Abstract Text: Acute myeloid leukemia (AML) is an heterogeneous malignancy with scarce treatment options in the relapsed or refractory (R/R) setting. CART cells have revolutionized the treatment of R/R multiple myeloma and B-cell malignancies; however, none has yet been approved for AML. CD84 (SLAMF5) is a member of the SLAM family of cell-surface immunoreceptors. Here, we validate the CD84 antigen as a novel target for AML and present a first-in-class CD84-directed CART cell (CART84) for AML. Patient primary AML blasts were analyzed by flow cytometry: while CD84 was overexpressed on their surface in the majority of AML cases, both de novo and at relapse, its expression was very low in CD34+ healthy hematopoietic stem/progenitor cells (HSPC). Moreover, healthy human tissues were analyzed by immunohistochemistry and CD84 expression was not found in the lung, liver, kidney, myocardium, skin, or brain, except in tissue monocytes/macrophages. We engineered second-generation CART cells with murine or fully human single chain variable fragments (scFv) and 4-1BB as a co-stimulatory domain (anti-CD84scFv-CD8αTM-4-1BB-CD3). CART84 exerted high cytotoxicity in vitro towards AML cells even at low effector:target ratios. In terms of safety, CART84 displayed a very low cytotoxic effect towards CD34+ HSPC, suggesting that CART84 may be less myelotoxic than other CART cells in AML. CART84 eliminated AML cells in vivo in a NSG mouse model using both AML cell lines and a patient-derived-xenograft (PDX). In summary, these results validate CD84 as a potential target for AML CART-cell therapy and support the therapeutic use of CART84 for R/R AML patients.
Learning Objectives:
CD84 can be used as a surface tumor associated antigen that can be targeted by specific immunotherapy.
CAR-T anti-CD84 can eliminate tumor cells of acute myeloid leukemia.
Different antibodies against CD84 show different functionality when they are used as scFV in a CAR.
.jpg "Manel Juan, MD, PhD photo")
