and received approval from the U.S. Food and Drug Administration (FDA) to be tested in human subjects. A drug or procedure may be approved by the FDA for use in one disease or condition, but be considered investigational in other diseases or conditions. Also called experimental.

A researcher in a clinical trial or clinical study.

Not able to survive.

Treated with radiation.

Research done in a laboratory. These studies may use test tubes or animals to find out if a drug, procedure, or treatment is likely to be useful. Laboratory studies take place before any testing is done in humans.

Inflammation of the larynx.

The area of the throat containing the vocal cords and used for breathing, swallowing, and talking. Also called voice box.

Cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of blood cells to be produced and enter the bloodstream.

A ranking system used to describe the strength of the results measured in a clinical trial or research study. The design of the study (such as a case report for an individual patient or a randomized double-blinded controlled clinical trial) and the endpoints measured (such as survival or quality of life) affect the strength of the evidence.

One of a pair of organs in the chest that supplies the body with oxygen, and removes carbon dioxide from the body.

A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Lymph nodes filter lymph (lymphatic fluid), and they store lymphocytes (white blood cells). They are located along lymphatic vessels. Also called lymph gland.

A type of immune cell that is made in the bone marrow and is found in the blood and in lymph tissue. The two main types of lymphocytes are B lymphocytes and T lymphocytes. B lymphocytes make antibodies, and T lymphocytes help kill tumor cells and help control immune responses. A lymphocyte is a type of white blood cell.

Cancer that begins in cells of the immune system. There are two basic categories of lymphomas. One kind is Hodgkin lymphoma, which is marked by the presence of a type of cell called the Reed-Sternberg cell. The other category is non-Hodgkin lymphomas, which includes a large, diverse group of cancers of immune system cells. Non-Hodgkin lymphomas can be further divided into cancers that have an indolent (slow-growing) course and those that have an aggressive (fast-growing) course. These subtypes behave and respond to treatment differently. Both Hodgkin and non-Hodgkin lymphomas can occur in children and adults, and prognosis and treatment depend on the stage and the type of cancer.

Having to do with lysis. In biology, lysis refers to the disintegration of a cell by disruption of its plasma membrane. Lysis can be caused by chemical or physical means (e.g., high-energy sound waves) or by a virus infection.

A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells.

Cancerous. Malignant tumors can invade and destroy nearby tissue and spread to other parts of the body.

Having to do with the breast.

A growth or lump of mast cells (a type of white blood cell). Mast cell tumors can involve the skin, subcutaneous tissue, and muscle tissue. Also called mast cell tumor.

A statistics term. The middle value in a set of measurements.

A form of cancer that begins in melanocytes (cells that make the pigment melanin). It may begin in a mole (skin melanoma), but can also begin in other pigmented tissues, such as in the eye or in the intestines.

A very thin layer of tissue that covers a surface.

The total of all chemical changes that take place in a cell or an organism. These changes make energy and the materials needed for growth, reproduction, and maintaining health. They also help get rid of toxic substances.

The spread of cancer from one part of the body to another. A tumor formed by cells that have spread is called a “metastatic tumor” or a “metastasis.” The metastatic tumor contains cells that are like those in the original (primary) tumor. The plural form of metastasis is metastases (meh-TAS-tuh-SEEZ).

Having to do with metastasis, which is the spread of cancer from one part of the body to another.

Too small to be seen without a microscope.

The smallest particle of a substance that has all of the physical and chemical properties of that substance. Molecules are made up of one or more atoms. If they contain more than one atom, the atoms can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms.

A type of protein made in the laboratory that can locate and bind to substances in the body, including tumor cells. There are many kinds of monoclonal antibodies. Each monoclonal antibody is made to find one substance. Monoclonal antibodies are being used to treat some types of cancer and are being studied in the treatment of other types. They can be used alone or to carry drugs, toxins, or radioactive materials directly to a tumor.

Having to do with or resembling the bone marrow. May also refer to certain types of hematopoietic (blood-forming) cells found in the bone marrow. Sometimes used as a synonym for myelogenous; for example, acute myeloid leukemia and acute myelogenous leukemia are the same disease.

