The
goal of vaccine therapy is to teach the immune system to recognize and
attack tumor cells.
Very
good phase II outcome data
suggests that vaccine therapies may increase the durations of
remission from chemotherapy well beyond what's expected in patients who develop
an immune response to a protein on the tumor cells.
In December 2007, Genitope announced a formal proof that
vaccines are active: "We are excited by these
results because the data clearly show that MyVax personalized
immunotherapy is a safe and active drug for follicular lymphoma patients.
Both arms of the trial appear to show activity. Patients who received
MyVax personalized immunotherapy and mounted a positive immune response to
the tumor-specific target demonstrated superior clinical outcomes compared
to patients who did not mount this specific immune response."
Source: Genitope
Trials are continuing to test therapeutic vaccines on patients with
lymphomas. Unfortunately
the Genitope phase III study did not meet it's primary endpoint, and we
await the opportunity to review the raw data and the interpretations
of that data
by independent experts.
The idiotype vaccine has the longest clinical research track record of any
vaccine strategy. It can be made in different ways, but the end result is
expected to be equivalent -- although this cannot be assumed and the FDA
is likely to require testing of each
variation of the Idiotype vaccine.
Each b-cell has a prominent
and unique marker on its surface that distinguishes
it from all other b-cell and and other cells in the body. This
marker is called the Idiotype or Id for short. For each individual with
lymphoma, each malignant cell has the same unique Idiotype marker because
each malignant cell usually
arises
from a single cell of origin.
This protein marker, the Id, is a receptor that's
specific to an antigen (bacteria, virus, etc.) that the particular b-cell is
designed to recognize and destroy.
The goal of Idiotype vaccine treatment is to "teach" the immune
system to target and attack this receptor - to treat it as a foreign
antigen. See More
Precisely described.
UPDATE:
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 process of creating an Idiotype vaccine starts with a biopsy
(sometimes blood) to acquire fresh tissue. Thanks to
impressive technologies, scientists have found ways to isolate this
protein from the tumor tissue and then produce it in sufficient
therapeutic quantities.
To make the vaccine more
visible to the immune system (immunogenic), the Idiotype is bound with an
adjuvant that is known to stimulate an immune response. The adjuvant
commonly used is called KLH. The result of the combination of Id and KLH
injected into a person is akin to blowing a cop whistle and holding up a
picture of a criminal. The goal is to trick the immune system into
thinking a normal protein is guilty by association -- foreign just like
the KLH. Current estimates are that this "trick" succeeds about
50% of the time for tested Idiotype vaccines. New dosing, techniques, and
methods of priming the immune system may improve the odds.
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 the many experts do not believe it likely that this type of treatment
will 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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