CAR T Cells Targeting an Intracellular Leukemia Antigen Promiscuously Presented by Diverse HLA-II Alleles
Evey Y.F. Zheng, Chung-Hsi Wang, Toshiki Ochi, Yota Ohashi, Fumie Ihara, Saori Fukao, Yusuke Ito, Giselle M. Boukhaled, Ben X. Wang, Dong-Hoon Han, Xinyu Wei, Priyanka Yolmo, Brian D. Burt, Kayoko Saso, Yukiko Matsunaga, Dalam Ly, Yuki Kagoya, Marcus O. Butler, Mark D. Minden, Naoto HiranoAbstract
Chimeric antigen receptor (CAR) technology has revolutionized B-cell malignancy treatment by enabling T cells to effectively recognize and target lineage-specific surface antigens. However, CAR T cells show limited efficacy against myeloid neoplasms and solid tumors due to challenges in identifying suitable surface targets. In this study, we present a CAR targeting the intracellular WT1 oncoprotein, cross-presented by surface HLA class II (HLA-II) alleles. WT1-CAR T cells, derived from an antibody raised solely against a WT1 peptide, recognized the WT1330–348 peptide promiscuously presented by 18 out of 20 tested HLA-II alleles, overcoming traditional HLA restrictions. WT1-CAR T cells specifically recognized leukemic cells in a WT1- and HLA-II–dependent manner and mediated an antitumor response in vitro and in vivo. This approach broadens CAR-targetable antigens beyond traditional HLA restrictions and offers a promising therapeutic option to a wide and genetically diverse patient population.
Significance:
Leveraging the promiscuous binding of HLA-II–peptide complexes, we developed a CAR T-cell approach targeting an intracellular oncoprotein WT1 presented across diverse HLA-II families. Our study establishes a framework for CAR therapies against intracellular antigens, extending potential CAR T-cell applications to new cancer types and patient populations.