Gamma delta TCR anti-CD3 bispecific molecules (GABs) as novel immunotherapeutic compounds
Van Diest, Eline; Hernández López, Patricia; Meringa, Angelo D.; Vyborova, Anna; Karaiskaki, Froso; Heijhuurs, Sabine; Gumathi Bormin, Jan; Van Dooremalen, Sanne; Nicolasen, Mara J.T.; Gatti, Lucrezia C.D.E.; Johanna, Inez; Straetemans, Trudy; Sebestyén, Zsolt; Beringer, Dennis X.; Kuball, Jürgen
(2021) Journal for ImmunoTherapy of Cancer, volume 9, issue 11, pp. 1 - 15
(Article)
Abstract
Background γ9δ2 T cells hold great promise as cancer therapeutics because of their unique capability of reacting to metabolic changes with tumor cells. However, it has proven very difficult to translate this promise into clinical success. Methods In order to better utilize the tumor reactivity of γ9δ2T cells and combine
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this with the great potential of T cell engager molecules, we developed a novel bispecific molecule by linking the extracellular domains of tumor-reactive γ9δ2TCRs to a CD3-binding moiety, creating gamma delta TCR anti-CD3 bispecific molecules (GABs). GABs were tested in vitro and in vivo for ability to redirect T lymphocytes to a variety of tumor cell lines and primary patient material. Results GABs utilizing naturally occurring high affinity γ9δ2TCRs efficiently induced αβT cell mediated phosphoantigen-dependent recognition of tumor cells. Reactivity was substantially modulated by variations in the Vδ2 CDR3-region and the BTN2A1-binding HV4-region between CDR2 and CDR3 of the γ-chain was crucial for functionality. GABs redirected αβT cells against a broad range of hematopoietic and solid tumor cell lines and primary acute myeloid leukemia. Furthermore, they enhanced infiltration of immune cells in a 3D bone marrow niche and left healthy tissues intact, while eradicating primary multiple myeloma cells. Lastly, GABs constructed from natural high affinity γ9δ2TCR sequences significantly reduced tumor growth in vivo in a subcutaneous myeloma xenograft model. Conclusions We conclude that GABs allow for the introduction of metabolic targeting of cancer cells to the field of T cell engagers.
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Keywords: antigen, Immunotherapy, lymphocyte activation, receptors, T-lymphocytes, translational medical research, Immunotherapy/methods, Humans, Neoplasms/drug therapy, Receptors, Antigen, T-Cell, gamma-delta/metabolism, Molecular Medicine, Oncology, Cancer Research, Immunology and Allergy, Pharmacology, Immunology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 2051-1426
Publisher: BioMed Central Ltd.
Note: Funding Information: Funding We thank the staff of the Flow Core Facility and the Multiplex Core Facility at the UMC Utrecht. We kindly thank Professor Erin Adams (The University of Chicago) for providing the CD277 KO HEK293T cell line and Halvard Boenig (Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt a. M., Germany) for providing feeder cells. Funding for this study was provided by ZonMW 43400003 and VIDI-ZonMW 917.11.337, KWF 2013-6426, 2014-6790 2015-7601, 2018-11393, 2018-11979, 2020-13403 to JK, KWF 2018-11393 2020-13403 to ZS, KWF 11979 and Marie Curie 749010 to DB.
(Peer reviewed)