RT Journal Article
SR Electronic
T1 A Bispecific Antibody Antagonizes Prosurvival CD40 Signaling and Promotes Vγ9Vδ2 T cell–Mediated Antitumor Responses in Human B-cell Malignancies
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 50
OP 61
DO 10.1158/2326-6066.CIR-20-0138
VO 9
IS 1
A1 de Weerdt, Iris
A1 Lameris, Roeland
A1 Scheffer, George L.
A1 Vree, Jana
A1 de Boer, Renate
A1 Stam, Anita G.
A1 van de Ven, Rieneke
A1 Levin, Mark-David
A1 Pals, Steven T.
A1 Roovers, Rob C.
A1 Parren, Paul W.H.I.
A1 de Gruijl, Tanja D.
A1 Kater, Arnon P.
A1 van der Vliet, Hans J.
YR 2021
UL http://cancerimmunolres.aacrjournals.org/content/9/1/50.abstract
AB 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 Vγ9Vδ2 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 bispecific Vγ9Vδ2 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 Vγ9Vδ2 T cells in the presence of CD40+ tumor cells induced potent Vγ9Vδ2 T-cell degranulation, cytotoxicity against CLL and MM cells in vitro, and in vivo control of MM in a xenograft model. The CD40-bispecific γδ T-cell engager demonstrated lysis of leukemic cells by autologous Vγ9Vδ2 T cells present in patient-derived samples. Taken together, our CD40 bispecific γδ T-cell engager increased the sensitivity of leukemic cells to apoptosis and induced a potent Vγ9Vδ2 T cell–dependent antileukemic response. It may, therefore, represent a potential candidate for the development of novel treatments for B-cell malignancies.