Novel T cell–based therapies for the treatment of B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), are thought to have strong potential. Progress, however, has been hampered by low efficacy and high toxicity. Tumor targeting by V9V2 T cells, a conserved T-cell subset with potent intrinsic antitumor properties, mediated by a bispecific antibody represents a novel approach promising high efficacy with limited toxicity. Here, we describe the generation of a bis pecific V9V2 T-cell engager directed against CD40, which, due to its overexpression and biological footprint in malignant B cells, represents an attractive target. The CD40-targeting moiety of the bispecific antibody was selected because it can prevent CD40L-induced prosurvival signaling and reduce CD40-mediated resistance of CLL cells to venetoclax. Selective activation of V9V2 T cells in the presence of CD40+ tumor cells induced potent V9V2 T-cell degranulation, cytotoxicity against CLL and MM cells in vitro, and in vivo control of MM in a xenograft model. The CD40-bispecific T-cell engager demonstrated lysis of leukemic cells by autologous V9V2 T cells present in patient-derived samples. Taken together, our CD40 bispecific T-cell engager increased the sensitivity of leukemic cells to apoptosis and induced a potent V9V2 T cell–dependent antileukemic response. It may, therefore, represent a potential candidate for the development of novel treatments for B-cell malignancies.
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