For scientists and biotech companies struggling to develop effective autologous cancer immunotherapeutics, recent clinical trial results may go a long way toward vindicating their herculean efforts and finally promote investor enthusiasm. In May 2009 Dendreon announced positive Phase III data in prostate cancer for Provenge, which is likely to become the first cancer vaccine approved by the FDA. Dendreon has spent more than $560 million to develop Provenge, and hopes to market the vaccine in 2010.
Needham and Co. managing director and analyst Mark Monane, M.D., has characterized Provenge as a game changer, saying that unlike conventional therapies, it offers patients benefits with few side effects. The cost for Provenge is expected to be somewhere between $30,000–50,000, and the therapy is expected to enjoy a 20% share of the market; there are roughly 230,000 new cases of prostate cancer every year in the U.S.
This projection and data presented at the recently held American Society of Clinical Oncology (ASCO) meeting, may infuse some excitement and cash back into the moribund and much-maligned cancer vaccine area. Realities that have sorely tested the most enthusiastic autologous cancer vaccine proponents included the costs of producing patient-specific tumor cells and antigens, big pharma lack of interest in one-off as opposed to off-the-shelf therapeutics, technological and manufacturing barriers, a highly risk-averse investment climate, repeated clinical failures in solid and liquid cancers, and healthcare coverage uncertainties around novel expensive treatments.
Achieving Personalized Therapy
We all hate the phrase “the patient failed the therapy,” when in reality the therapy failed the patient. Therefore, the possibility of patient- and cancer-specific effectiveness, as well as nontoxic immunotherapeutics remains compelling. Acknowledging a major paradigm-shift in treating cancer, the theme of ASCO this year was “Personalizing Cancer Care.” This theme suggests the potential of individualized therapy to change cancer treatment and acknowledges that, according to ASCO president, Richard L. Schilsky, M.D., “Each patient with cancer is different—biologically, clinically, economically, and socially—and a one size fits all approach to treating cancer is not optimal.”
In the context of this evolving treatment climate, the positive Provenge data as well as results from one of three late-stage trials testing autologous cancer vaccines for lymphoma provide clinical evidence supporting use of such personalized therapies. At the same time, reasons why only one of three very similar vaccines was successful in treating lymphoma illustrates the challenges and complexities inherent in development of immunotherapeutics for cancer.
The vaccine that showed promise in Phase III was BiovaxID, an autologous lymphoma vaccine manufactured by Biovest International. Development of the vaccine began its long, hard road to Phase III studies over 20 years ago at Stanford University. The first Phase III trial with the vaccine was initiated by the NCI, then sponsored by Biovest. Biovest and its parent company, Accentia Biopharmaceuticals, both entered into Chapter 11 bankruptcy late in 2008.
BiovaxId comprises the tumor surface protein, also known as idiotype or Id, specific to an individual patient’s tumor with an immune adjuvant KLH plus an immunostimulatory growth factor GM-CSF. It is intended to stimulate an active and long-lasting, specific immune response against an individual patient's tumor cells. Since the vaccine is tumor-specific, noncancerous cells should remain unaffected, unlike treatment with Rituxan which also deletes normal B cells as well as cancerous lymphoma B cells.
Patients with previously untreated, advanced-stage follicular lymphoma were treated with a specific chemotherapy regimen, PACE, to produce clinical disease remission. Patients in complete remission were randomized at a ratio of 2:1 to received BiovaxID or KLH and GM-CSF without the idiotype. The primary trial endpoint was disease-free survival.
Analysis of data from 117 trial participants in complete remission showed that progression-free survival was 44.2 months among patients receiving BiovaxID and 30.6 months in those receiving the control vaccine. After an average follow up of 4.7 years, patients who got BiovaxID had a 38% lower risk of lymphoma recurrence than those receiving the control vaccine.
Hurdles to Overcome
While results are encouraging, they beg the question: Why did two other similar vaccines—Genitope's MyVax and Favrille’s Mitumprotimub-1—fail Phase III trials? In comparing these trials, two researchers involved in the development of BiovaxID, Larry Kwak, M.D., Ph.D., currently chair, lymphoma/myeloma and professor at the University of Texas MD Anderson Cancer Center, and Stephen J. Schuster, M.D., associate professor of medicine at the Abramson Cancer Center of the University of Pennsylvania cited several differences in the trials: Only patients in complete remission were randomized in the BiovaxID clinical study, whereas the MyVax trial included patients in partial remission, and the Mitumprotimub-t trial included those in partial remission and with stable disease.
The trial results, according to Drs. Kwak and Schuster, suggest that a minimal residual disease state may be required for the vaccine-induced immune response to be effective. They further pointed out that BiovaxID idiotope was produced using the heterohybridoma method, while MyVax and Mitumprotimub-t are recombinant proteins—Id protein is produced via PCR and recombinant technology to create synthetic Ids that may or may not correctly mimic the vaccine target.
Both companies had hoped to simplify the autologous idiotype manufacturing process, a historical show-stopper for potential investors in terms of cost and time. Dr. Kwak says, “The bottom line is that recombinant proteins may be very different products that are not necessarily bioequivalent, and this is one of the potential factors that explain differences between the trial outcomes.”
Leerink Swan analyst Howard Liang, Ph.D., notes that the financial community is focused on Dendreon’s Provenge right now. He believes, though, that “Autologous manufacturing is not the deal breaker it used to be. If these vaccines work for really difficult-to-treat diseases, the manufacturing issues will be worked out.”