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The importance of dealing with immunosuppressive Tregs in the context of immunotherapy has become the subject of numerous articles over the past several years. An oft cited study from 2005 stated: “Therefore, CD4+CD25+ T cells maintained an environment in the tumor that concealed the immunogenicity of tumor cells to permit progressive growth of antigenic tumors. Our study illustrates that the suppression of antitumor immunity by regulatory T cells occurs predominantly at the tumor site, and that local reversal of suppression, even at a late stage of tumor development, can be an effective treatment for well-established cancers.” http://www.jem.org/cgi/content/full/201/5/779

Another widely cited retrospective study of Epithelial Ovarian Cancer in PNAS found that the greatest indicator of increased survival was the ratio of CD8 T cells to CD4 CD25 regulatory T cells. http://www.pnas.org/cgi/content/full/102/51/18538

Now a new study published in the current issue of the Journal of Immunology analyzing tumor tissue from many different types of cancer reports that a certain subgroup of CD8 effector T cells, CD8+CD28– T cells, are also immunosuppressive: “The unprecedented observation was made that CD8+CD28– T regulatory lymphocytes are almost constantly present and functional in human tumors, being able to inhibit both T cell proliferation and cytotoxicity. CD4+CD25+ T regulatory lymphocytes associate with CD8+CD28– T regulatory cells so that the immunosuppressive activity of tumor-infiltrating regulatory T cell subsets, altogether considered, may become predominant.“ The ratio between other types of CD8 T cells and CD8+CD28– T cells becomes critical; the amount of CD8+CD28– T cells has an inverse statistically significant relationship with survival. These immunosuppressive CD8 cells are preferentially recruited to tumors by chemokines that the tumors secrete. The study concludes that the use of whole cell immunotherapies probably introduces some immunosuppressive as well as effector cells, that it appears appropriate if not mandatory that agents countering the effects of Tregs be used, and the use of biologic agents such as GM-CSF as adjuvants must be evaluated carefully since they have the ability to stimulate immunosuppressive as well effector functions. CD8+CD28– T Regulatory Lymphocytes Inhibiting T Cell Proliferative and Cytotoxic Functions Infiltrate Human Cancers The Journal of Immunology, 2007, 179: 4323-4334. The Journal of Immunology, 2007, 179: 4323-4334. http://www.jimmunol.org/cgi/content/abstract/179/7/4323

This study is just another link in the chain of evidence that further supports the importance of the use of chemotherapy to dramatically increase the efficacy of cancer vaccines and immunotherapies. This can involve the use of cyclophosamide to deplete Tregs prior to the infusion of adoptive T cells, such as used in melanoma by the NCI’s Steven Rosenberg and colleagues, or, where priming of T cells is required, as in the case of Provenge and GVAX , by docetaxel that both attacks rapidly proliferating cells, such as CD4CD25 Tregs reacting to a CD8 effector T cell attack and can destroy fixed cancer cells and CD8+CD28– T cells in tumors through the innate immune system’s phagocytosis destruction of target cells.

Despite the popular appeal of believing that immunotherapies with low toxicity can break immune tolerance to cancer and achieve widespread efficacy in significantly increasing survival in HRPC without the help of chemotherapies such as cyclophosamide, docetaxel and others, IMHO, the data on the use of the combination therapy of cancer vaccines and docetaxel in HRPC clearly trumps that of either alone. A few lucky HRPC patients may achieve major increases in survival using immunotherapies alone, but the 9901 and 9902a data strongly suggests that those patients on the average do far worse in terms of both median and 36 month survival than those using combination therapy. In this supposed new era of adaptive clinical trials, therapy choices of future patients would clearly benefit from a subgroup analysis of combination use of vaccines and docetaxel (which , in the case of 9902b and Vital 1, could be prospectively specified as an alternate regulatory path to approval), such as Dr. Petrylak presented last November, as compared to either therapy alone, even where the subsequent use of docetaxel (and possible vaccine boosters) is “uncontrolled”, but data is available from treating docs. In addition, it is possible that patients receiving vaccine and docetaxel might achieve clearly statistical significance in median survival, whether compared to an allocated alpha or 0.05, at the interim look, while vaccine only patients or the composite of combination and vaccine only patients might not. Statistical purists and FDA traditionalists might argue against “too many bites of the apple”, but one can hope that ultimately the FDA would put the interests of dying patients first and allow a regular or conditional approval of a combination therapy subgroup if it shows statistical significance for increased survival, even if the ITT group as a whole did not.