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goal of vaccine therapy is to teach the immune system to recognize and
attack tumor cells.
Background: There is a molecule on b-cells that is specific to the
shape of a bacteria, or virus, or ... anything foreign to the body,
which is called an antigen. This receptor fits like a key to a lock in
order to bind the antigen.
When a b-cell becomes malignant, all of the descendents of the cell
inherit the same b-cell receptor, which, unlike cd20, is expressed only
on the tumor cells
To make the vaccine, a portion of this receptor, called the idiotype was
isolated from the tumor sample and then replicated by different
techniques. The idiotype protein was then coupled with KLH, a highly
immunogenic substance derived from a shellfish.
So the vaccine was part tumor antigen and part shellfish: Id-KLH. The
idiotype for each patient's FL is unique to the patient's tumor - hence
it is called a customized or personalized vaccine.
It was an ingenious concept: to try to teach the immune system to
consider the idiotype to be like KLH, something to reject. The hope was
that the immune system would create antibodies against the idiotype -
helping to get rid of any tumor cells that survived chemo.
Unfortunately, when tested in two large randomized studies (Genitope and
Favrille) the control group did as well as those who had the custom
vaccine, which was given as injections under the skin following
induction therapy (chemo in one, rituxan in the other) along with an
immune stimulant.
The Biovest version of the idiotype vaccine - the first to start testing
and last to "finish" -- never completed enrollment because the induction
therapy (PACE) was too toxic. It showed a better result for those
receiving the vaccine, but it was not a statistically significant
difference - could well have been coincidental - the number of patients
in the study was not large enough to provide certainty.
See right column for detailed comments
NOTE: An immune response as a result of vaccination with idiotype
vaccine is not the same as a response to treatment - it's an indication that your body created
antibodies against the idiotype component of the vaccine. Whether that translates into immune cells killing of tumor cells is not
known.
So the phase III study was designed to find this out by measuring time to progression in the two groups. If the vaccine arm had a
significantly longer time to progression than the control group we could have concluded that
vaccine - by helping the body to recognize a tumor antigen -- was an indirect causal factor in the delay of recurrence.
The vaccine itself does not interact with the tumor; the hope is that the antibodies created in response to the vaccine will bind to the idiotype on
the tumor cells and lead to their death (similar to how rituxan works, but
the binding site is the idiotype instead of cd20.
How could it be that an immune response (antibodies against idiotype) would
not make a clinical difference? As noted by Suzanne, detecting a response
may not tell us about the strength of the response: the amount of anti-idiotype antibody that your body created in response to vaccine. It
might not be enough to affect a significant proportion of the tumor cells.
Also, even if there is enough antibody it doesn't mean it will lead to
killing of tumor cells. Consider that not everybody that receive rituxan
(an antibody) will have tumor regressions. Perhaps the binding of the anti-idiotype antibodies is weak or has an imperfect affinity to the
receptor on the tumor, or the tumor is resistant to death from this effect
....
So the idiotype vaccine is injected into the skin. The immune system takes
it up, and hopefully creates antibodies against the idiotype in the
vaccine, which should correspond to the idiotype on the tumor. The antibodies created by the body in reaction to the vaccine can be detected in
a test, and if so would be called an immune response to the idiotype of the
vaccine. These antibodies may or may be a good fit to the tumor, may or may not be in sufficient quantity to have an effect; and may or may not lead
to tumor regressions.
The injection of the
vaccine (Id+KLH) is followed by an injection of GM-CSF in the same
location. GM-CSF is a colony
stimulating factor that can increase the number of immune cells and help
specialized immune cells, called dendritic cells, to mature. The job of
dendritic cells is to present foreign antigens to other types of immune
cells to help complete the immune "education" process.
The Idiotype vaccine has
been tested mainly as a follow up treatment to chemotherapy - so-called
consolidation therapy. After a rest period the vaccine is given with the goal of
teaching the immune system to kill off any residual cells that have
survived the chemotherapy. One pilot study (that accrued patients very
quickly) is testing the efficacy of the Id vaccine on untreated patients
without the use of any chemotherapy. Another pilot study (by Favrille)
tested
the feasibility of using the Id vaccine to regress tumors in previously treated
patients
without pretreatment with chemotherapy. A phase III controlled study
is also testing the ability of the Idiotype vaccine to improve response to
Rituxan therapy.
It's important to
realize that this approach is unproven in lymphoma and that the many experts do not believe it likely that this type of treatment
could benefit patients with bulky or progressing disease.
Passive versus Active
Immunotherapy.