The National Cancer Institute, part of the National Institutes of Health of the United States Department of Health and Human Services, is the Federal Government's principal agency for cancer research. The National Cancer Institute conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the National Cancer Institute Web site at http://www.cancer.gov. Also called NCI.

A type of immune cell that has granules (small particles) with enzymes that can kill tumor cells or cells infected with a virus. is a type of white blood cell. Also called NK cell, NK-large granular lymphocyte, and NK-LGL.

Surgery to remove a kidney or part of a kidney. In a partial nephrectomy, part of one kidney or a tumor is removed, but not an entire kidney. In a simple nephrectomy, one kidney is removed. In a radical nephrectomy, an entire kidney, nearby adrenal gland and lymph nodes, and other surrounding tissue are removed. In a bilateral nephrectomy, both kidneys are removed.

Having to do with nerves or the nervous system, including the brain and the spinal cord.

Cancer that arises in immature nerve cells and affects mostly infants and children.

An ability to invade and live in neural tissue. This term is usually used to describe the ability of viruses to infect nerve tissue.

A bird virus that is being studied in the treatment of cancer. It may be used to kill cancer cells directly, or it may be given as a cancer vaccine to stimulate the body’s immune system. Newcastle disease virus is a type of biological response modifier and vaccine therapy. Also called NDV.

In biology, refers to viruses that do not kill infected cells by disrupting their plasma membranes.

Not harmful or destructive.

An extract made from cancer cells.

The lysis (breakdown) of cancer cells. This can be caused by chemical or physical means (for example, strong detergents or high-energy sound waves) or by infection with a strain of virus that can lyse cells.

By or having to do with the mouth.

A cancer of the bone that usually affects the large bones of the arm or leg. It occurs most commonly in young people and affects more males than females. Also called osteogenic sarcoma.

Having to do with the ovaries, the female reproductive glands in which the ova (eggs) are formed. The ovaries are located in the pelvis, one on each side of the uterus.

The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer. The overall survival rate is often stated as a five-year survival rate, which is the percentage of people in a study or treatment group who are alive five years after diagnosis or treatment. Also called survival rate.

A term used to describe cancer that can be felt by touch, usually present in lymph nodes, skin, or other organs of the body such as the liver or colon.

Having to do with the pancreas.

A type of virus that has hemagglutinin-neuraminidase proteins in the outer coat and RNA as the genetic material. Measles (rubeola) virus, mumps virus, and Newcastle disease virus are paramyxoviruses.

A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. Also called partial response.

A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. Also called partial remission.

PDQ is an online database developed and maintained by the National Cancer Institute. Designed to make the most current, credible, and accurate cancer information available to health professionals and the public, PDQ contains peer-reviewed summaries on cancer treatment, screening, prevention, genetics, complementary and alternative medicine, and supportive care; a registry of cancer clinical trials from around the world; and directories of physicians, professionals who provide genetics services, and organizations that provide cancer care. Most of this information, and more specific information about PDQ, can be found on the NCI's Web site at http://www.cancer.gov/cancertopics/pdq. Also called Physician Data Query.

A measure of how well a patient is able to perform ordinary tasks and carry out daily activities.

The first step in testing a new treatment in humans. These studies test the best way to give a new treatment (for example, by mouth, intravenous infusion, or injection) and the best dose. The dose is usually increased a little at a time in order to find the highest dose that does not cause harmful side effects. Because little is known about the possible risks and benefits of the treatments being tested, phase I trials usually include only a small number of patients who have not been helped by other treatments.

A study to test whether a new treatment has an anticancer effect (for example, whether it shrinks a tumor or improves blood test results) and whether it works against a certain type of cancer.

An inactive substance or treatment that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.

Refers to a clinical study in which the control patients receive a placebo.

The outer membrane of a cell.

Research using animals to find out if a drug, procedure, or treatment is likely to be useful. Preclinical studies take place before any testing in humans is done.

The original tumor.

Offspring; the product of reproduction or replication.

In medicine, the course of a disease, such as cancer, as it becomes worse or spreads in the body.

Cancer that is growing, spreading, or getting worse.

Multiplying or increasing in number. In biology, cell proliferation occurs by a process known as cell division.

