A novel preclinical immunocompetent CAR T cell mouse model for solid tumors

Abstract

Abstract Chimeric antigen receptor (CAR) T cells therapies have made substantial progress in treating blood cancers in humans. However, CAR T therapies currently have several limitations, including the lack of a persistent anti-tumor memory population to limit relapse and poor efficacy against solid tumors. Many studies on CAR T therapies have used immunocompromised xenograft mouse models, limiting the translational impact of the results. Furthermore, mouse models have largely focused on cancers in the blood while neglecting solid tumors. To improve the relevance of preclinical studies of CAR T cell therapy and to understand the mechanisms underlying some of the current CAR T therapy limitations, we have created a novel immunocompetent mouse model. This model consists of three components: murine CD8 T cells expressing the human CD19 CAR, syngeneic murine tumor cell lines expressing a truncated human CD19 (CD19t) serving as the tumor antigen, and an immunocompetent mouse tolerized to human CD19t and the CD19 CAR. Our results demonstrate that the CD19 CAR T cells can efficiently target the CD19t-expressing tumor lines. Furthermore, tolerized recipient mice do not reject implanted syngeneic CD19t-expressing tumors or adoptively transferred CD19 CAR-expressing T cells. This model now provides a platform to study the in vivo biology of CAR T cells with respect to localization, exhaustion, and functional reinvigoration; to investigate best approaches to treating multiple solid tumors with distinct microenvironments; and to test the preclinical efficacy of novel CAR T strategies.