Passive immunotherapy,
such as Rituxan, involves infusion of antibody that induces an immune
response to attack the cells it binds to. The infused antibody has a
half life and thus, a limited duration of clinical activity. In
theory, idiotype vaccines can induce long lasting active immunity,
in which the body produces antibody against the tumor antigen as a result
of recognition of this antigen being abnormal (foreign). Thus, the
immune response involves memory and can be active for a very long time ...
It can be activated by the presence of tumor expressing the idiotype
antigen and not dependent on infusions of antibody. Another
potential advantage of idiotype vaccine is that it activates immunity
against tumor cells only. Normal cells will not be harmed.
Finally, it's important
to note that only the results of controlled clinical trials can inform us
just how effective active immunotherapy with idiotype vaccines will be,
and for how many patients. Detecting an immune response to the
idiotype antigen does not guarantee the patient will receive clinical
benefit. The malignant cells may have ways to evade or suppress an
immune response, for example. By November 2007 the results of
Genitope study should provide the earliest indication about the efficacy
for this version of the idiotype vaccine. The different idiotype
vaccine may not all be equivalent in potential, and the choice of
conditioning therapy could also influence the outcomes significantly.
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The antibodies
are magic bullets which find their targets by themselves, so as to strike at the parasites
as hard and the body cells as lightly as possible.
"The
Greek root word for "unique" is idiotype, and that is the term
used to describe the specific shape and structure of antibody molecules, which sit on the
surface of B cells like receptors, tasting and testing scraps of protein in the
bloodstream."
- Stephen S. Hall, A Commotion In The Blood
B-cell with Idiotype protein.
Click to enlarge
Comment on
BIOVEST PACE-vaccine study
In the BIOVEST study patient-specific idiotype vaccine was tested in patients who achieved a Complete
Response (CR) after PACE chemotherapy, compared to a placebo vaccine
The study never completed enrollment, which is required to achieve statistical
significance* -- to exclude the influence of chance - in this case the normal variation in outcomes to
the same pretreatment.
*NOTE: If you did a randomized study and gave each group identical
placebo (saline) after the same chemo, by chance (based on differences in the patients and
underlying disease) one group would do better than the other. So even
for a large randomized study the magnitude of the difference in outcome must
be sufficient to exclude the effect of chance - for example, that one
group had disease more sensitive to chemo than
the other.
So in the BIOVEST study full enrollment was never completed, because of the toxicity of the PACE chemo and the low CR rate, required to be eligible to receive the vaccine.
So for the patients who achieved a CR and received vaccine the
Progression Free Survival (PFS) favored the vaccine arm in the BIOVEST study, but was judged by the sponsor (and its advisors) to be of marginal statistical
significance ... not strong enough for the sponsor to bring the data before FDA to apply for marketing approval, but also suggesting that the vaccine might be active and effective.
Since the CR rate with the highly toxic PACE was low, many participants were not in the analysis .... In other words: a *big percentage* of patients who entered the study did not respond well enough to PACE to
receive vaccine or the control vaccine.
NOTE: You get but one chance to have first primary therapy for a lymphoma, probably this is your best chance to
achieve a durable remission, so the low CR rate for PACE is potentially a liability for the
majority of the participants - in the intent-to-treat population.
Since the standard of care for induction therapy is now CVP-R or CHOP-R,
B-R, or RIT ... the sponsor would have to begin again to test the vaccine after use of
one these induction protocols.
However, since Rituxan and RIT depletes normal b-cells (antibody producing cells), it's
not known if the idiotype vaccines
(possibly mediated by antibody against idiotype) will be active after R-based chemo
or RIT.
I truly have no personal opinion or expectation regarding the promise of vaccines,
or any investigational agent. I've come to realize they are called investigational for a reason.
So far, the Genitope and Favrille studies were good controlled studies (fair tests) which showed no difference (no effect for vaccine).
The Biovest study shows a possibility of activity and benefit, but falls
short of proof because of the low enrollment, and "the possibility of
imbalanced arms." [Meaning the risk factors, such as disease
status, age, etc., may have been higher in one arm.]
"This third trial differed from the other two by having a greater
proportion of patients who were in complete remission at the time of
vaccination. If validated, this result might provide additional evidence for
the value of vaccination in the minimal disease state." ~ Brody,
Kohrt, Marabelle, Levy
But even if the Biovest study completed enrollment it would not have informed us if PACE followed by
vaccine is better than Rituxan-based chemo alone... which brings us to Dr.
Levy's comment:
... in the time since patients were recruited, rituximab has added a powerful advantage in improving the treatment of follicular lymphoma.
There still could be a role for vaccination, but there need to be trials in which the vaccine Is given before and/or after treatment with chemotherapy plus rituximab, he said.
How much did the study miss by in terms of enrollment?