A molecule made up of amino acids that are needed for the body to function properly. Proteins are the basis of body structures such as skin and hair and of substances such as enzymes, cytokines, and antibodies.

The overall enjoyment of life. Many clinical trials assess the effects of cancer and its treatment on the quality of life. These studies measure aspects of an individual’s sense of well-being and ability to carry out various activities.

A disease of the nervous system caused by the rabies virus. Rabies is marked by an increase in saliva production, abnormal behavior, and eventual paralysis and death.

The use of high-energy radiation from x-rays, gamma rays, neutrons, protons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body near cancer cells (internal radiation therapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that travels in the blood to tissues throughout the body. Also called irradiation and radiotherapy.

A surgical procedure to remove most or all of the lymph nodes that drain lymph from the area around a tumor. The lymph nodes are then examined under a microscope to see if cancer cells have spread to them.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

In genetics, describes DNA, proteins, cells, or organisms that are made by combining genetic material from two different sources. Recombinant substances are made in the laboratory and are being studied in the treatment of cancer and for many other uses.

Refers to cancer that has grown beyond the original (primary) tumor to nearby lymph nodes or organs and tissues.

In oncology, a lymph node that drains lymph from the region around a tumor.

A surgical procedure to remove some of the lymph nodes that drain lymph from the area around a tumor. The lymph nodes are then examined under a microscope to see if cancer cells have spread to them.

A decrease in the size of a tumor or in the extent of cancer in the body.

The return of signs and symptoms of cancer after a period of improvement.

The most common type of kidney cancer. It begins in the lining of the renal tubules in the kidney. The renal tubules filter the blood and produce urine. Also called hypernephroma.

To make a copy or duplicate of something.

In biology, refers to the reproduction cycle of viruses. A repliction cycle begins with the infection of a host cell and ends with the release of mature progeny virus particles.

The organs that are involved in breathing. These include the nose, throat, larynx, trachea, bronchi, and lungs. Also called respiratory system.

In medicine, an improvement related to treatment.

In biology, refers to a cell that is not dividing.

Looking back at events that have already taken place.

A study that compares two groups of people: those with the disease or condition under study (cases) and a very similar group of people who do not have the disease or condition (controls). Researchers study the medical and lifestyle histories of the people in each group to learn what factors may be associated with the disease or condition. For example, one group may have been exposed to a particular substance that the other was not. Also called case-control study.

One of the two types of nucleic acids found in all cells. In the cell, RNA is made from DNA (the other type of nucleic acid), and proteins are made from RNA. Also called ribonucleic acid.

A cancer of the bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.

A person who has studied science, especially one who is active in a particular field of investigation.

An error in choosing the individuals or groups to take part in a study. Ideally, the subjects in a study should be very similar to one another and to the larger population from which they are drawn (for example, all individuals with the same disease or condition). If there are important differences, the results of the study may not be valid.

Any of a group of simple sugar molecules.

A problem that occurs when treatment affects healthy tissues or organs. Some common side effects of cancer treatment are fatigue, pain, nausea, vomiting, decreased blood cell counts, hair loss, and mouth sores.

Flat cell that looks like a fish scale under a microscope. These cells cover inside and outside surfaces of the body. They are found in the tissues that form the surface of the skin, the lining of the hollow organs of the body (such as the bladder, kidney, and uterus), and the passages of the respiratory and digestive tracts.

Cancer that is neither decreasing nor increasing in extent or severity.

Cancer that began in tissue covering the ovary and is found in one or both of the ovaries. Stage I is divided into stages IA, IB, and IC. In stage IA, cancer is found in a single ovary. In stage IB, cancer is found in both ovaries. In stage IC, cancer is found in one or both ovaries and one of the following is true: (1) cancer is found on the outside surface of one or both ovaries; or (2) the capsule (outer covering) of the tumor has ruptured (broken open); or (3) cancer cells are found in fluid from the peritoneal cavity (the body cavity that contains most of the organs in the abdomen).

Cancer has spread outside the colon and/or rectum to nearby tissue, but it has not gone into the lymph nodes. Also called Dukes B colorectal cancer.

