Cell Genesys' GVAX: A Multi-Trick Pony

| About: Cell Genesys (CEGE)

A cancer vaccine is a treatment aimed at stimulating the patient’s immune system to act against cancer. Unlike other cancer therapies, such as chemotherapy and radiotherapy, cancer vaccines do not target or damage cancer cells directly. Instead, they assist the immune system in recognizing and generating an immune response against cancer cells. When it comes to developing cancer vaccines, many possible strategies exist, all of which are founded on presenting and provoking an immune response against one or more cancer-related antigens. An antigen is an element which can be recognized and attacked by the immune system. In the context of cancer vaccines, the term antigen is typically referred to different molecules presented on the external side of cancer cells.

Many attempts to develop cancer vaccines have been made throughout the years, none of which ever managed to reach approval stages. With several candidates currently in clinical trials, it is possible that in the near future there will be at least one commercially available cancer vaccine. Cell Genesys’ GVAX is a platform which has been used for developing some promising cancer vaccine candidates, which are undergoing multiple clinical trials.

The current low valuation of Cell Genesys (CEGE) implies that the market views GVAX as a one-trick pony. However, GVAX should be regarded as a multi-trick pony since it is a revolutionary platform for developing cancer vaccines for a substantial number of different cancers. Several months ago, I discussed the concept behind GVAX as a cancer vaccine in general, and about the prospects of GVAX for prostate cancer in particular. Nevertheless, there may be additional tricks under GVAX’s belt, apart from treating prostate cancer.

GVAX is composed of whole cancer cells genetically modified to secrete the immune stimulatory molecule, GM-CSF (granulocyte-macrophage colony-stimulating factor). GM-CSF has been proven to be a crucial growth and activation factor for a subgroup of immune cells called antigen-presenting cells (APCs), which play a vital role in the initiation of any systemic immune response. The GVAX cells are injected to cancer patients with the goal of manifesting an immune response through the stimulation of APCs. In order to prevent the GVAX cells from multiplying and creating new tumors once inside the body, they are lethally irradiated to prevent further cell division. Upon entering the blood circulation of a cancer patient, the GM-CSF secreted by the GVAX cells stimulates the patient’s immune system to recognize the GVAX cells as hostile and to attack them. Hopefully, since GVAX cells share many antigens with each patient’s cancer cells, this response will also be channeled against the patient’s cancer cells.

cell genesisPredicting future success of drug candidates is very hard, let alone in an early-stage field such as cancer vaccines. With numerous cancer vaccines candidates currently being evaluated, it would be irresponsible to bet on just one approach or one platform, as there may be more than one winning strategy. Still, a thorough examination of the philosophy behind GVAX’s attributes and clinical data from several trials leads to the inevitable conclusion that GVAX has differentiated itself from the herd by presenting a truly innovative and elegant concept for cancer vaccines. Although being unique is by no means a guarantee for clinical success, there are several attributes, which make GVAX a very promising platform.

What Makes GVAX Unique?

One of the most important features in GVAX is its universality. The concept behind GVAX is applicable to numerous cancer types, since theoretically, any type of cancer cell can be genetically modified to secrete GM-CSF, making it a potential cancer vaccine. For example, in order to create GVAX for pancreatic cancer, Cell Genesys chose a pancreatic cancer cell-line, inserted the GM-CSF gene into the cells, irradiated them and the vaccine was ready. For the treatment of leukemia, the company did the same with leukemia cells and so on. However, each type of cancer includes so many types of available cell-lines, that choosing the right cell-line is of extremely high importance. Furthermore, since it is possible to combine more than one cell-line per vaccine, GVAX’s diversity potential, as a platform, is tremendous.

Another apparent advantage is the fact that in GVAX’s case, all the stages of the immune response occur inside the patient’s body. The first stage of every anti-cancer immune response involves the exposure of a special group of immune cells, called Antigen Presenting Cells (APCs) to cancer antigens. This exposure is the basis of enhancing any immune response, making it extremely crucial. Some cancer vaccines like Dendreon’s Provenge and Northwest’s Biotherapeutics DCVax, involve taking out APCs from the patient’s body and conducting the exposure stage in vitro (outside of the body). These activated cells are then re-administered into each patient and will hopefully ignite a specific immune response against cancer cells inside the body. Cell Genesys takes a different approach, similar to that of traditional vaccines, by injecting patients with the cancer antigens themselves (in the form of cancer cells). Thus, the immune cells are exposed to the cancer antigens in vivo (inside the body), in their natural environment. Both approaches have demonstrated clinical activity, however, considering the astounding complexity of biological systems and the huge success conventional vaccines have had, “keeping it natural” simply looks like a better idea.

