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Very good phase II outcome data suggested 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.

Trials are continuing to test therapeutic vaccines on patients with lymphomas.  The Genitope and Favrille methods have not proven effective.  Biovest, however, reports a positive outcome in its

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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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

RE: BIOVEST PACE-vaccine study study

Question:  I'm really not sure what all this means  - I had asked specific questions [of sponsor and FDA], such as: when might it be available for patients in this country; will most insurance companies cover this procedure; that sort of thing. I wasn't able to obtain a real answer.

Reply: 

In the Biovest study patient-specific idiotype vaccine was tested in patients who achieved a CR after PACE chemotherapy, compared to a placebo vaccine 

The study never completed enrollment, which is required to achieve statistical significance (to exclude the effects of chance - in this case the normal variation in outcomes to same pretreatment). 

More participants were needed ... but enrollment was a problem (for good reason) because of the toxicity of the PACE chemo and the low CR rate, relative to Rituxan-based chemo - the new standard of care.

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 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 get a durable remission, so the low CR rate for PACE is potentially a liability for the majority of the participants.) 

The standard of care for induction therapy is now CVP-R or CHOP-R, or RIT ... so vaccine must be studied after use of these protocols. 

However, since Rituxan depletes normal b-cells (antibody producing cells), it's not a given that vaccines (possibly mediated by antibody against idiotype) will be active after R-based chemo. 

By law, it's up to the company to sponsor trials for unapproved agents in the US ... which is mainly dependent on funding - finding investors, etc. This rule is based on legislation ... Congressional mandate, not by FDA.

While FDA could not reveal information about a pending study (also by law), this is not the case in this case, because it has not been submitted to FDA by the sponsor for approval ... You might want to ask the sponsor why they have not done so if they believe the study data proves the vaccine is active? 

I 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, but even if that study had been completed 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 below. 

~ KarlS (independent commentary)

Follicular Lymphoma: Experimental Vaccine Extends Disease-Free Survival  oncology-times.com

Dr. Levy noted that 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. 

Also needed are methods to produce the vaccine more quickly. Dr. Levy's conclusion: a qualified yes that the trial is a positive result. But, he said, much more work needs to be done.

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CLINICAL TRIALS

NEWS & RESOURCES

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-  Comparing idiotype vaccine procedures 

TOPIC SEARCH: Dendritic Vaccine | Idiotype vaccine 

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- Some Vaccine Contacts -

Idiotype Vaccine Therapy for Untreated follicular small cleaved and follicular mixed cell low-grade NHL 

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