A novel CD94-targeting CAR T cell therapy for cytotoxic subtypes of T/NK-cell malignancies

作者：C. Le, Jinsheng Weng, Jingwei Liu, Federico Aletti, Xiaoyun Cheng, Yongfu Tang, Sridevi Patchva, Matthew Richard, Maya Balakumaran, Mario L. Marques‐Piubelli, Luisa M. Solis, Wei Lü, Chun‐Yen Lin, Fuliang Chu, Jingjing Cao, Abdur Rehman, Lubna Rehman, Kamini Singh, Owhofasa Agbedia, Sushanth Gouni, Faezeh Darbaniyan, Kumudha Balakrishnan, Neeraj K. Saini, Christopher R. Flowers, Swaminathan P. Iyer, Francisco M. De La Vega, Sattva S. Neelapu · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-2337 · 被引用次数：1 · 研究领域：CAR-T cell therapy research、Immune Cell Function and Interaction、Cutaneous lymphoproliferative disorders research

Abstract Introduction: Chimeric antigen receptor (CAR) T cell therapy targeting pan-B-cell antigens has shown unprecedented efficacy in B-cell malignancies and is clinically tolerable despite the induction of B-cell aplasia as an on-target, off-tumor effect. But targeting pan-T-cell antigens with CAR-T for T-cell lymphomas (TCL) is risky as induction of T-cell aplasia could lead to life-threatening infections and may require rescue with allogeneic stem cell transplantation. To address this challenge, we developed a CAR-T product to target a cell-of-origin antigen in T/NK-cell malignancies. Specifically, we describe a CAR-T product against CD94, a C-type lectin receptor expressed on subsets of normal NK (40-70%), gd (40-60%), and CD8 T cells (<10%), with the goal of targeting T/NK-cell neoplasms arising from these cytotoxic immune cells. Methods and Results: Consistent with its known expression profile, evaluation of 33 normal human tissues by immunohistochemistry (IHC) showed CD94 expression in rare lymphocytes in secondary lymphoid organs but absent in all other cell types and tissues. This result was also supported by scRNAseq data from 25 normal human tissues from the Human Protein Atlas. By contrast, evaluation T/NK-cell lymphomas (N=46) by IHC showed that CD94 is highly expressed in all NK/TCLs (N=15) and hepatosplenic TCLs (N=7) and a few other subtypes such as enteropathy-associated TCL and primary cutaneous CD8+ cytotoxic TCL. CD94 was also found to be high in ...