An additional key differentiator of GVAX is its multi-antigen approach. While many cancer vaccines are aimed at manifesting an immune response against a specific cancer-related antigen, Cell Genesys is using whole cancer cells as antigens. Each cancer cell has countless potential antigens that can be targeted by the immune system. By using whole cancer cells, and sometimes even more than one strain, the amount of potential cancer antigens is immense. Thus, the immune response generated by GVAX might be less focused, but much broader and has the potential of impacting a wider population of cancer cells. In contrast to what many think, the population of cancer cells in a patient’s body is very heterogeneous. In many cases, different cancer cells from the same tumor may present different sets of antigens, especially in more advanced stages of the disease. Stimulating the immune system to recognize multiple antigens may result in a response against cancer cells, which would otherwise evade a single-antigen oriented immune response. Furthermore, scientists postulate that there are still a lot of undiscovered cancer-related antigens. By using whole cancer cells, GVAX enables an immune response against unknown as well as known cancer-related antigens. The beauty of this approach is that drug developers don’t have to know specifically which antigens trigger an immune response, as long as the job is done by the immune system.

Most cancer vaccines involve antigens which are not presented to the immune system in their fully natural state, i.e. on the surface of cancer cells. These antigens are often referred to as recombinant antigens. For example, Dendreon uses a recombinant version of prostatic acid phosphatase (PAP), an antigen present in the vast majority of prostate tumors. In GVAX’s case, the cancer-related antigens are presented to the immune system on real cancer cells, in their original conformation. Hence, the chances for accurate recognition of cancer antigens and immune response channeling towards actual tumors might be better.

GVAX can be patient specific, where cancer cells are taken specifically from each patient, genetically modified to secrete GM-CSF followed by irradiation and re-administered to the specific patient only. GVAX can also be non- patient-specific with the same types of cells used for all patients. Though the company has developed both patient-specific and non-patient –specific candidates, it has decided to focus on the latter.

Being a non-patient specific treatment makes production more reliable and cheaper, as the company does not have to deal with logistics such as getting each patient’s sample and shipping it back to the treatment facility on time. In addition, it is not always technically possible to generate a patient-specific GVAX cancer vaccine for every patient. Antigenics’ Oncophage® is a good example of a patient-specific cancer vaccine, as each patient undergoes surgery, to remove part or all of the cancerous tissue, followed by shipping of the tumor tissue to Antigenics’ manufacturing facility in Massachusetts. There, a specific antigen called heat shock protein gp96 is extracted from the tissue, re-sent to the medical center and administered to the patient. One must admit that although such a strategy may possess clinical benefits, this complicated procedure seems to be more expensive and to have more points of failure as oppose to an off-the–shelf treatment.

Although the trend in cancer therapy is clearly towards personalized therapy, an off-the-shelf product like GVAX is not necessarily therapeutically inferior to its patient-specific counterpart. In fact, it might have a significant advantage in the long run, considering the immune memory that can be created by cancer vaccines. Genetic instability is one of the hallmarks of cancer, as cancer cells constantly evolve by acquiring mutations and modifying exhibited antigens. These changes are a fundamental cause of treatment-resistance and disease recurrence, often demonstrated by cancer. A patient with early-stage disease who receives a cancer vaccine based on cells of advanced-stage disease could develop immunity against the advanced stages of the disease. Thus, non-personalized cancer vaccines have the potential of functioning as preventative treatments, blocking the formation of advanced-stage tumors. Such a preventative effect, which is still in the form of speculation, could be a huge differentiator for non-patient-specific cancer vaccines.

