ENHANCEMENT OF ANTI-TUMOR IMMUNITY BY INHIBITION OF TGF-B SIGNALING IN PATIENS WI

Yale University, New Haven CT

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Abstract

Treatment for patients with metastatic melanoma is inadequate. A subset of metastatic melanoma[unreadable] patients can undergo meaningful tumor regression in response to agents that modify lymphocyte activation[unreadable] and/or expansion, for example, IL-2, anti-CTLA4, or IL-2 in combination with transfer of ex vivo expanded[unreadable] tumor-infiltrating lymphocytes (TIL). However, most patients receiving these therapies fail to respond or to[unreadable] achieve lasting benefit. Preclinical studies conducted in our laboratories and confirmed by other investigators[unreadable] provide strong evidence that inhibition of TGF-beta signaling can markedly enhance the anti-tumor activity of[unreadable] CD8+ cytotoxic T-lymphocytes (CTL) in animal models. We propose to extend these studies to determine[unreadable] optimal approaches for clinical development of agents that inhibit TGF-beta signaling in combination with IL-2,[unreadable] IL-2 + TIL, anti-CTLA4, or other related immunotherapeutic manipulations. The goal of the clinical trials[unreadable] proposed in this application is to improve the rate and quality of tumor responses in patients with metastatic[unreadable] melanoma and to reduce the morbidity and mortality from this disease.[unreadable] In Aim 1 we propose to confirm the improved anti-tumor effects of CD8+ TGFRII-DNR cells (CD8+[unreadable] lymphocytes with the transgene for the dominant negative transforming growth factor beta receptor II) in mouse[unreadable] models and to determine if the anti-tumor activity of CD8+ TGFRII-DNR cells can be improved by addition of[unreadable] IL-2, addition of anti-CTLA4, and/or addition of anti-CD137. Furthermore, we propose to further characterize[unreadable] the mechanisms by which TGF-betaattenuates anti-tumor lymphocyte responses, in particular, to determine if[unreadable] the effects of TGF-beta are directly on CD8+ CTL or indirectly through induction of Treg (T regulatory cells[unreadable] which inhibit CD8+ and CD4+ anti-tumor lymphocyte responses), to determine the role of tumor driven TGF-[unreadable] beta in induction of Treg, and to determine whether and how Treg attenuate CD8+ CTL mediated tumor[unreadable] rejection. In Aim 2, we propose to create a retroviral vector carrying the TGFRII-DNR gene suitable for use[unreadable] in human clinical trials, to develop methods for transduction and expansion of human melanoma-derived TIL,[unreadable] and to characterize the cell product. We will also use mouse melanoma models to determine the optimal[unreadable] conditions necessary to maximize the anti-tumor effects of TGFRII-DNR CTL, and will use the results of the[unreadable] experiments to guide the design of a clinical trial. In Aim 3, we propose to evaluate non-genetic[unreadable] (pharmacologic) approaches to inhibit TGF-beta combined with an immunotherapy. Finally, in Aim 4, we[unreadable] propose to conduct proof of concept clinical trials in which TGF-beta inhibition is combined with an immune[unreadable] therapy. We propose that one of the clinical trials will involve adoptive transfer of melanoma TIL carrying the[unreadable] gene for TGFRII-DNR.