CD70-Targeting CAR NK Cells Overcome BCMA Downregulation and Improve Survival in High-risk Multiple Myeloma Models.

CD70 is highly expressed in many cancers, including multiple myeloma. We show in two cohorts of patients with multiple myeloma that CD70 is elevated in several high-risk disease categories and correlates with poor survival. These findings were validated using single-cell RNA sequencing, flow cytometry, and IHC. Moreover, we demonstrate the feasibility of targeting CD70 in myeloma using NK cells engineered with a chimeric antigen receptor (CAR) incorporating the CD70 cognate receptor CD27 and IL-15 (CAR27/IL-15). CAR27/IL-15 NK cells exerted potent in vitro and in vivo cytotoxicity against CD70+ multiple myeloma cells, comparable with CAR27/IL-15 T cells, and remained effective in BCMA knockout models. Collectively, these results establish CD70 as a promising therapeutic target for high-risk multiple myeloma, particularly for patients who relapse after BCMA-directed therapy, providing preclinical support for the ongoing phase I/II clinical trial of CD70-targeting CAR NK cells (NCT05092451). SIGNIFICANCE: We demonstrate that CD70 expression is elevated in patients with high-risk multiple myeloma and in patients with t(4;14) translocation. CD70-targeting CAR NK cells exhibit potent cytotoxicity against CD70+ multiple myeloma cells and significantly improve survival in xenograft mouse models of multiple myeloma, even in the absence of BCMA expression. See related commentary by Benson Jr and Caligiuri, p. 166.