John, Chen, and Deng et al. capitalized on the widespread expression of LILRB4 on the M5 subset of AML, including CD34+ leukemic stem cells, and lack of expression on most normal tissues (except for monocytes), to develop a CAR T cell targeting LILRB4. LILRB4 CAR T cells were highly cytotoxic to M5 AML in vitro and in vivo, extending survival in a xenograft model. No effect of the CAR T cells was observed on hematopoietic cell populations in ex vivo human CD34+ hematopoietic colony forming assays or in a human-reconstituted murine model despite in vitro cytotoxicity to primary monocytes.
To effectively improve treatment for acute myeloid leukemia (AML), new molecular targets and therapeutic approaches need to be identified. Chimeric antigen receptor (CAR)-modified T cells targeting tumor-associated antigens have shown promise in the treatment of some malignancies. However, CAR-T cell development for AML has been limited by lack of an antigen with high specificity for AML cells that is not present on normal hematopoietic stem cells, and thus will not result in myelotoxicity. Here we demonstrate that leukocyte immunoglobulin-like receptor-B4 (LILRB4) is a tumor-associated antigen highly expressed on monocytic AML cells. We generated a novel anti-LILRB4 CAR-T cell that displays high antigen affinity and specificity. These CAR-T cells display efficient effector function in vitro and in vivo against LILRB4(+) AML cells. Furthermore, we demonstrate anti-LILRB4 CAR-T cells are not toxic to normal CD34(+) umbilical cord blood cells in colony-forming unit assays, nor in a humanized hematopoietic-reconstituted mouse model. Our data demonstrate that anti-LILRB4 CAR-T cells specifically target monocytic AML cells with no toxicity to normal hematopoietic progenitors. This work thus offers a new treatment strategy to improve outcomes for monocytic AML, with the potential for elimination of leukemic disease while minimizing the risk for on-target off-tumor toxicity.
Author Info: (1) Department of Pediatrics, Pediatric Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (2) Department of Physiology, University of Tex
Author Info: (1) Department of Pediatrics, Pediatric Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (2) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (3) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (4) Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Houston Health Science Center, Houston, TX 77030, USA. (5) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (6) Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (7) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (8) Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Houston Health Science Center, Houston, TX 77030, USA. (9) Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Houston Health Science Center, Houston, TX 77030, USA. Electronic address: zhiqiang.an@uth.tmc.edu. (10) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: alec.zhang@utsouthwestern.edu.
