Peptide-Specific CAR T cells Recognize WT1 Promiscuously Presented by Diverse HLA Class II Alleles
Peptide-Specific CAR T cells Recognize WT1 Promiscuously Presented by Diverse HLA Class II Alleles
Wang, C.-H.; Zheng, E. Y. F.; Ochi, T.; Ohashi, Y.; Ihara, F.; Fukao, S.; Boukhaled, G. M.; Wang, B. X.; Han, D.-H.; Wei, X.; Burt, B. D.; Saso, K.; Matsunaga, Y.; Ly, D.; Kagoya, Y.; Butler, M. O.; Minden, M.; Hirano, N.
AbstractChimeric antigen receptor (CAR) technology has revolutionized the treatment of B-cell malignancies by enabling T cells to effectively target cancer-specific surface antigens. However, efficiency against other hematological cancers and solid tumors is limited by the scarcity of suitable surface targets. Here, we present a novel CAR strategy that targets intracellular oncoproteins cross-presented by diverse HLA-class-II (HLA-II) alleles. Exemplified by targeting the intracellular Wilms\' tumor 1 (WT1) oncoprotein, we developed a WT1 specific CAR, engineered from an antibody specific for HLA-II presented WT1. These WT1-CAR T cells promiscuously recognized WT1330-348 presented by 18 out of 20 tested HLA-II alleles, thereby overcoming traditional HLA restrictions. WT1-CAR specifically recognized leukemic cells in a WT1- and HLA-II-dependent manner and mediated robust antitumor responses in vitro and in vivo. This innovative approach to CAR T cell development transcends traditional HLA restrictions and offers a promising therapeutic option for a wide and genetically diverse patient population.