Abstract A6: The synergy between IL-12 priming of CD8 T cells and lymphodepletion is mediated by host IL-7.

Adoptive T-cell transfer therapy (ACT) is a promising approach for the treatment of metastatic melanoma. Using the pmel-1 transgenic mouse as a source of melanoma-reactive CD8 T-cells, our lab has shown that priming these tumor-specific cells ex vivo with IL-12 (pmel IL-12 ) prior to ACT results in significant anti-tumor synergy and enhanced persistence in combination with cyclophosphamide (CTX). Here we demonstrate that other currently accepted lymphodepletion approaches, total body irradiation (TBI) alone or in combination with CTX, are also capable of synergizing with ACT of pmel IL-12 . Interestingly, all 3 regimens (CTX, TBI and CTX + TBI) showed a similar ability to synergize with pmel IL-12 , suggesting a common underlying mechanism. To elucidate the mechanism(s) behind this observed synergy, we evaluated whether the persistence of pmel IL-12 cells transferred into a lymphopenic host required the cytokines IL-7 and IL-15, which are known to be increased in the host post lymphodepletion. We found that the early expansion of pmel IL-12 in an irradiated host was partially dependent on IL-7, but not IL-15, as both the percentage and total number of donor cells recovered from spleens of irradiated hosts 1-week after ACT were greatly diminished in mice treated with an antibody against the IL-7 receptor alpha, CD127, or with an IL-7 neutralizing antibody (clone M25). In vitro these pmel IL-12 cells were able to proliferate in response to IL-7 to a much greater extent than pmel CD8 T-cells activated without IL-12. Together, these findings demonstrate that activated CD8 T cells primed with IL-12 display enhanced responsiveness to IL-7, and that IL-7 is necessary for maximal persistence of these cells in an irradiated host. Therefore, we conclude that the observed synergy between IL-12 priming of CD8 T cells and lymphodepletion is due in part to increased availability of host IL-7 after lymphodepletion. Citation Format: Christopher Bryce Johnson, Bennett R. May, Colleen A. Cloud, Mark P. Rubinstein, David J. Cole. The synergy between IL-12 priming of CD8 T cells and lymphodepletion is mediated by host IL-7. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A6.