To achieve statistical significance
the study required about 563 pts for 2:1 randomization in order to randomize
375 pts to either arm *
250 pts in the vaccine arm
124 pts in the control arm …
* Because a CR was needed to be randomized, the study had to enroll more
than 375 patients because not everyone gets a CR.
The study managed to randomize a fraction of the needed patients - 117 pts,
of these:
76 pts were randomized to the vaccine arm
(far short of the goal of 250)
41 pts in the control arm
source: Follicular Lymphoma: Experimental Vaccine Extends Disease-Free Survival
oncology-times.com
~ KarlS (independent commentary)
CLINICAL TRIALS
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Clinical Benefit of Idiotype Vaccines: Too Many Trials
for a Clever Demonstration? RRCT.pdf
Commentary, Maurizio Bendandi1,2,3*
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NEWS & RESOURCES
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Recognition of live phosphatidylserine-labeled tumor cells by dendritic
cells: a novel approach to immunotherapy of skin cancer. Shurin MR,
Potapovich AI, Tyurina YY, Tourkova IL, Shurin GV, Kagan VE. Cancer
Res. 2009 Mar 15;69(6):2487-96. Epub 2009 Mar 10. PMID:
19276376
Dendritic cells (DC) loaded with tumor antigens from
apoptotic/necrotic tumor cells are commonly used as vaccines for cancer
therapy. However, the use of dead tumor cells may cause both tolerance
and immunity, making the effect of vaccination unpredictable. To deliver
live tumor "cargoes" into DC, we developed a new approach
based on the "labeling" of tumors with a phospholipid
"eat-me" signal, phosphatidylserine.
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Oct
2008: Biovest Announces BiovaxID® Anti-Cancer Vaccine Prolongs
Cancer-Free Survival by 44%
that the median duration of complete remission in the BiovaxID arm of
the study was 44.2 months which is clinically and statistically
significant compared to the control arm, median duration of cancer-free
survival of 30.6 months. BiovaxID prolonged the cancer-free survival by
13.6 months or 44% (p-value = 0.045; HR = 1.6) with a median follow up
of 56.6 months (range 12.6 to 89.3 months). Press
release
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Sept 2008 - Pilot vaccine report: Vaccination with autologous tumor-loaded dendritic cells induces clinical and immunological responses in indolent B cell lymphoma patients with relapsed and measurable disease: a pilot study.
Blood. 2008 Sep 22. PMID:
18809757
Collectively these results [single arm study, N= 18] demonstrate that
vaccination with tumor-loaded DCs may induce both T and B cell responses
and produces clinical benefits in indolent NHL patients with measurable
disease.
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Basic research: Follicular lymphoma B cells induce the conversion of conventional CD4(+) T cells to T-regulatory cells.
Int J Cancer. 2008 Sep 23. PMID: 18814264
Our study provides evidence for a tumor-specific mechanism by which
FL tumor cells promote immune escape through the induction of Treg.
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Outcomes: Summary of
MyVax Personalized Immunotherapy Phase 3 Clinical Trial Results media.corporate-ir.net
pdf
"Genitope believes that the failure of its MyVax Phase 3
clinical trial to meet its primary endpoint was due to unrecognized
activity in the non-specific immunotherapy."
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Bad news:
Genitope halts MyVax work, examines future bizjournals.com
... said it will suspend work on its cornerstone personalized cancer
vaccine, MyVax, for follicular non-Hodgkin's lymphoma.
Also see our commentary
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Genitope
Corporation Reports Initial Results of Phase 3 Clinical Trial of
MyVax(R) Personalized Immunotherapy Dec 2007
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Background: Genetic
vaccines - Google
books
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Preclinical: A novel
proteoliposomal vaccine elicits potent antitumor immunity in mice.
Blood. 2007 Jun 15;109(12):5407-10. Epub 2007 Mar 9. PMID:
17351111
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Opinion: The Disease is the Remedy
time.com
"In addition to showing that the vaccine can prolong
remission, Bendandi's trial attempted to solve the long-standing
problem of quantifying the results of custom-made treatments.
"
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ASH 2003 Update: Cellular Therapies and Vaccines for Hematologic Malignancies
Conference Coverage ~ cancerconsultants.com
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Harvesting and handling tissue in preparation for
vaccines PAL
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Background: Cancer vaccines fact sheet
cancer.gov
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Ronald Levy MD, David Fisher MD
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Testing Vaccines for Non-Hodgkin's Lymphoma
Healthology
(Nov 2003) |
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Stimulation of cytotoxic T cells against idiotype
immunoglobulin of malignant lymphoma with protein-pulsed or idiotype-transduced
dendritic cells
bloodjournal.org/cgi/content/full/95/4/1342
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Treating cancer with vaccines cancer.gov
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Immune-based therapies PAL
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Cancer vaccine notes PAL
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