Gamma delta TCR anti-CD3 bispecific molecules (GABs) as novel immunotherapeutic compounds

Eline Van Diest, Patricia Hernández López, Angelo D. Meringa, Anna Vyborova, Froso Karaiskaki, Sabine Heijhuurs, Jan Gumathi Bormin, Sanne Van Dooremalen, Mara J.T. Nicolasen, Lucrezia C.D.E. Gatti, Inez Johanna, Trudy Straetemans, Zsolt Sebestyén, Dennis X. Beringer, Jürgen Kuball

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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 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.
Original languageEnglish
Article numbere003850
Pages (from-to)1-15
JournalJournal for ImmunoTherapy of Cancer
Volume9
Issue number11
DOIs
Publication statusPublished - 23 Nov 2021

Keywords

  • antigen
  • Immunotherapy
  • lymphocyte activation
  • receptors
  • T-lymphocytes
  • translational medical research
  • Immunotherapy/methods
  • Humans
  • Neoplasms/drug therapy
  • Receptors, Antigen, T-Cell, gamma-delta/metabolism

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