Table of Contents Purpose of This PDQ Summary Overview General Information History Laboratory/Animal/Preclinical Studies
Human/Clinical Studies 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.
Information about the following is included in this summary:
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 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, which is written in less technical language.
Back to Top 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, 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.
Back to Top 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:
- The infection of cancer patients with a lytic strain of NDV.
- The use of oncolysates, i.e., preparations
containing plasma membrane fragments from NDV-infected cancer calls, as
anticancer vaccines.
- 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]
Table 1. Strains of NDV Tested in
Human/Clinical Cancer Studiesa
NDV Strain
|
Strain Type
|
Formulation
|
Suggested Mechanism(s) of
Action
|
Reference
Citation(s)
|
73-T |
Lytic |
Infectious virus |
Cancer cells killed by virus; stimulation of immune system |
[21] |
73-T |
Lytic |
Oncolysate vaccineb |
Stimulation of immune system |
[12,36,39,54,57,59,61-64] |
Ulster |
Nonlytic |
Infected tumor-cell vaccine |
Stimulation of immune system |
[43,44,46-52,65-67] |
MTH-68 |
Lytic |
Infectious virus |
Cancer cells killed by virus; stimulation of immune
system |
[1,7,55,60] |
Italien |
Lytic |
Oncolysate vaccine/infectious virus |
Stimulation of immune system; cancer cells killed by
virus |
[56,58] |
Hickman |
Lytic |
Infectious virus |
Cancer cells killed by virus; stimulation of immune
system |
[73] |
PV701 |
Lytic |
Infectious virus |
Cancer cells killed by virus; stimulation of immune
system |
[53] |
aSee text for more details.
|
bOncolysates are prepared from virus-infected cancer cells; they consist
primarily of cell membrane fragments and contain virus proteins and cancer
cell proteins.
|
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-
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]
-
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.
Back to Top 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 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 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.
References
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Nelson NJ: Scientific interest in Newcastle disease virus is reviving. J Natl Cancer Inst 91 (20): 1708-10, 1999.
[PUBMED Abstract]
-
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]
-
Nemunaitis J: Oncolytic viruses yesterday and today. J Oncol Manag 8 (5): 14-24, 1999.
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Webb HE, Smith CE: Viruses in the treatment of cancer. Lancet 1 (7658): 1206-8, 1970.
[PUBMED Abstract]
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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]
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Sinkovics J, Horvath J: New developments in the virus therapy of cancer: a historical review. Intervirology 36 (4): 193-214, 1993.
[PUBMED Abstract]
-
Cassel WA, Garrett RE: Newcastle disease virus as an antineoplastic agent. Cancer 18: 863-8, 1965.
-
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]
-
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.
-
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.
-
Sinkovics JG, Howe CD: Superinfection of tumors with viruses. Experientia 25 (7): 733-4, 1969.
[PUBMED Abstract]
-
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]
-
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]
-
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]
-
Kirn DH, McCormick F: Replicating viruses as selective cancer therapeutics. Mol Med Today 2 (12): 519-27, 1996.
[PUBMED Abstract]
-
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]
-
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]
-
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]
-
Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998.
[PUBMED Abstract]
-
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]
-
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]
-
Sinkovics JG, Horvath JC: Newcastle disease virus (NDV): brief history of its oncolytic strains. J Clin Virol 16 (1): 1-15, 2000.
[PUBMED Abstract]
-
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]
-
Csatary LK: Viruses in the treatment of cancer. Lancet 2 (7728): 825, 1971.
[PUBMED Abstract]
-
Schirrmacher V, Ahlert T, Heicappell R, et al.: Successful application of non-oncogenic viruses for antimetastatic cancer immunotherapy. Cancer Rev 5: 19-49, 1986.
-
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]
-
Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. New York, NY: Garland Publishing, 1994.
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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]
-
DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers, 1997.
-
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]
-
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]
-
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]
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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]
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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]
-
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]
-
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]
-
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]
-
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]
-
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]
-
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]
Back to Top 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.
NDV and Cancer Immunotherapy
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
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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]
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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]
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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]
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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]
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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.
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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]
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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]
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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]
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Cassel WA, Garrett RE: Newcastle disease virus as an antineoplastic agent. Cancer 18: 863-8, 1965.
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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.
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Schirrmacher V, Ahlert T, Heicappell R, et al.: Successful application of non-oncogenic viruses for antimetastatic cancer immunotherapy. Cancer Rev 5: 19-49, 1986.
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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.
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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.
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[PUBMED Abstract]
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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]
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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.
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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.
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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.
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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.
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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]
-
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]
-
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]
-
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]
-
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]
-
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]
-
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]
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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]
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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]
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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]
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Schirrmacher V: Active specific immunotherapy: a new modality of cancer treatment involving the patient's own immune system. Onkologie 16: 290-6, 1993.
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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]
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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]
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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]
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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.
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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]
Back to Top 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.
Immunotherapy with Oncolysates
The following information is summarized in a table 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.
