Replies to post #54885 on Biotech Values

[AlpineBV_Miller]

guess Gold could have fielded Monane's Treg question better and show his depth of knowledge in the field.

Mitch knows very well the developments in the field in this regard and follows them as closely as you'd expect any biotech CEO to follow them. With the Provenge data in hand (that Petrylak presented), he's simply one of the camp that believes chemo following is the right approach.

We have a good-natured disagreement over this that we discuss a few times a year when we run into each other at conferences or have some otherwise unscheduled time to chat.

I'm pretty sure the science will prove me right that pre-treatment is the right way to get an immediate efficacy boost for an active immunotherapy.

For active immunos like Provenge that provide a lasting immune response, chemo after may also be effective not because of effects on the T-cell system but because they might pop open cells that release the target antigen and spur a "revitalization" of the immune system response.

It may turn out that both Mitch and I are right. That's an interesting thought because it would put active immuno as the default center piece of cancer treatment.

[rancherho]

“The key observations of this study are, first, that human CD4+CD25hiFoxp3+ Tregs divide rapidly in vivo but have limited capacity for extensive self-renewal, and second, that it is very likely that these cells are continuously recruited from the memory CD4+ T cell pool." In addition, since CD4+CD25hiFoxp3+ T cells have been found consistently to have a highly differentiated phenotype, it is likely that the regulatory cues only have an effect on CD4+ T cells that have been activated to proliferate extensively.”
“In this context, survival factors, such as IL-2, that have been shown to be essential for the generation of CD4+CD25hiFoxp3+ T cells may be effective in part through their ability to counteract the susceptibility of these cells to apoptosis (49–51).” Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo . J. Clin. Invest. 116:2423-2433 (2006). doi:10.1172/JCI28941.
http://www.jci.org/cgi/content/full/116/9/2423
"In patients with progressive disease, the mean frequency of Tregs was 7.72% before treatment and increased to 16.7% after the first cycle of IL-2 and remained elevated after cycle 1 (772.3/mL, 9.06%). These increased levels were maintained through the second cycle of treatment (Fig 5C). In contrast, while patients achieving a complete response had slightly higher mean frequency of Tregs (9.0%) before treatment and maintained at a mean of 9.2% after cycle 1, the mean frequency dropped to 1.2% after cycle 2. The differences among the three response status groups are statistically significant with P = .004 (Table 2). Furthermore, this correlation remains significant after adjusting for the ALCs (Table 3)."Data from IL-2 and IL-2R knockout mice suggest that IL-2 is required for the generation and peripheral maintenance of Tregs."Characterization of CD4+CD25+ Regulatory T Cells in Patients Treated With High-Dose Interleukin-2 for Metastatic Melanoma or Renal Cell Carcinoma
Giovanni C. Cesana, Gail DeRaffele, Seth Cohen, Dorota Moroziewicz, Josephine Mitcham, John Stoutenburg, Ken Cheung, Charles Hesdorffer, Seunghee Kim-Schulze, Howard L. Kaufman
From the Tumor Immunology Laboratory, Department of Surgery and Biostatistics, Columbia University Medical Center, New York, NY Journal of Clinical Oncology, Vol 24, No 7 (March 1), 2006: pp. 1169-1177 http://jco.ascopubs.org/cgi/content/full/24/7/1169
One of the primary effects of docetaxel is to interfere with the mitosis of rapidly proliferating cells, leading to their apoptosis. Il-2 is linked to the proliferation of T cells during an immune attack. In other studies CD4CD25 Tregs have been shown to have preferential affinity for IL-2 causing Tregs to increase rapidly at the site of an immune attack, even if not systemically. Tregs not only would have increased susceptibility to docetaxel because of that response, but as the above studies suggest, have limited replicative ability to begin with. Much as in the IL-2 melanoma and RCC studies of Dr. Kaufman et al at Columbia, Tregs should spike in response to an immune attack on a tumor and its microenvironment, but be rapidly depleted by docetaxel to a lower level than at the outset. JMHO.

Another observation that Gold completely missed, IMO, was that Table 7 in the FDA statistical Briefing Materials for the AC, CD54 cell count or upregulation was not statistically significant for survival contrary to what he again suggested at the CC (but is only a manufacturing potency marker as Dr. Prevost correctly and definitely stated at the AC). http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4291B1_03a.htm
Recall that CD54 (ICAM-1) is a marker for mature dendritic antigen presenting cells, which according to Dr. Small's Ph2 study represented a median of about 15% of some 2.4 billion total nucleated cells (TNC)in a Provenge. Per Table 7, TNC cell count was statistically significant for survival.
Again according to the Ph2 study, "The patients’ T-cell and B-cell (antibody) responses to the PAP-GM-CSF construct PA2024 were measured before treatment and every 4 weeks thereafter. The 31 patients had little or no pre-existing T-cell proliferation responses to PA2024, whereas 100% developed T-cell proliferation responses after infusion of Provenge."
"PA2024 consists of PAP fused to the targeting element GM-CSF. T-cell responses to each of these components were examined. No patient had pre-existing T-cell responses to PAP isolated from human seminal fluid; whereas after treatment with Provenge, 10 (38%) of 26 patients developed a T-cell response to PAP."(My comment: DNDN's Ph3 T cell stimulation data was measured by responses to the fusion protein and described as representative of its priming against human PAP, even though the reason PA2024 is used was due to the difficulty in getting T cell stimulation results to human PAP) "Antibodies to PAP and GM-CSF were evaluated by specific ELISA on serum samples obtained at baseline and then every 4 weeks. None of the patients had pre-existing antibodies to PAP (isolated from human seminal fluid); whereas after treatment, 16 (52%) of 31 patients had antibodies." Immunotherapy of Hormone-Refractory Prostate Cancer With Antigen-Loaded Dendritic Cells
By Eric J. Small, Paige Fratesi, David M. Reese, George Strang, Reiner Laus, Madhusudan V. Peshwa, Frank H. Valone Journal of Clinical Oncology, Vol 18, Issue 23 (December), 2000: 3894-3903
http://jco.ascopubs.org/cgi/content/full/18/23/3894
Docetaxel is known to increase the activation of macrophages, which destroy antibody marked cancer cells in a process of phagocytosis. Thus, although never discussed, docetaxel's strengthening of a humoral, antibody related destruction of human PAP expressing cells might be as important as its destructive impact on rapidly proliferating Tregs at a tumor site allowing a cellular, T cell immune attack to become effective since Ph2 data suggests that a higher percentage of human PAP expressing cells reacted to antibodies than T cells. Ultimately, docetaxel's synergistic MofA impact, IMO, benefitting both humoral and cellular immunity is probably quite similar for Provenge and GVAX.

>>I guess Gold could have fielded Monnane's Treg question better and show his depth of knowledge in the field.<<
IMO, shallow waters indeed.

[microcapfun]

>>The following excerpt from a GVAX + Docetaxel animal study provided some evidence of docetaxel actually slightly increased circulating antigen-specific T cells. Sorry to clutter the board. But again, it might not help to promote a competitor..<<

Competitor?? This isn't the Dendreon board, is it?

I find it interesting that Cell Genesys is carrying out a large Phase 3 pivotal trial of GVAX + taxotere, when (to my knowledge) there has never been any *clinical* trial testing the combination, even in healthy volunteers. Mouse studies are one thing, but why would the FDA sign on with an SPA for a combination untested in people?

micro