IMST-48. PRIMING OF HOST T CELL MEMORY IS REQUIRED FOR THE EFFICACY OF ADOPTIVE CELL THERAPY

Abstract

Good clinical outcomes in response to adoptive cellular therapies are correlated with anti-tumor function, intratumoral migration, and persistence of adoptively transferred tumor-specific T cells. Our group has developed a highly efficacious adoptive cell therapy (ACT) against intracranial glioma that meets these criteria. Further evaluation of our adoptive cell therapy platform reveals that ACT also primes host-derived T cells, and our OBJECTIVE is to demonstrate that this phenomenon is required for efficacy of adoptive immunotherapy. We employ bone marrow-derived dendritic cells pulsed with tumor-derived RNA to ex vivo expand tumor-specific T lymphocytes (TTRNA-T cells). These cells are adoptively transferred into tumor bearing mice followed by dendritic cell vaccines. Tumor bearing mice receive lymphodepletive host conditioning and bone marrow rescue prior to adoptive transfer. Adoptive cell therapy with TTRNA-T cells is efficacious in up to 40% intracranial glioma bearing immunocompetent C57BL/6 hosts, but this efficacy is abrogated in both CD4 and CD8 depleted mice. In addition, no efficacy was observed when ACT was administered to tumor-bearing immunodeficient Rag 1-/- mice. In glioma bearing C57BL6 mice that receive ACT, host-derived T cells upregulate a memory phenotype. These host-derived CD8+ cells mount central memory, and CD4+ cells mount both central memory and effector phenotypes. Serial transfer of these host-derived T cells into naïve mice provided protective immunity against a tumor challenge. Secondary transfer of these CD4+ and CD8+ T cells and their progeny into yet another set of naïve mice also provided protective immunity. After primary and secondary serial transfers, these cells expanded in their new hosts, and upregulated both effector and memory phenotypes, indicating self-renewal and multipotency. These data together strongly suggest a role of host immunity in adoptive immunotherapy. Activation of host T cells plays a crucial role in generating effective anti-tumor responses in adoptive immunotherapeutic strategies.