Cancer that began in tissue covering the ovary and has spread from one or both ovaries into other areas of the pelvis. Stage II is divided into stages IIA, IIB, and IIC. In stage IIA, cancer has spread to the uterus and/or the fallopian tubes. In stage IIB, cancer has spread to other tissues within the pelvis. In stage IIC, cancer has spread to the uterus and/or fallopian tubes and/or other tissue within the pelvis and cancer cells are found in fluid from the peritoneal cavity (the body cavity that contains most of the organs in the abdomen).

Tumor cells have spread to organs and lymph nodes near the colon/rectum. Also called Dukes C colorectal cancer.

Cancer that began in tissue covering the ovary and has spread from one or both ovaries to other parts of the abdomen. Stage III is divided into stages IIIA, IIIB, and IIIC. In stage IIIA, the tumor is found in the pelvis only, but cancer cells have spread to the surface of the peritoneum (tissue that lines the abdominal wall and covers most of the organs in the abdomen). In stage IIIB, cancer has spread to the peritoneum and is 2 centimeters or smaller in diameter. In stage IIIC, cancer has spread to the peritoneum and is larger than 2 centimeters in diameter and/or has spread to lymph nodes in the abdomen. Cancer that has spread to the surface of the liver is stage III disease.

Cancer may have spread to nearby lymph nodes and has spread to other parts of the body, such as the liver or lungs. Also called Dukes D colorectal cancer.

Cancer that began in tissue covering the ovary is found in one or both ovaries and has spread beyond the abdomen to distant parts of the body. Ovarian cancer that is found in tissues of the liver is stage IV disease.

Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. Also called significant.

Beneath the skin.

A procedure to remove or repair a part of the body or to find out whether disease is present. An operation.

A large cell-like structure formed by the joining together of two or more cells. The plural is syncytia.

A malignant tumor that develops in the synovial membrane of the joints.

Affecting the entire body.

A type of immune cell that can attack foreign cells, cancer cells, and cells infected with a virus. T cells can also help control immune responses. A T cell is a type of white blood cell. Also called T lymphocyte and thymocyte.

A disease in which certain cells of the lymph system (called T lymphocytes) become cancerous.

Having to do with treating disease and helping healing take place.

Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects.

An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancerous), or malignant (cancerous). Also called neoplasm.

Refers to the number of cancer cells, the size of a tumor, or the amount of cancer in the body. Also called tumor load.

Cells, tissues, or animals used to study the development and progression of cancer, and to test new treatments before they are given to humans. Animals with transplanted human tumors or other tissues are called xenograft models.

A protein made by white blood cells in response to an antigen (substance that causes the immune system to make a specific immune response) or infection. Tumor necrosis factor can also be made in the laboratory. It may boost a person’s immune response, and also may cause necrosis (cell death) of some types of tumor cells. Tumor necrosis factor is being studied in the treatment of some types of cancer. It is a type of cytokine. Also called TNF.

A protein or other molecule that is unique to cancer cells or is much more abundant in them. These molecules are usually found in the plasma (outer) membrane, and they are thought to be potential targets for immunotherapy or other types of anticancer treatment.

A clinical study that lacks a comparison (i.e., a control) group.

Treated with a vaccine.

Treatment with a vaccine.

A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. A vaccine can help the body recognize and destroy cancer cells or microorganisms.

Having to do with the vagina (the birth canal).

Having to do with a virus.

Refers to the ability of a virus or a bacterium to cause damage to its host.

In medicine, a very simple microorganism that infects cells and may cause disease. Because viruses can multiply only inside infected cells, they are not considered to be alive.

An antibody that binds to a virus and interferes with its ability to infect a cell.

Having to do with the viscera, which are the soft internal organs of the body, including the lungs, the heart, and the organs of the digestive, excretory, reproductive, and circulatory systems.

Refers to a blood cell that does not contain hemoglobin. White blood cells include lymphocytes, neutrophils, eosinophils, macrophages, and mast cells. These cells are made by bone marrow and help the body fight infections and other diseases. Also called leukocyte and WBC.

Vaccine made from whole tumor cells that have been changed in the laboratory.

A disease in which malignant (cancer) cells are found in the kidney, and may spread to the lungs, liver, or nearby lymph nodes. Wilms tumor usually occurs in children younger than 5 years old.

The cells of one species transplanted to another species.