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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The following information is summarized in a table 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.

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:

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

The researchers found that the use of lower initial doses of virus allowed the administration of higher subsequent doses. A complete response was reported for 1 patient, and partial tumor regression was observed in 8 patients. Thirteen patients had stable disease for periods of time that lasted from 4 months to more than 30 months. Five patients died during the trial: 4 due to progressive disease and 1 due, possibly, to a treatment-related complication (see Adverse Effects 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.

References

1. 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]
   
   
2. 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]
   
   
3. 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]
   
   
4. 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.  [PUBMED Abstract]
   
   
5. Mallmann P: Autologous tumor-cell vaccination and lymphokine-activated tumor-infiltrating lymphocytes (LAK-TIL). Hybridoma 12 (5): 559-66, 1993.  [PUBMED Abstract]
   
   
6. 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. 
   
   
7. 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. 
   
   
8. Anton P, Kirchner H, Jonas U, et al.: Cytokines and tumor vaccination. Cancer Biother Radiopharm 11 (5): 315-8, 1996.  [PUBMED Abstract]
   
   
9. 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.  [PUBMED Abstract]
   
   
10. Murray DR, Cassel WA, Torbin AH, et al.: Viral oncolysate in the management of malignant melanoma. II. Clinical studies. Cancer 40 (2): 680-6, 1977.  [PUBMED Abstract]
    
    
11. Cassel WA, Murray DR: Treatment of stage II malignant melanoma patients with a Newcastle disease virus oncolysate. Nat Immun Cell Growth Regul 7 (5-6): 351-2, 1988.  [PUBMED Abstract]
    
    
12. Kirchner HH, Anton P, Atzpodien J: Adjuvant treatment of locally advanced renal cancer with autologous virus-modified tumor vaccines. World J Urol 13 (3): 171-3, 1995.  [PUBMED Abstract]
    
    
13. Nemunaitis J: Oncolytic viruses yesterday and today. J Oncol Manag 8 (5): 14-24, 1999. 
    
    
14. Liebrich W, Schlag P, Manasterski M, et al.: In vitro and clinical characterisation of a Newcastle disease virus-modified autologous tumour cell vaccine for treatment of colorectal cancer patients. Eur J Cancer 27 (6): 703-10, 1991.  [PUBMED Abstract]
    
    
15. Ockert D, Schirrmacher V, Beck N, et al.: Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma. Clin Cancer Res 2 (1): 21-8, 1996.  [PUBMED Abstract]
    
    
16. Ahlert T, Sauerbrei W, Bastert G, et al.: Tumor-cell number and viability as quality and efficacy parameters of autologous virus-modified cancer vaccines in patients with breast or ovarian cancer. J Clin Oncol 15 (4): 1354-66, 1997.  [PUBMED Abstract]
    
    
17. Ahlert T: Tumor cell vaccination and IL-2 therapy. Hybridoma 12 (5): 549-52, 1993.  [PUBMED Abstract]
    
    
18. Bohle W, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in colorectal cancer patients with virus-modified autologous tumor-cell vaccine. First clinical results with tumor-cell vaccines modified with live but avirulent Newcastle disease virus. Cancer 66 (7): 1517-23, 1990.  [PUBMED Abstract]
    
    
19. Lehner B, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in curatively resected colorectal cancer patients with a virus-modified autologous tumor cell vaccine. Cancer Immunol Immunother 32 (3): 173-8, 1990.  [PUBMED Abstract]
    
    
20. Pomer S, Schirrmacher V, Thiele R, et al.: Tumor response and 4 year survival data of patients with advanced renal cell carcinoma treated with autologous tumor vaccine and subcutaneous r-IL-2 and IFN-alpha2b. Int J Oncol 6: 947-54, 1995. 
    
