With all the fervor around Dendreon’s (NASDAQ:DNDN) Provenge there is renewed interest in cancer vaccines, a therapeutic approach which deals with stimulating the body's immune system to attack tumors. This approach is based on the notion that our immune system is capable of recognizing and responding to various types of tumors, once it recognizes them as such. It is presumed that cancer cells are constantly created in our body, but in most cases, our immune system manages to recognize these cells and get rid of them by using an impressive repertoire of mechanisms. Unfortunately, in some cases, those cancer cells manage to evade the surveillance of the immune system and begin to multiply in an uncontrolled manner, leading to the creation of tumors. Almost ten years after the approval of Rituximab, the first monoclonal antibody for cancer, it seems like the time is right for another flavor of cancer immunotherapy - cancer vaccines.
In recent years, there have been some great improvements in the field of cancer therapy thanks to early diagnosis and new forms of therapies, such as monoclonal antibodies and nanoparticle-coated compounds. For over two decades, cancer vaccines have demonstrated impressive results in early pre-clinical trials, which gave rise to great expectations within the scientific community. Unfortunately, scientists couldn’t replicate the early phase success into clinical trials, but there are finally some encouraging signs . With several promising candidates which are currently being evaluated in clinical trials, the cancer vaccine field might become the next big thing in cancer therapy.
An immune response is a complicated, dynamic and multi-phased process, which is orchestrated by a vast number of factors. Like many other biological processes, the immune response is certainly not easily manipulated. The ideal cancer immunotherapy should target cancer cells exclusively without attacking any normal cells in the body. The problem is that biological systems are so complex and sometimes even chaotic that it is virtually impossible to predict the specific kind of treatment that would yield the desirable effect. Unfortunately, drug development is still limited to the classic trial and error approach, which produces dozens and hundreds of ineffective potential treatments for every one that actually works. Bearing in mind that tumors are actually cells that, by definition, manage to evade the immune system ( they wouldn’t exist otherwise), manifesting an immune response directed at those cells is even more challenging. Cell Genesys (CEGE) might have found a formula for an effective, specific cancer vaccine with limited side effects - GVAX. Their approach can theoretically be applied to many kinds of cancer, though the most advanced results are with Hormone Refractory Prostate Cancer [HRPC].
GVAX is similar to traditional vaccines against pathogens like bacteria and viruses. Such traditional vaccines involve the injection of a weakened pathogen or some structural part of it, which is identified and recognized by the immune system. A minor immune response against the vaccine results in immunity towards the pathogen so that next time it enters the body, there will be a swift, strong and systemic response against it. Cell Genesys is taking a similar approach but with some differences. First, the pathogens in this case are cancer cells which are not external pathogens but self derived cells. Second, the vaccine is not given to healthy people but only to people who already have advanced stage prostate cancer. Third, whereas most pathogens can be recognized by the immune system even without any external help, (vaccines simply give the immune system a nice head start), the ultimate goal with GVAX is to make the immune system recognize those cancer cells which it cannot recognize in the first place.
GVAX for Prostate Cancer is comprised of 2 lines of whole prostate tumor cells. These cell lines are considered to be very advanced and malignant so they contain many common antigens (an element recognized by the immune system) found in metastatic prostate c!
ancer. The cells have been modified to constantly produce and secrete granulocyte macrophage colony stimulating factor (GM-CSF). GM-CSF is an important immune stimulatory molecule that leads to the activation of a group of immune cells called Antigen Presenting Cells (APCs). It’s the combination of the antigens GVAX cells express and the GM-CSF they secrete that should generate an effective immune response against prostate tumors.
Before being injected into patients, the cells undergo lethal irradiation in order to prevent them from multiplying, turning them into a scaffold for presenting many cancer related antigens. The basic idea is that once the body's immune system encounters those GVAX cells, the GM-CSF will stimulate the immune cells to recognize those cells as a threat and initiate an immune response directed at them.
The first stage of the immune response against GVAX is swallowing and processing of the cells by APCs. The next step is the most crucial one, where those APCs migrate to special areas called lymph nodes and present parts of the GVAX cells to other immune system components. By doing so, APCs act as the body’s “intelligence arm”, alerting the immune system that there are unwanted guests in the body and show what they look like.
Once that happens, another type of immune cells called lymphocytes is created and activated. Those lymphocytes can specifically recognize certain antigens that are presented to them by APCs. They are released into the blood stream, looking for those intruders. Upon the encounter with the GVAX cells, the lymphocytes attack and destroy them either by secreting antibodies or by attacking cells with toxic compounds. Hopefully, each patient’s prostate tumor cells will express at least one common antigen with the GVAX cells. As a result, once lymphocytes come across a prostate tumor, they will attack it, even though until that point, the tumor managed to evade the immune system
Using whole cancer cells instead of only structural parts might prove to be a good vaccination vehicle. The GVAX cells express a large repertoire of antigens, as compared to Dendreon's Provenge , which may prove advantageous. Where Provenge might trigger an immune response against only one specific antigen (However, there is a risk that the immune response triggered by GVAX will not be focused enough; hence, it might be a reaction against a wider spectrum of antigens but also a less potent one.
Another attribute of GVAX is that it is not personalized therapy. Although tumors from different patients share some common antigens, there are differences between tumors each patient bares. The GVAX cells might resemble to the actual tumor cells in the patient's body, but they are certainly not identical so that might lead to a compromise in specificity. On the other hand, such a universal solution might be much cheaper and simpler to use. There is no need to take anything out of the patient's body, but simply inject the vaccine. On top of those off-the-shelf qualities, using GVAX might even have an advantage over using each patient’s tumors because one of the main problems of advanced stage tumors is the fact they constantly change via mutations and may even spread to other organs as metastases, which may not be recognized by vaccination using the primary tumor. Using two advanced prostate cancer cell lines for the vaccine might trigger an immune response against those metastases even before they develop.
