CAR T Cells Targeting an Intracellular Leukemia Antigen Promiscuously Presented by Diverse HLA-II Alleles

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy excels against B-cell malignancies by targeting surface antigens.
• Limited efficacy in myeloid neoplasms and solid tumors stems from difficulties in identifying suitable surface targets.

Purpose of the Study:

• To develop a CAR T-cell therapy targeting the intracellular Wilms Tumor 1 (WT1) oncoprotein.
• To overcome traditional human leukocyte antigen (HLA) restrictions in CAR T-cell therapy.

Main Methods:

• Generated WT1-specific CAR T cells using an antibody against a WT1 peptide.
• Assessed WT1-CAR T-cell recognition of WT1 peptide presented by various HLA class II (HLA-II) alleles.
• Evaluated WT1-CAR T-cell antitumor activity in vitro and in vivo.

Main Results:

• WT1-CAR T cells recognized the WT1330-348 peptide presented by 18 of 20 tested HLA-II alleles, demonstrating promiscuous binding.
• WT1-CAR T cells specifically targeted leukemic cells in a WT1- and HLA-II-dependent manner.
• Demonstrated in vitro and in vivo antitumor responses mediated by WT1-CAR T cells.

Conclusions:

• Developed a CAR T-cell strategy targeting intracellular antigens via HLA-II cross-presentation.
• Broadened CAR-targetable antigens beyond traditional HLA restrictions.
• Established a framework for CAR therapies against intracellular targets, expanding applications to diverse patient populations and cancer types.