Human/Clinical Studies
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.
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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