GM-CSF has been known as one of the most powerful immune stimulators. As such, it is often co-administered with cancer vaccines in order to stimulate the immune response. However, this co-administration is not targeted, as the GM-CSF is distributed throughout the patient’s body regardless of the vaccine location. Since GVAX cells constantly produce and secrete GM-CSF, even after being injected to the patient, there is always a local high GM-CSF concentration around them. Therefore, upon encountering antigen-presenting cells, the GVAX cells have better chances to induce a stronger immune stimulation than cancer vaccines which are simply co-administered with GM-CSF.

GVAX is being evaluated in multiple ongoing clinical trials for the treatment of prostate cancer, pancreatic cancer and Leukemia.

GVAX for Prostate Cancer

GVAX for prostate cancer is Cell Genesys’ most promising and advanced-stage candidate. It is composed of two prostate cancer cell-lines that contain many common antigens found in metastatic prostate cancer. The need for better treatment for this deadly disease, which is the second leading cause of cancer death in men in the United States, is obvious, especially among patients with advanced-stage disease. GVAX is currently being evaluated in two phase III trials for the treatment of prostate cancer in its advanced (metastatic) stages, after patients cease to respond to hormone therapy and radiation. This state is referred to as metastatic Hormone Refractory Prostate Cancer (mHRPC) and is generally associated with poor prognosis. With a yearly death toll reaching 60,000 men in the US & Europe, the potential of an effective treatment that results in prolonged survival is huge.

Although very big, the market for mHRPC is awfully crowded, with many promising agents in clinical development, including numerous cancer vaccines (like Dendreon's Provenge and Northwest’s DCVax-Prostate) and numerous promising chemotherapy agents. The most impressive performance was achieved by combining Taxotere and Celgene's Thalidomide, which resulted in a median survival of 25.9 months compared with 14.7 months for the Taxotere alone arm in a phase II trial. Although in most clinical trials Taxotere achieved a median survival of 17-20 months, 25.9 months still represents a substantial improvement.

Cell Genesys has reported encouraging results from five clinical trials of GVAX for prostate cancer including two phase II trials.

The first phase II trial included 34 mHRPC patients, whose cancer had spread to the bones and other tissues. This patient population, which is usually treated with chemotherapy, was administered with GVAX for prostate cancer as their sole anti-cancer therapy. Originally, all of the 34 patients were supposed to receive the same dose of GVAX. However, since in the first 24 patients to be enrolled, no severe side effects were observed, researchers decided to administer a higher dose of GVAX to the remaining patients. Hence, the first group (24 patients) was administered with a low dose of GVAX for prostate cancer while the second group (10 patients) received a higher dose. Overall Median survival for the 34 patients came at 26.2 months, more than 6 months better than the historic figures achieved by Taxotere chemotherapy plus prednisone, the standard therapy for mHRPC. Furthermore, the median survival for the 10 patients who received the higher dose, which is currently being employed in the phase III trials, was an impressive 34.9 months.

Updated results from the more recent phase II trial were published this April. The trial enrolled 80 patients with metastatic HRPC who were split into three dose groups. The median survival for the 22 patients who were treated with a similar dose to the currently employed dose in the phase III trials was, again, 35 months.

The striking similarity in the survival of the two groups who received a dose similar to the one currently employed in the phase III, is an encouraging sign because consistent results are considered to be more reliable. Additionally, an obvious dose dependent effect was observed, since higher doses gave rise to better survival figures. A dose-dependent response should be one of the most important indications in assessing any drug’s activity. Even more encouraging is the fact that in both groups, the predicted survival was around 22 months. However, this data should not be regarded as anything but an indication due to the small number of patients and the lack of control groups. If such a survival improvement is achieved in one of the ongoing phase III trials, it will represent an impressive achievement for GVAX, both as a potential drug for prostate cancer and as a concept in general.

When patients in the phase II trials were evaluated for immunological response against prostate tumors, there was a broad response in the majority of patients against many prostate cancer antigens. These immunological responses were demonstrated by identification of antibodies and T lymphocytes directed against specific prostate tumor associated antigens. Interestingly, although the GVAX for prostate cancer is a non- patient-specific treatment, immune responses were predominantly patient-specific and unique from patient to patient. Hence, the GVAX cells, which are not identical to each patient’s cancer cells, manifested a personalized specific immune response within each patient’s body.

