“Of interest, those patients who developed an immune response to native PAP had a longer time to disease progression (TTP; 34 weeks v 13 weeks; P = .03).” From Dr. Small’s Phase 2 report.
“The PA2024 T-cell stimulation index is a measure of specific T-cell responsiveness against the target antigen. This exploratory analysis was performed in a subset of patients for whom cells could be processed within 24 hours of collection, thus precluding the need to freeze the cells before analysis. All analyses were performed before study unblinding. The median ratio of the T-cell stimulation index at 8 weeks versus baseline (preinfusion) was approximately eight-fold higher in sipuleucel-T- versus placebo-treated patients (16.91 Wilcoxon v 1.99; Wilcoxon rank sum P < .001).’ (Emphasis mine)
1. These remarks are quoted from last July's JCO article by Small et al. The Phase 2 study by Burch et al from the Mayo Clinic published in 2004 in The Prostate commented on the difficulty in getting any T cell stimulation to human PAP in Provenge treated patients, suggesting several possible reasons for it. Dr. Small never explained how a reaction to PA2024 is “a measure of “ human PAP. This issue was pointed out in the FDA Briefing Materials. The follow-up question at the AC as to why there is little or no T cell stimulation to human PAP was entirely predictable. When asked, DNDN did not even have a hypothesis to explain it.
2. The new AACR article is interesting in that the authors, all NCI docs, were heavily involved in the failed Therion prostate cancer vaccine and probably in many of the some 30+ therapeutic cancer vaccines that the NCI has tried without success over the last 10 or more years. The scientific analysis of the antigen cascade effect of the Phase 2 trial of the Therion PROSTVAC vaccine targeting PSA was first rate, even if the results were less so, showing that it also targeted human PAP and three other AIPC antigens, but with even less avidity than its 3.3 T cell stimulation index against PSA. In comparison, all the Provenge T cell stimulation index data against the PA2024 antigen, which is after all not native to the human body, is far higher, but what does it mean? Since DNDN’s entire antigen cassette technology relates to joining cancer antigens with GM-CSF in large fusion molecules, one would have thought that this issue would have been exhaustively studied.
3. Dr. Niederhuber, the head of the NCI gave a great talk at the opening of the second day at the FDA / NCI workshop, where he predicted that the first successes for cancer vaccines and immunotherapies would come in combination therapies. Even the renowned Dr. Steven Rosenberg, mentor of Dr. Mule' of the Provenge AC panel, and his NCI associates use chemo and radiation to deplete Tregs to enable their genetically engineered adoptive T cells to cause partial and complete remissions in some 50% of their end stage melanoma patients having large well vascularized tumors. His adoptive T cell protocol only targets one melanoma antigen. However, it is remarkably successful against all established melanoma tumors, suggesting that it is uniquely expressed in all such tumors, or, alternatively, that it is also assisted by the antigen cascade process the AACR authors describe. Rosenberg makes no secret that his adoptive T cell protocol should be applicable to all epithelial cancers, including prostate cancer. The need to break a patient’s tolerance to established tumors to make immunotherapies effective regretfully for patienrs does not equate to the more benign “silver bullet ”prospect of three doses of Provenge with flu like side effects being all that is necessary for substantially increased survival. It does, however, reflect the complex, dynamic biologic system that our immune systems are. The AACR article reflects the probability that Provenge, as a stand alone therapy, like many other therapeutic cancer vaccines, may extend survival for some without causing the regression of established tumors, but that does not necessarily equate to establishing statistical significance when applied broadly to larger groups in the absence of supportive combination therapies.
4. The likely truth is that assuming Provenge primes T cells against some antigen characteristic of AIPC cells and assuming that these primed effector CD8 T cells continue to circulate for relatively long periods in a patient's blood, the T cells still require combination use with Taxotere or some other adjuvant to allow them to extravasate from blood toward target tumor cells and overcome established Treg defenses. This was a primary element in Dr. Petrylak's presentation last November recommending a new Provenge protocol utilizing Taxotere after Provenge and therafter followed with a Provenge booster. Petrylak pointed out that Taxotere’s initiation of macrophage attacks on AIPC cells may be synergistic with a vaccine primed T cell attack. If anyone thinks that an increase in median survival for the Provenge + Taxotere combination of 14 months as compared to the Halabi projected survival for those not taking that combination for the 81 patients who took both therapies in the 9901 and 9902a trials had no effect on Provenge's long term survival results, there's a bridge in Brooklyn for sale.
5. Where does this leave AIPC patients? CEGE is conducting a 600 patient Phase 3 Vital 1 trial of GVAX for prostate cancer vs. Taxotere, as well as a 600 patient Vital 2 study comparing GVAX + Taxotere against Taxotere alone, in both cases with survival as the pimary end point. While both trials are enrolling slowly, they also provide for interim looks. My prediction is that Vital 1 may be marginally statistically significant, while Vital 2 will definitely be so. Even the Therion PROSTVAC data showed that its use prior to Taxotere increased TTP over either alone, and probably will ultimately show some increased overall survival. Combination therapies will be vital in the development of all immunotherapies. While they might not eliminate chemotherapies, they will reduce and optimize their use. Before long, the NCI and Dr. Rosenberg’s genetically engineered adoptive T cells will be tested in critically ill AIPC patients, achieving prior Treg depletion with chemotherapy. DNDN should back Dr, Petrylak in an open label salvage trial since his analysis and suggested protocol is many years ahead of that used in 9902b and points to the role that Provenge, used in a combination therapy, can play in prostate cancer over the long term. Competition is definitely coming. Then again, the absence of Drs. Small and Petrylak at the AC and their silence since then is hardly reassuring. Have the attacks of Provenge supporters on fellow clinical investigators in oncology who lead studies of different therapies and the silence of DNDN in calming the rhetoric gone on for too long?
6. Fascinating science and all JMHO. Since this is a national holiday for all Americans I will not comment on DNDN’s BOD and CEO, but simply wish everyone, especially our service men and women and their families, a great 4th of July.