Table 2. Studies of NDV Oncolysates in Which
Therapeutic Benefit Was Assesseda,b
Reference Citation(s)
|
Type of Study
|
Type of Cancer
|
No. of Patients: Enrolled; Treated; Controlc
|
Strongest Benefit Reportedd
|
Concurrent Therapye
|
Level
of Evidence Scoref
|
[9,10] |
Phase I trial |
Advanced melanoma |
13;
13;
None |
Complete tumor response, 1
patient |
Yes |
3iiiDii |
[1,2,4,11] |
Phase II trial |
Advanced melanoma |
32;
32;
Historical controls |
Improved overall survival |
No |
3iiA |
[1,2,11] |
Phase II trial |
Advanced melanoma |
51;
51;
Historical controls |
Improved overall survival |
No |
3iiA |
[6] |
Phase II trial |
Advanced melanoma |
24;
24;
Historical controls |
None |
No |
3iiDi |
[8,12] |
Phase II trial |
Advanced renal cell |
208;
203;
Historical controls |
Improved disease-free survival |
Yes |
3iiiDi |
[5,7] |
Phase II trial |
Metastatic breast or ovarian |
22;
22;
None |
Complete/partial tumor response, 9 patients |
Yes |
3iiDiii |
No. = number.
|
aSee text for more details.
|
bOncolysates are prepared from virus-infected cancer cells; they consist
primarily of cell membrane fragments and contain virus proteins and cancer
cell proteins.
|
cNumber of patients treated plus number of patients control may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were given the treatment being studied AND for whom results were reported; historical control subjects are not included in number of patients enrolled.
|
dThe strongest evidence reported that the treatment under study has
anticancer activity or otherwise improves the well-being of cancer patients.
See text and glossary for definition of terms.
|
eChemotherapy, radiation therapy, hormonal therapy, or cytokine therapy
given/allowed at the same time as oncolysate treatment.
|
fFor information about levels of evidence analysis and an explanation of
the level of evidence scores, see Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.
|
Immunotherapy with Whole Cell Vaccines
The following information is summarized in a table 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 section) in the whole cell vaccines will
make them more effective remains to be determined.
Table 3. Studies of NDV-Infected
Tumor Cell Vaccines in Which Therapeutic Benefit Was
Aassesseda
Reference Citation(s)
|
Type of Study
|
Type of Cancer
|
No. of Patients: Enrolled; Treated; Controlb
|
Strongest Benefit Reportedc
|
Concurrent Therapyd
|
Level
of Evidence Scoree
|
[14,21] |
Phase II trial |
Metastatic colorectal |
23;
23;
Historical controls |
Improved disease-free survival |
No |
3iiA |
[15] |
Phase II trial |
Advanced colorectal |
57;
48f; Historical controls |
Improved overall survival |
No |
3iiiA |
[16] |
Retrospective analysis |
Early breast |
63;
63;
Internal controlsg |
Improved overall survival |
Yes |
3iiiA |
|
|
Metastatic breast |
27;
27;
Internal controlsg |
None |
Yes |
3iiiA |
|
|
Metastatic ovarian |
31;
31;
Internal controlsg |
None |
Yes |
3iiiA |
[18] |
Phase II trial |
Various advanced |
43;
31;
None |
Complete tumor response, 1
patient |
Yes |
3iiiDiii |
[20] |
Phase II trial |
Metastatic renal cell |
40;
40;
Historical controls |
Improved overall survival,
11 patients with complete/partial responses |
Yes |
3iiiA |
[22] |
Phase II trial |
Ovarian |
82;
24h; None |
Improved disease-free survival |
Yes |
3iiDi |
No. = number.
|
aSee text for more details.
|
bNumber of patients treated plus number of patients control may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were given the treatment being studied AND for whom results were reported; historical control subjects are not included in number of patients enrolled.
|
cThe strongest evidence reported that the treatment under study has
anticancer activity or otherwise improves the well-being of cancer patients.
See text and glossary for definition of terms.
|
dChemotherapy, radiation therapy, hormonal therapy, or cytokine
therapy given/allowed at the same time as vaccine therapy.
|
eFor information about levels of evidence analysis and an explanation of
the level of evidence scores, see Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.
|
fOnly 48 patients were treated with NDV-infected tumor cell
vaccines; the remaining patients were treated with another type of
vaccine.
|
gThe patients were divided into groups that received a high-quality
vaccine or a low-quality vaccine; the low-quality vaccine groups served as the
controls; 32, 13, and 18 patients with early breast cancer, metastatic breast
cancer, and metastatic ovarian cancer, respectively, received high-quality
vaccines; the corresponding low-quality vaccine groups contained 31,14, and 13
patients.
|
hThere were 39 evaluable patients in this study, but findings were
reported for only 24 patients.
|
Infection of Patients with NDV (including strain MTH-68)
The following information is summarized in a table 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:
- A single dose of NDV given once every 28 days (17 patients).
- A single dose of NDV given 3 times during a 1-week period, repeated every 28 days (13 patients).
- 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).
- 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 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.