GVAX for prostate cancer is currently being evaluated in two multi-center, international phase III trials. Both trials are randomized, comparative and involve a substantial number of patients, 600 each. The first phase III clinical trial (VITAL-1) was initiated 3 years ago and compares GVAX to Taxotere + prednisone, for the treatment of metastatic HRPC in its early stages (Asymptomatic). Recruitment has just been completed with interim data expected to be released in the first half of 2008 and final data expected to be presented in 2009.

The second Phase III clinical trial (VITAL-2) commenced in 2005 and evaluates the combination of GVAX + Taxotere Vs. Taxotere + prednisone. This trial involves metastatic HRPC patients who have cancer-related pain and poorer survival prospects compared to the VITAL-1 patient population. A timeline for data release from this trial, which unfortunately will be of shorter duration due to poorer survival, has not been given yet.

Both trials are of high importance; however VITAL-2, where GVAX is combined with Taxotere, seems to be more intriguing. GVAX and Taxotere each belong to totally different subclasses of therapy. While GVAX is an immunotherapy treatment aimed at manifesting an immune response against tumors, Taxotere is a chemotherapy agent that indiscriminately prevents cells from multiplying and eventually leads to programmed cell death. The combination of chemotherapy and cancer vaccines is perceived to be problematic because chemotherapy’s alleged negative effect on the immune system. While chemotherapy agents inhibit cell growth and division, cancer vaccines are aimed at stimulating growth and division of immune cells. However, mounting evidence indicates that not only is it possible to combine Taxotere with cancer vaccines, this high- profile chemotherapy drug may actually exert beneficial effects on the immune response induced by cancer vaccines. Evidence includes clinical results from a phase II trial, which evaluated the combination of Taxotere with Therion's virus-based cancer vaccine for mHRPC and trials evaluating GVAX for Melanoma in mice, which showed that Taxotere had a synergistic effect on the cancer vaccine’s ability to delay tumor growth.

Cell Genesys is also collaborating with Medarex in evaluating GVAX for mHRPC in combination with Ipilimumab (where do they come up with those names….), a monoclonal antibody that stimulates the immune system. Ipilimumab is expected to influence a wide variety of malignancies since it activates a group of immune cells called cytotoxic T lymphocytes (CTLs), rather than targeting cancer cells directly. In many cases, cancer cells can inhibit activation of CTLs by binding to a special receptor (CTLA4) presented by these highly critical immune cells. Ipilimumab was designed to bind the CTLA4 receptor and to prevent the inhibition of CTLs. Hence; the combination of the two drug candidates is very reasonable. In a phase I/II trial, GVAX was given to 12 patients in a dose level similar to that of the phase III trials in combination with 4 dose levels of Ipilimumab. PSA (Prostate-specific Antigen) declines of greater than 50% were observed in 5 out of the six patients who had received the two highest doses. These responses were maintained in four of these patients for at least six months. Just like the other phase II trials of GVAX as mono-therapy, there was clear evidence of immunologic stimulation like enhanced T cell activity and cancer-specific antibody production that occurred in a dose-dependent manner. Furthermore, each patient who responded to the treatment had a unique profile of cancer-related antibodies, an indication of a patient-specific response. Following these results, the two companies decided to recruit additional patients who will be given GVAX + Ipilimumab in the second highest dose (3mg/kg). The company expects more data from the trial will be published later this year

Targeting early stages in prostate cancer is another area Cell Genesys is evaluating for its GVAX for prostate cancer. In July of 2006, the company published results from a phase I/II trial, which included 21 early stage patients after surgical removal of all or part of the prostate gland. 16 patients showed a statistically significant decrease in the rate of rise of PSA (PSA slope) with one patient having a bigger than 50% reduction in PSA levels. In the patients who responded to GVAX, there was evidence of an immune response in the form of antibodies against prostate cancer-related antigens.

GVAX for Pancreatic Cancer

Pancreatic cancer represents a major challenge for the drug development industry. It is the fourth leading cause of cancer death in the United States, with 37,000 people forecasted to be diagnosed every year in the US alone. In its early stages, pancreatic cancer can be treated with surgery (resection), unfortunately, however, there are still no reliable means for early detection of the disease. Consequently, only patients who are diagnosed at the disease’s early stages (20% of diagnosed patients) can actually undergo surgery, with the remaining 80% left with no real alternative. Currently, the mean life expectancy is 15-18 months for patients with early local disease and 3-6 months for patient with advanced metastatic disease. In addition to the lack of tools for early detection, pancreatic cancer cells are naturally resistant to the majority of current chemotherapies and radiation therapies. Thus there is an urgent need for new non-chemo/radio therapeutic treatments targeting both early and advanced stages.

