Authors
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 Hirano
Published in
Blood cancer discovery. Pages OF1-OF16. Aug 14, 2026. Epub Aug 14, 2026.
Abstract
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.
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.
PMID:
42599152
Bibliographic data and abstract were imported from PubMed on 14 Aug 2026.
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