I have no position in DNDN, but have great respect for walldiver, ocyan and many of the other posters on Ihub, so I will depart from my intention not to post and make a few comments on the science and MOA of Provenge:
1. The multi institution rapid auropsy program in AIPC showed that patients died from slow growing metastases in visceral organs that were largely undetected until the autopsies.
2. The Provenge clinical trials exclude patients with known visceral mets, but as noted above, most are undetected in any event. Logically, sicker patients could be expected to be more likley to have undetected visceral mets.
3. Any immunotherapy based on adoptive T cells or the priming of T cells by dendritic antigen presenting cells, such as Provenge, is subject to the body's immunosuppressive effects, primarily caused by regulatory T cells, assuming, of course, that the T cells last long enough in vivo to be impacted by Tregs.
4. Provenge itself might have some impact on metastacizing PC cells unprotected by Tregs, but acting alone, IMHO, it is unlikely to be able to overcome the Treg defenses of established tumors. This appears to be substantiated by the absence of any statistically significant impact of Provenge (or of any experimental therapeutic cancer vaccine acting alone)on eliminating known lesions. If in later stage patients the mets have already been established in visceral organs, but remain undetected, the prognosis for any Provenge only treatment would be poor.
5. Dr. Niederhuber, the NCI chief, stressed at the FDA / NCI workshop that the first FDA approved immunotherapies would likely be combination therapies. The efforts of the NCI's Dr. Rosenberg and others suggests that a primary goal of combination therapies would be to deplete Treg defenses. Any analysis of the Provenge MofA and the combination effects with Taxotere suggests that this need to overcome Tregs will also be true wrt to Provenge.
6. Crossover Provenge made from thawed white blood cells does not appear as effective as Provenge made from fresh white blood cells, presumably giving the ITT patients a therapeutic as well as timing advantage over control patients. However, after an ITT patient or crossover patient receives Provenge, his therapy choices are no longer controlled, although survival continues to be monitored. The nature and timing of any post Provenge therapy for 9902b patients between ITT and placebo patients may have a substantial impact on survival statistics, especially in the case of sicker patients where quicker and more dramatic rescue is vital.
7. The fact that natural PAP does not precipitate a strong T cell stimulation response, as Dr. Burch of the Mayo clinic reported in his Phase 2 report, and that the reported strong T cell proliferation data resulting from Provenge therapy is only to the fusion antigen was an obvious question to expect from the AC panel (BTW, I emailed DNDN to expect this), and was raised in the FDA Briefing Materials, but inexplicably when DNDN presenters were asked this question, they did not even propose an hypothesis to explain it (as Dr. Burch himself had proposed). DNDN was also asked at the AC meeting for some suggested biologic marker to differentiate those who would benefit from Provenge from those who might not, a question also asked at the AC panel for Xinlay in AIPC. Dr. Petrylak asked the same question at the BIO2007 conference, to which Gold responded by suggesting that CD54 upregulation was such a biologic marker. Thankfully, Dr. Prevost cleared that misunderstanding up at the AC meeting by pointing out that CD54 upregulation was only a manufacturing potency marker and not a biologic marker, but neither she nor any DNDN presenter could offer any possiblities for a single or composite biologic marker predicting therapy success for a given AIPC patient.
8. In the absence of any DNDN hypothesis or substantiated explanation of its MofA, the AC panel was left to rely on mixed statistical support. The 13-4 vote on substantial evidence of efficacy was heartening in that regard, and in the absence of the unacceptable CMC preapproval inspection of DNDN's NJ facility, might have carried the day. When faced with CMC delays in any event, it was not surprising that a conservative and risk averse bureacracy such as the FDA would ask for more clinical efficacy data while CMC issues were being resolved. Remember that it was not only Drs, Scher, Hussein and Fleming that objected to the statistical basis for the AC vote in the Cancer Letter, but also the incoming President elect of ASCO.
9. For the sake of every AIPC patient, I hope that DNDN is working hard to provide a well substantiated MofA to support any mixed statistical data from its future interim survival analysis. DNDN, its patients and shareholders, should appreciate, however, that the relative impact of follow-up therapies (Taxotere, other taxanes, CTLA-4 blockers, etc.) may have unpredictable impacts that extrapolation of statistical results from the 9901 and 9902a trials to projected 9902b results may not account for.
10. I will once again withdraw from active posting, but I very much appreciate the science, statistical and other solid debate that Ihub posters now seem uniquely inclined to bring to any analysis of DNDN and Provenge.
rancherho