Cell Genesys has recently published updated results from a phase II trial that evaluated GVAX as a post-resection therapy (adjuvant therapy), which aims at dealing with both local and distant tumor recurrence after surgery. As mentioned above, this kind of treatment is applicable to only 20% of diagnosed cases, who can undergo surgery, but it is still a fairly large market. Even though the overall trend in early-stage pancreatic cancer is in favor of adjuvant therapy, there are still disagreements about its feasibility. Analysis of recent trials suggests treatments based on gemcitabine (Eli Lilly‘s Gemzar®) should be favored for adjuvant therapy. Hence, GVAX for pancreatic cancer should either be proven more effective than gemcitabine or demonstrate a synergistic effect when given in combination with gemcitabine. Recent results from a clinical trial evaluating gemcitabine chemotherapy given after resection are ambivalent. Although the trial hasn't demonstrated significant difference in overall survival (22.1 months with gemcitabine vs. 20.2 months with placebo), there was an improvement in median disease-free survival (13.4 months with gemcitabine vs. 6.9 months with the control group). The results made adjuvant therapy after pancreatic resection more acceptable, but still controversial. In earlier trials, gemcitabine in combination with chemotherapy and radiation proved to slightly improve overall survival rates when compared to chemotherapy alone (20.1-20.5 vs. 15.5-16.9 months).

Results from a phase II clinical trial evaluating GVAX for pancreatic cancer in 60 patients with early-stage pancreatic cancer were published in June this year. In 52 (88%) of the patients, the cancer had spread to regional lymph nodes by the time of the operation. GVAX was administered to patients who undergone surgery before and after standard adjuvant radiation therapy and 5-flourouracil chemotherapy. The median overall survival rate was 26.8 months for the GVAX trial, 4 months better than recently published gemcitabine results. Furthermore, median disease-free survival was approximately 16 months, which compares favorably to the 13.4 months disease-free survival recently reported in the gemcitabine study. In the GVAX trial, there were some encouraging immunological indications among patients who responded well to the treatment. These patients showed functional evidence of vaccine-induced T cell immunity against the pancreatic cancer tumor associated antigen, mesothelin. This immunological finding implies that a stimulation of the patients’ immune response against the pancreatic cancer occurred. Of note, when researchers examined general survival data for all pancreatic cancer patients resected at the medical center, who received chemo-radiation, median survival was approximately 21 months, almost 5 months shorter than in the GVAX trial. Again, in order to assess which treatment is superior, GVAX for pancreatic cancer must be compared with gemcitabine directly in a head-to-head trial. Anything else should be regarded as a vague indication, due to the differences between the trials. For example, gemcitabine was administered alone, while GVAX was part of a combination regimen. Supposedly, it gives GVAX a relative advantage, but clinical trials, which evaluated gemcitabine in combination with other treatments, could not demonstrate an additive effect. Regarding patient population, the gemcitabine trial included many more patients (179 in the gemcitabine arm), but relatively less patients whose cancer had spread to their lymph nodes (71%).

There are currently three ongoing clinical trials evaluating GVAX for the treatment of pancreatic cancer, with the majority of the related expenses is financed by the Johns Hopkins Kimmel Cancer Center. Two of these trials are a result of comparing the 3-year survival rates of the completed trial’s patients to those of general patient population who have undergone resection followed by conventional chemoradiation in Johns Hopkins. In the first 3 years following the trial, GVAX demonstrated a clear advantage over the standard therapy. However, standard therapy led to better survival rates from 3 years and beyond. This observation led researchers to the postulation that giving additional GVAX doses after the primary treatment (booster vaccination) might lead to better survival rates for longer periods. The concept of booster administration, which is common in conventional vaccines (HBV vaccine, for example) might lead to an immune response with a long-lasting effect. It might also mean that administration of GVAX should be spread over longer periods, perhaps years, in order to have an optimal long-term effect.

The first trial involves additional (booster) administrations of GVAX to patients from the completed phase II trial.