Another advantage of the GVAX approach is the fact that the first stage of the immune response occurs inside the body (in vivo), the natural environment in which immune cells typically operate in. In the case of Provenge, the initial response occurs in an "antigen cassette" outside the body.
There have been 3 main clinical trials evaluating GVAX’s safety and efficacy. In a phase I/II trial, 21 patients received what we can now call weekly very low doses of GVAX (120 million cells). Although there wasn’t any substantial clinical effect, GVAX proved to have a favorable safety profile. Phase I trials are generally used to assess the safety and maximal tolerated dose of a drug candidate by monitoring side effects. In many cases, Phase I clinical trials involve healthy participants, but in cancer therapy most drugs have so many severe side effects, that they are conducted only among cancer patients. The only goal in such trials is to see whether there are toxicities and side effects related to the drug, and in the case of GVAX, things look pretty good.
The next trial was a phase II trial (G-9803) that included 34 patients who were given 500 million cell prime intradermal injection followed by 100 or 300 million cells every 14 days for 24 weeks or until disease progression. Median survival rate was 26.2 months, better than the 19.3 months Taxotere (the gold standard for HRPC treatment) achieved in a recent large scale trial.
The second Phase II trial (G-0010) included 80 patients who were divided into 3 groups. Group 1 received 200 million cells monthly (Low dose), Group 2 received 200 million cells biweekly (medium dose) Group 3 received 500 million cells as an initial dose followed by 300 million cells biweekly (high dose).
When the 3 groups were examined for antibody generation against at least one of the the GVAX cells, the results were 87% for the high dose, 72% for the medium dose and 40% for the low dose. I couldn’t find any details about Median survival rate for the whole trial, but the compan!
y stated that the 22 patients who received the highest dose ha!
d a median survival rate 35 months. That’s an impressive number, no doubt, especially when compared to the less than 20 months Taxotere achieves.
The Bad News:
In clinical trials size does matter. Small-scale trials involving tens of patients are a nice starting point, but mustn’t be regarded as statistically significant. Phase II trials are generally conducted in order to find the optimal dose or regimen. Only a large multi-center trial which involves at least several hundred patients can be relied upon. Actually, history is full of promising drugs that had positive results in small-scale experiments but failed to demonstrate efficacy in larg!
e scale trials. Another reason to be suspicious is that four patients have withdrawn consent to further follow-up and thus were censored in the analysis. I don’t have any information about these specific 4 patients but I assume that when a patient withdraws consent for participating in the assessment, it doesn’t mean he was too happy with the drug.
Another must have is a comparison with a placebo or another drug in the same trial. Moreover, in order to neutralize unwanted effects, the trial must be a double blind trial, which means neither the patients nor the doctors know who’s getting the drug and who’s getting a placebo or the standard therapy. In all the trials so far, patients who participated in the trial knew that they got the drug since nobody actually received a placebo.
The Good News:
The fact that a cancer vaccine shows favorable results in two separate phase II trials is very encouraging. Though I couldn’t find any information about response rates of patients in the low and medium arm of the 2nd phase II trial, there is obviously a dose dependent reaction in some immunological and clinical parameters. It is very common to see variability in patient reaction in those kinds of trials. In many cases there are people for whom the drug is much more beneficiary than others, regardless of the dose each patient received. Researchers can’t always put their finger on the reasons for those differences. This time, the better response rate correlated with higher doses, implies that GVAX might actually have an effect.
The company compared the median survival results to historical results of Taxotere. In many cases, the comparable historic data is indeed, historical, which means that the data was obtained from old and irrelevant clinical trials. Luckily, only 2 months ago, Sanofi-Aventis proudly announced results of a large trial involving HRPC patients conducted between the years 2000-2002. The Overall median survival rate was 19.3 months. Again, one mustn’t draw any definitive conclusions without a direct comparison, but this apparently impressive difference is more of a positive indication than a negative one.
Looking at popular therapy regimes for treating advanced cancer, it is pretty clear that a combination of several treatments achieves favorable results.
Most combinations involve drugs from different types, like the very common use of chemotherapy with hormonal treatment. Since cancer vaccines operate in a totally different manner when compared with other therapies, it therefore has good chances to complement current treatments. A current phase III trial is examining the effect of GVAX, given in combination with Taxotere. Combination with traditional chemotherapy might represent the highest potential for the treatment of advanced cancer.
Looking at results from published clinical trials, in many cases, clinical trials results are far from being satisfactory. Not only that most types of advanced cancers remain incurable, the improvement in survival of each new drug is sometimes marginal, ranging from few months to a year. We mustn’t forget that patients typically enroll to clinical studies when they have no other choice. In other words, participants in those trials are in a rather advance, sometimes even terminal stage of the disease, which makes them a very challenging target. It is reasonable to assume that drugs which are marginally effective in clinical trials would become more effective when administered to the general population of patients, especially for those with earlier stage disease.
In summary, although GVAX's clinical results are still preliminary, it looks like this approach of using whole GM-CSF secreting cancer cells as a vaccine might be effective in treating Prostate cancer as well as many other kinds of cancers. Hopefully, Cell Genesys has found the delicate balance required in order to manifest a specific, tolerable immune response against different kinds of Cancers.