Dual-antigen targeted iPSC-derived chimeric antigen receptor-T cell therapy for refractory lymphoma

Abstract We generated dual-antigen receptor (DR) T cells from induced pluripotent stem cells (iPSC) to mitigate tumor antigen escape. These cells were engineered to express a chimeric antigen receptor (CAR) for the antigen cell surface latent membrane protein 1 (LMP1; LMP1-CAR) and a T cell receptor directed to cell surface latent membrane protein 2 (LMP2), in association with human leucocyte antigen A24, to treat therapy-refractory Epstein-Barr virus-associated lymphomas. We introduced LMP1-CAR into iPSC derived from LMP2-specific cytotoxic T lymphocytes (CTL) to generate rejuvenated CTL (rejT) active against LMP1 and LMP2, or DRrejT. All DRrejT-treated mice survived >100d. Furthermore, DRrejT rejected follow-up inocula of lymphoma cells, demonstrating that DRrejT persisted long-term. We also demonstrated that DRrejT targeting CD19 and LMP2 antigens exhibited a robust tumor suppressive effect and conferred a clear survival advantage. Co-operative antitumor effect and in vivo persistence, with unlimited availability of DRrejT therapy, will provide powerful and sustainable T cell immunotherapy.