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

Abstract CD70 is highly expressed in many cancers, including multiple myeloma (MM). We show in two cohorts of patients with MM 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 immunohistochemistry. Moreover, we demonstrate the feasibility of targeting CD70 in myeloma using natural killer (NK) cells engineered with a chimeric antigen receptor (CAR) incorporating the CD70 cognate receptor CD27 and IL-15. CAR27/IL-15 NK cells exerted potent in vitro and in vivo cytotoxicity against CD70+ MM cells, comparable to 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 MM, 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).