Table 4. Studies of Cancer Treatment by
Infection of Patients With NDVa
Reference Citation(s)
|
Type of Study
|
NDV Strain
|
Type of Cancer
|
No. of Patients: Enrolled; Treated; Controlb
|
Strongest Benefit Reportedc
|
Concurrent Therapyd
|
Level
of Evidence Scoree
|
[30] |
Case series |
MTH-68 |
Various advanced |
4;
4;
None |
Complete tumor regression, 2
patients |
Yes |
4 |
[31] |
Phase II trial |
MTH-68 |
Various advanced |
59;
33;
26, placebo |
Improved overall survival |
No |
2A |
[32] |
Case report |
73-T |
Advanced cervical |
1;
1;
None |
Partial tumor regression |
No |
None |
[33] |
Anecdotal report |
MTH-68 |
Various metastatic |
3;
3;
None |
Tumor regression |
Unknown |
None |
[34] |
Case report |
MTH-68 |
Glioblastoma multiforme |
1;
1;
None |
Partial tumor regression |
Yes |
None |
[35] |
Case report |
Hickman |
Acute myeloid leukemia |
1;
1;
None |
Partial response |
Yesf |
None |
[36] |
Phase I trial |
PV701 |
Various advanced |
79;
79;
None |
Partial tumor regression, 8
patients |
Unknown |
3iiiDiii |
No. = number.
|
aSee text for more details.
|
bNumber of patients treated plus number of patients control may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of patients who were given the treatment being studied AND for whom results were reported; historical control subjects are not included in number of patients enrolled.
|
cThe strongest evidence reported that the treatment under study has
anticancer activity or otherwise improves the well being of cancer patients.
See text and glossary for definition of terms.
|
dChemotherapy, radiation therapy, hormonal therapy, or cytokine
therapy given/allowed at the same time as virus treatment.
|
eFor information about levels of evidence analysis and an
explanation of the level of evidence scores, see Levels of Evidence for Human Studies of Cancer
Complementary and Alternative Medicine.
|
fThis patient was treated with chemotherapy and 5 other types of
virus in addition to NDV.
|
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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.
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Cassel WA, Murray DR, Phillips HS: A phase II study on the postsurgical management of Stage II malignant melanoma with a Newcastle disease virus oncolysate. Cancer 52 (5): 856-60, 1983.
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Mallmann P: Autologous tumor-cell vaccination and lymphokine-activated tumor-infiltrating lymphocytes (LAK-TIL). Hybridoma 12 (5): 559-66, 1993.
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Plager C, Bowen JM, Fenoglio C, et al.: Adjuvant immunotherapy of M.D. Anderson Hospital (MDAH) stage III-B malignant melanoma with Newcastle disease virus oncolysate. [Abstract] Proceedings of the American Society of Clinical Oncology 9: A-1091, 281, 1990.
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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.
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Anton P, Kirchner H, Jonas U, et al.: Cytokines and tumor vaccination. Cancer Biother Radiopharm 11 (5): 315-8, 1996.
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Cassel WA, Murras DR, Torbin AH, et al.: Viral oncolysate in the management of malignant melanoma. I. Preparation of the oncolysate and measurement of immunologic responses. Cancer 40 (2): 672-9, 1977.
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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.
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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.
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Nemunaitis J: Oncolytic viruses yesterday and today. J Oncol Manag 8 (5): 14-24, 1999.
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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.
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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.
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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]
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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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Möbus V, Horn S, Stöck M, et al.: Tumor cell vaccination for gynecological tumors. Hybridoma 12 (5): 543-7, 1993.
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Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998.
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Schirrmacher V: Active specific immunotherapy: a new modality of cancer treatment involving the patient's own immune system. Onkologie 16: 290-6, 1993.
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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.
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-
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.
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-
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.
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-
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]
-
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.
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-
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]
Back to Top 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 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
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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]
-
Emergency Preparedness Information eXchange.: Foreign Animal Diseases: Newcastle Disease. Burnaby, B.C., Canada: Telematics Research Lab, Simon Fraser University, 2002. Available online. Last accessed May 2, 2006.
-
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]
-
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]
-
Kirn DH, McCormick F: Replicating viruses as selective cancer therapeutics. Mol Med Today 2 (12): 519-27, 1996.
[PUBMED Abstract]
-
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]
-
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]
-
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]
-
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]
-
Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998.
[PUBMED Abstract]
-
Moss RW: Alternative pharmacological and biological treatments for cancer: ten promising approaches. J Naturopathic Med 6 (1): 23-32, 1996.
-
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.
-
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]
-
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]
-
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]
-
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]
-
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]
-
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]
-
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.
-
Anton P, Kirchner H, Jonas U, et al.: Cytokines and tumor vaccination. Cancer Biother Radiopharm 11 (5): 315-8, 1996.
[PUBMED Abstract]
-
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]
-
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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Mallmann P: Autologous tumor-cell vaccination and lymphokine-activated tumor-infiltrating lymphocytes (LAK-TIL). Hybridoma 12 (5): 559-66, 1993.
[PUBMED Abstract]
Back to Top 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.
Back to Top 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.
Back to Top More Information
Additional Information about CAM Therapies
About PDQ
Other PDQ Summaries
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).
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