TY - JOUR
T1 - A Bispecific Antibody Antagonizes Prosurvival CD40 Signaling and Promotes Vγ9Vδ2 T cell-Mediated Antitumor Responses in Human B-cell Malignancies
AU - de Weerdt, Iris
AU - Lameris, Roeland
AU - Scheffer, George L
AU - Vree, Jana
AU - de Boer, Renate
AU - Stam, Anita G
AU - van de Ven, Rieneke
AU - Levin, Mark-David
AU - Pals, Steven T
AU - Roovers, Rob C
AU - Parren, Paul W H I
AU - de Gruijl, Tanja D
AU - Kater, Arnon P
AU - van der Vliet, Hans J
N1 - Funding Information:
I. de Weerdt reports grants from Lava Therapeutics during the conduct of the study, as well as a patent for novel CD40-binding antibodies (WO2020/159368) pending, issued, and licensed to Lava Therapeutics. R. Lameris reports grants from Lava Therapeutics during the conduct of the study, as well as grants from Lava Therapeutics outside the submitted work. G.L. Scheffer reports a grant from Lava Therapeutics and a patent for novel CD40-binding antibodies (WO2020/159368) pending and licensed to Lava Therapeutics. J. Vree reports grants from Lava Therapeutics during the conduct of the study. M.-D. Levin reports other from AbbVie (travel grant), Janssen (travel grant), and Roche (travel grant) outside the
Publisher Copyright:
© 2021 American Association for Cancer Research Inc.. All rights reserved.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - 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 Vg9Vd2 T cells in the presence of CD40
+ tumor cells induced potent Vg9Vd2 T-cell degranulation, cytotoxicity against CLL and MM cells in vitro, and in vivo control of MM in a xenograft model. The CD40-bispecific gd T-cell engager demonstrated lysis of leukemic cells by autologous Vγ9Vδ2 T cells present in patient-derived samples. Taken together, our CD40 bispecific gd 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.
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 Vg9Vd2 T cells in the presence of CD40
+ tumor cells induced potent Vg9Vd2 T-cell degranulation, cytotoxicity against CLL and MM cells in vitro, and in vivo control of MM in a xenograft model. The CD40-bispecific gd T-cell engager demonstrated lysis of leukemic cells by autologous Vγ9Vδ2 T cells present in patient-derived samples. Taken together, our CD40 bispecific gd 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.
UR - http://www.scopus.com/inward/record.url?scp=85100416648&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-20-0138
DO - 10.1158/2326-6066.CIR-20-0138
M3 - Article
C2 - 33177109
VL - 9
SP - 50
EP - 61
JO - Cancer Immunology Research
JF - Cancer Immunology Research
SN - 2326-6066
IS - 1
ER -