Replies to post #5160 on Dendreon Corp fka DNDNQ

[rancherho]

1. An unfortunate outcome that is perhaps instructive in other ways. OvaRex apparently used a non humanized, murine monoclonal antibody which incorporates a CA125 antigen common in ovarian cancers to elicit a human anti-murine antibody (HAMA) against it. The idea is that the reaction against the mouse CA125 would cause the in vivo generation of B-cell related antibodies against CA125 antigen expressing ovarian cancer cells.http://www.mctrc.org/en/rp/studies/altare.htm
There are potentially several problems with this approach, a major one being that T cell tolerance against CA125 antigens may already be established by the tumors, meaning that a likely attenuated macrophage only response against OvaRex marked cancer cells might ensue.

2. There is a fascinating if complex report on two studies and an editorial in the current Journal of Immunology titled "Pillars of Immunology" that states, in part: “These B cells exposed to a TNP-conjugated carrier, presented the carrier-derived epitopes to carrier specific class II MHC restricted T cells 1000-fold more efficiently than did TNP-specific B cells exposed to an unmodified carrier” Bridging B cell and T cell Recognition of Antigen, PILLARS OF IMMUNOLOGY, J Immunol 2007 179: 7191-7192 http://www.jimmunol.org/current.shtml

3. One possible reading of this material is that an immune attack that combines targeting of cancer cells with B cell antibodies, a th2 humoral immune attack, as well as with a T cell, th1 cellular immune attack, might be far superior to either one alone or to a straight math sum of each response taken alone.

4. There may be some foundation for this in Dr. Small’s Ph2 report on Provenge at: http://jco.ascopubs.org/cgi/content/full/18/23/3894 In it, he reported: “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” and “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” This would also be consistent with Neuvenge increasing efficacy against HER2/neu breast cancer after failure of Herceptin, a hmab targeting the same antigen.

5. Small’s study also noted interesting aspects relating to the use of GM-CSF and the importance of whole protein as opposed to peptides for cellular immunotherapies. “The GM-CSF element in our prostate antigen is essential to in vitro antigen processing, but there are several reasons why we believe that GM-CSF does not otherwise contribute to Provenge’s in vivo effects. First, the cells are washed extensively before infusion, and the quantity of residual GM-CSF is negligible. Secondly, most investigators use dendritic cells prepared in the presence of GM-CSF, and there is, to our knowledge, no evidence that the in vivo activity of those dendritic cells is caused by an adjuvant effect of GM-CSF. Thirdly, our preclinical studies compared infusions of dendritic cells pulsed with the fusion protein with injections of the fusion protein itself. Unlike the antigen-pulsed dendritic cells, the PAP-GM-CSF fusion protein did not elicit T-cell responses to PAP. Finally, we have performed a clinical trial that involved subcutaneous injections of the fusion protein and observed that the injections did not stimulate T-cell or antibody responses”
“Protein-pulsed dendritic cells may be more effective than single peptide-pulsed dendritic cells for stimulating immunity because of the larger repertoire of antigens present in the protein and the resulting ability to elicit both CD4+ helper cells and CD8+ effector cells.”

6. All of this is also consistent with increasing efficacy with subsequent docetaxel since it is reported to activate macrophages, thereby improving the antibody effected killing of cancer cells by phagocytosis, as well as depleting rapidly proliferating Tregs, increasing the efficacy of a T cell attack. Other cellular based immunotherapies that also have an antibody arm, such as GVAX, may have similar attributes. JMHO.