Host conditioning approach and choice of target epitope determine the success of adoptive T cell immunotherapy against oncogene-induced established tumors (P2068)

Abstract

Abstract Host conditioning regimens can dramatically enhance adoptive T cell-based therapies for some cancers. We investigated the unique and combined contributions of whole body irradiation (WBI) and agonist anti-CD40 conditioning to successful adoptive immunotherapy in a mouse model of autochthonous cancer. Line Rip1-Tag4 mice develop pancreatic islet cell tumors due to expression of the SV40 large T antigen oncogene from the rat insulin promoter. Using transfer of T cell receptor transgenic CD8+ T cells specific for two unique determinants in T antigen (designated TCR-I or TCR-IV), we demonstrate that successful control of established tumors in these mice is both regimen- and epitope-dependent. WBI conditioning alone minimally enhanced T cell accumulation and persistence, while anti-CD40 alone transiently enhanced the subdominant TCR-I but not the immunodominant TCR-IV response. Combining anti-CD40 with WBI conditioning enhanced the magnitude and duration of both T cell responses, but only TCR-I cells accumulated and persisted at high levels in the pancreas. Mice that received combined conditioning plus TCR-I transfer had an increased life span, and showed histological signs of anti-tumor immunity. Lack of therapeutic impact by TCR-IV T cells was associated with development of an unusual differentiation phenotype following antigen recognition in vivo. The results indicate that target selection and conditioning regimen dramatically influence the efficacy of adoptive T cell therapy.