    
21. Schlag P, Manasterski M, Gerneth T, et al.: Active specific immunotherapy with Newcastle-disease-virus-modified autologous tumor cells following resection of liver metastases in colorectal cancer. First evaluation of clinical response of a phase II-trial. Cancer Immunol Immunother 35 (5): 325-30, 1992.  [PUBMED Abstract]
    
    
22. Möbus V, Horn S, Stöck M, et al.: Tumor cell vaccination for gynecological tumors. Hybridoma 12 (5): 543-7, 1993.  [PUBMED Abstract]
    
    
23. Proebstle TM, Staib G, Kaufmann R, et al.: Autologous active specific immunization (ASI) therapy for metastatic melanoma [abstract from Fifth World Conference on Cancers of the Skin]. Melanoma Res 3: A-133, 35, 1993. 
    
    
24. Schirrmacher V: [Anti-tumor vaccination] Zentralbl Chir 125 (Suppl 1): 33-6, 2000.  [PUBMED Abstract]
    
    
25. Pomer S, Thiele R, Staehler G, et al.: [Tumor vaccination in renal cell carcinoma with and without interleukin-2 (IL-2) as adjuvant. A clinical contribution to the development of effective active specific immunization] Urologe A 34 (3): 215-20, 1995.  [PUBMED Abstract]
    
    
26. Stoeck M, Marland-Noske C, Manasterski M, et al.: In vitro expansion and analysis of T lymphocyte microcultures obtained from the vaccination sites of cancer patients undergoing active specific immunization with autologous Newcastle-disease-virus-modified tumour cells. Cancer Immunol Immunother 37 (4): 240-4, 1993.  [PUBMED Abstract]
    
    
27. Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998.  [PUBMED Abstract]
    
    
28. Schirrmacher V: Active specific immunotherapy: a new modality of cancer treatment involving the patient's own immune system. Onkologie 16: 290-6, 1993. 
    
    
29. Schirrmacher V, Schlag P, Liebrich W, et al.: Specific immunotherapy of colorectal carcinoma with Newcastle-disease virus-modified autologous tumor cells prepared from resected liver metastasis. Ann N Y Acad Sci 690: 364-6, 1993.  [PUBMED Abstract]
    
    
30. Csatary LK, Moss RW, Beuth J, et al.: Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 19 (1B): 635-8, 1999 Jan-Feb.  [PUBMED Abstract]
    
    
31. Csatary LK, Eckhardt S, Bukosza I, et al.: Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect Prev 17 (6): 619-27, 1993.  [PUBMED Abstract]
    
    
32. Cassel WA, Garrett RE: Newcastle disease virus as an antineoplastic agent. Cancer 18: 863-8, 1965. 
    
    
33. Csatary LK: Viruses in the treatment of cancer. Lancet 2 (7728): 825, 1971.  [PUBMED Abstract]
    
    
34. Csatary LK, Bakács T: Use of Newcastle disease virus vaccine (MTH-68/H) in a patient with high-grade glioblastoma. JAMA 281 (17): 1588-9, 1999.  [PUBMED Abstract]
    
    
35. Wheelock EF, Dingle JH: Observations on the repeated administration of viruses to a patient with acute leukemia. A preliminary report. N Engl J Med 271(13): 645-51, 1964. 
    
    
36. Pecora AL, Rizvi N, Cohen GI, et al.: Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol 20 (9): 2251-66, 2002.  [PUBMED Abstract]
    
    
37. Nelson NJ: Scientific interest in Newcastle disease virus is reviving. J Natl Cancer Inst 91 (20): 1708-10, 1999.  [PUBMED Abstract]
    
    
38. Moss RW: Alternative pharmacological and biological treatments for cancer: ten promising approaches. J Naturopathic Med 6 (1): 23-32, 1996. 
    