The second ongoing trial is another 60-patient trial evaluating GVAX in booster administrations following pancreatic cancer surgery and adjuvant radiation and chemotherapy.

The third trial is conducted on patients with metastatic pancreatic cancer, who, as previously stated have very poor prognosis. This population represents 80% of pancreatic patients so the market opportunity here is bigger. On the other hand, advanced pancreatic cancer is much more challenging than its early stages. With so many top selling successful cancer drugs such as Pfizer’s Camptosar® and Genentech’s Avastin® proven ineffective for treating metastatic pancreatic cancer, even after encouraging phase II results, the odds for success are rather slim. On the other hand, even a minor survival improvement may be enough, as demonstrated by Genentech’s Tarceva®, which was granted FDA approval based on a two-week survival benefit. The aggressive nature of pancreatic cancer and the absence of gemcitabine from this trial’s regimen, make it the most ambitious GVAX evaluation at the moment. The trial includes co-administration of GVAX and Imclone’s Erbitux®, a monoclonal antibody targeting EGFR, which is a member of a receptor family that leads to cell growth and proliferation. Although in recently published clinical results Erbitux failed to demonstrate anti-cancer activity in combination with gemcitabine in patients with metastatic pancreatic cancer, it might still demonstrate an additive effect in combination with GVAX. In addition, pancreatic cancer cells are notorious for their ability to inhibit anti-cancer immune response. This inhibition might be coped with (to some extent) by downregulation of members of the EGFR family, a possible effect of Erbitux. Hence, even if Erbitux cannot inhibit tumor growth in pancreatic cancer directly, it might make it more sensitive to the immune response GVAX induces in patients.

Since gemcitabine is the current standard of care in advanced pancreatic cancer, it would only be logical to try to combine it with GVAX. The overall median survival achieved by gemcitabine is in the neighborhood of 6 months, so there is a lot of room for improvement. There is also room for evaluating GVAX for pancreatic cancer in combination with other treatments. Again, combining chemotherapy agents like gemcitabine with cancer vaccines would at first seem to be counterproductive. However, clinical and pre-clinical data revealed that in some cases, gemcitabine does not suppress the host's immune response and it might even enhance the efficacy of cancer vaccines. Another possible combination might be with anti-angiogenic agents like Pfizer’s axitinib.

GVAX for Chronic Myelogenous Leukemia [CML]

Chronic Myelogenous Leukemia [CML] is a common type of leukemia, in which certain types of white blood cells multiply in an uncontrolled manner in the bone marrow. Currently, there are approximately 30,000 people living with CML in the US, with more than 4500 cases diagnosed per year. Mortality rate is relatively low, with a five-year survival rate among leukemia patients recently reported to be 89%. The low mortality rate is achieved thanks to continuous treatment with Novartis’ Glivec, a potent inhibitor of the protein BCR-ABL, which was approved in 2001. BCR-ABL has been proven to be essential for the development of the disease, making it a desirable target for inhibition. It is also considered to be an accurate genetic marker for assessing disease stages and progression.

CML has three phases: chronic-phase, accelerated-phase and blast-crisis CML. Without any intervention, patients gradually progress to the accelerated phase, and finally to myeloid blast crisis, which eventually leads to death. Fortunately, the majority of patients are diagnosed in the chronic phase and maintained in that condition for many years thanks to Glivec therapy.

Glivec is extremely effective among the vast majority of patients, however, it rarely cures the disease. Only 10%-20% of CML patients achieve complete remission of the disease with Glivec, with the rest maintaining detectable disease despite taking Glivec on a regular basis. In addition, a 4% per year incidence of Glivec resistance has been documented among Glivec recipients. In this case, Glivec is no longer effective and other strategies are sought after. The only viable alternative curative therapy for CML is stem-cell transplantation. Unfortunately, this kind of treatment is impractical in the majority of cases because of elderly patients’ inability to tolerate the severe side effects and lack of a suitable stem-cell donor. Thus there is room in the CML market for treatments which can be used either as a second-line therapy in cases where Glivec fails, or to augment Glivec’s therapeutic activity.

