Beschreibung:
Abstract Lymphomas, with an estimated 80,000 new cases, are the 5th most common cancer in the United States and the majority of lymphoma subtypes are incurable and in need of novel, mechanistically distinct therapies. Two approaches to potently increase the anti-tumor potential of T cells are: checkpoint blockade (e.g. anti-CTLA-4 and anti-PD-1 antibodies) and adoptive T-cell transfer into lympho-depleted recipients. We have developed a novel therapy combining these approaches into ‘checkpoint-blockade-primed immunotransplant’ comprised of: -treatment of tumor-bearing host with anti-CTLA-4 and/or anti-PD-1 antibodies -splenocyte harvest and transfer to lympho-depleted recipient Whereas checkpoint blockade alone has minimal anti-tumor effect in the pre-clinical model, our results show that the combined therapy results in superior anti-tumor immunity as seen by increased production of tumor-reactive IFN γ positive T-cells. Treatment of both tumor-bearing donor and recipient with checkpoint antibodies induces cure of the majority of recipients, in a CD8, NK, and IFNγ-dependent manner. Furthermore, we have demonstrated that CD8 T cells exposed to checkpoint blockade and transfer into the lymphopenic host demonstrate greater: -in vivo serum levels of IL-15 and IL-7 -surface expression levels of IL-15R and IL-7R -in vitro STAT5 phosphorylation in response to common γ-chain cytokines -in vivo proliferation in response to exposure to cognate tumor antigen Ongoing studies will seek to assess the dependence of the above observations (cytokine production, proliferation, anti-tumor effect) on specific common γ-chain cytokines, the role of lymphopenia in inducing T cell trafficking to tumor versus healthy tissue, and guide development of the immunotransplant model to optimize the amplification of anti-tumor immunity for near-term clinical translation. Citation Format: Netonia Marshall, Thomas Marron, Judith Agudo, Brian Brown, Joshua Brody. Immunotransplant: Merging checkpoint blockade and T-cell transfer into lymphodepleted recipients [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B107.