    
39. Sinkovics J, Horvath J: New developments in the virus therapy of cancer: a historical review. Intervirology 36 (4): 193-214, 1993.  [PUBMED Abstract]
    
    
40. Plaksin D, Porgador A, Vadai E, et al.: Effective anti-metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with Newcastle disease virus (NDV). Int J Cancer 59 (6): 796-801, 1994.  [PUBMED Abstract]
    
    
41. Von Hoegen P, Weber E, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. Augmentation of the tumor-specific T cell response in the absence of an anti-viral response. Eur J Immunol 18 (8): 1159-66, 1988.  [PUBMED Abstract]
    
    
42. Schirrmacher V, Schild HJ, Gückel B, et al.: Tumour-specific CTL response requiring interactions of four different cell types and recognition of MHC class I and class II restricted tumour antigens. Immunol Cell Biol 71 ( Pt 4): 311-26, 1993.  [PUBMED Abstract]
    
    
43. Bosslet K, Schirrmacher V, Shantz G: Tumor metastases and cell-mediated immunity in a model system in DBA/2 mice. VI. Similar specificity patterns of protective anti-tumor immunity in vivo and of cytolytic T cells in vitro. Int J Cancer 24 (3): 303-13, 1979.  [PUBMED Abstract]
    
    
44. Schirrmacher V, Haas C, Bonifer R, et al.: Human tumor cell modification by virus infection: an efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther 6 (1): 63-73, 1999.  [PUBMED Abstract]
    
    
45. Schirrmacher V, Ahlert T, Heicappell R, et al.: Successful application of non-oncogenic viruses for antimetastatic cancer immunotherapy. Cancer Rev 5: 19-49, 1986. 
    
    
46. Schirrmacher V, Haas C, Bonifer R, et al.: Virus potentiation of tumor vaccine T-cell stimulatory capacity requires cell surface binding but not infection. Clin Cancer Res 3 (7): 1135-48, 1997.  [PUBMED Abstract]
    
    
47. Bier H, Armonat G, Bier J, et al.: Postoperative active-specific immunotherapy of lymph node micrometastasis in a guinea pig tumor model. ORL J Otorhinolaryngol Relat Spec 51 (4): 197-205, 1989.  [PUBMED Abstract]
    
    
48. Schirrmacher V, Heicappell R: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. II. Establishment of specific systemic anti-tumor immunity. Clin Exp Metastasis 5 (2): 147-56, 1987 Apr-Jun.  [PUBMED Abstract]
    
    
49. von Hoegen P, Zawatzky R, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. III. Potentiation of tumor-specific cytolytic T cell activity via induction of interferon-alpha/beta. Cell Immunol 126 (1): 80-90, 1990.  [PUBMED Abstract]
    
    
50. Schirrmacher V, von Hoegen P, Heicappell R: Virus modified tumor cell vaccines for active specific immunotherapy of micrometastases: expansion and activation of tumor-specific T cells. Prog Clin Biol Res 288: 391-9, 1989.  [PUBMED Abstract]
    
    
51. Schirrmacher V, von Hoegen P, Heicappell R: Postoperative activation of tumor specific T cells by immunization with virus-modified tumor cells and effects on metastasis. Adv Exp Med Biol 233: 91-6, 1988.  [PUBMED Abstract]
    
    
52. von Hoegen P, Heicappell R, Griesbach A, et al.: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. III. Postoperative activation of tumor-specific CTLP from mice with metastases requires stimulation with the specific antigen plus additional signals. Invasion Metastasis 9 (2): 117-33, 1989.  [PUBMED Abstract]
    
    
53. Patel BT, Lutz MB, Schlag P, et al.: An analysis of autologous T-cell anti-tumour responses in colon-carcinoma patients following active specific immunization (ASI). Int J Cancer 51 (6): 878-85, 1992.  [PUBMED Abstract]
    
    
54. Ilan Y, Sauter B, Chowdhury NR, et al.: Oral tolerization to adenoviral proteins permits repeated adenovirus-mediated gene therapy in rats with pre-existing immunity to adenoviruses. Hepatology 27 (5): 1368-76, 1998.  [PUBMED Abstract]
    
    
55. Ilan Y, Chowdhury JR: Induction of tolerance to hepatitis B virus: can we 'eat the disease' and live with the virus? Med Hypotheses 52 (6): 505-9, 1999.  [PUBMED Abstract]
    
    

Back to Top

< Previous Section  |  Next Section >