Cell Genesys published results from a rather small phase II clinical trial at the annual meeting of the American Society of Clinical Oncology [ASCO] in June 2006. Nineteen CML patients with molecular evidence of persistent leukemia, despite taking Glivec for more than one year, were treated with GVAX for leukemia in combination with Glivec. The addition of GVAX demonstrated impressive results, with five patients achieving complete disappearance of BCR-ABL and additional five achieving a greater than 90% reduction in the levels of this important marker. As previously mentioned, lower levels of BCR-ABL have been proven to be strongly correlated with overall and progression –free survival. Encouragingly, responses were ongoing in 9 out of the 10 responders, when examined 14 months post treatment. Although the size of the trial makes it very hard to project the real effect of the drug, the fact GVAX was proven highly effective in over 50% of patients is very encouraging.

At the moment, there are three ongoing trials assessing GVAX for treatment of CML. Most of the expenses related to these trials are financed by The Johns Hopkins Kimmel Cancer Center.

The first trial is an extension study of the initial Phase 2 trial involving 11 patients who had a decrease in their BCR-ABL levels, but could not reach a sustained complete response. This trial examines continuous GVAX administration over a longer period of time, similar to the trials in pancreatic cancer.

A second trial currently being conducted is a phase II randomized trial in 56 patients with CML who have persistent molecular evidence of disease following Glivec therapy. Patients were divided into two cohorts, one receiving GVAX + Glivec and the other receiving interferon-alpha + GM-CSF + Glivec. Interferon-alpha is another naturally occurring stimulator of the immune system. The comparison between GM-CSF secreting cells [GVAX] and free interferon-alpha + GM-CSF is very interesting because it can demonstrate the advantages of a specific, directed stimulation of the immune response, versus a general, untargeted stimulation. In other words, the fact that GM-CSF is secreted in a specific context (by the GVAX cells) as oppose to evenly distributed through the body, will hopefully lead to a more focused response against leukemia cells.

The third trial is a Phase I trial in 18 patients with poor risk myelodysplastic syndrome, an earlier stage of leukemia, which might transform in time into Leukemia.

Five Aspects of Consistency

With the risk of sounding like a broken record, all the positive indications coming from GVAX are far from being concrete evidence. Showing efficacy and good safety profile in numerous small clinical trials is never a substitution for large phase III trials, which often have contradicting results to earlier clinical trials. Bearing this in mind, there seems to be a great deal of consistency in GVAX’s case.

First, the same platform was used to create cancer vaccines against 3 different kinds of cancer and demonstrated favorable results when compared to historical data for the current standard therapies. Second, a systemic immune response was observed in all the trials, mainly in patients who responded to the treatment. This is an indication for GVAX’s ability to stimulate the immune system in multiple cancer types. Third, there were almost no severe side effects throughout the trials, making GVAX’s safety profile superior to that of standard treatments like chemotherapy and bone marrow transplantation. As a result, it may become an ideal treatment especially for people who cannot cope with standard therapy. Furthermore, it opens the way for combining GVAX with conventional treatments. Fourth, in GVAX for prostate cancer, not only did the results from 2 different clinical trials compare favorably to available treatments, survival figures were almost identical. Fifth, the Sidney Kimmel Cancer Center at Johns Hopkins, one of the leading oncology centers in the US, chose to conduct and finance follow-on trials for both GVAX for pancreatic cancer and GVAX for Leukemia. The center is entitled to milestone payments and royalties derived from future sales of the drug, if successful, which makes this move an even bigger reinforcement. The medical center professionals would have never have agreed to finance these trials if they hadn’t regarded GVAX as a promising treatment.

Even after reviewing Cell Genesys’ promising prospects, it must be clear that any company in clinical stages is a speculative high-risk play by definition. Bearing in mind that in drug development there are many more failures than successes, it would be foolish to expect Cell Genesys to be different from any other company in this frustrating field. However, the impressive consistency demonstrated by GVAX in multiple clinical trials for multiple types of cancer combined with ongoing clinical evaluations for more than 10 different conditions and regimens make GVAX very compelling in terms of risk/reward ratio, even if most trials fail.

Moreover, GVAX as a platform can be used for the development of a respectable array of new cancer vaccines. So not only GVAX is a multi-trick pony (at least in earlier clinical stages) it can be taught new tricks as well.

Who said you can't teach an old pony new tricks?

Disclosure: Author is long CEGE

CEGE 1-yr chart:

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