TEGs: T cells Engineered to express a high affinity Gamma delta (γδ) TCR for metabolic targeting of refractory hematological malignancies
Guido Kierkels1*, Trudy Straetemans1*, Sabine Heijhuurs1, Cordula Gründer1, Koen Jansen1, Ruud Doorn1, Tineke Aarts-Riemens1, Zsolt Sebestyen1, and Jürgen Kuball1
1Department of Hematology and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
*contributed equally to the study
Background: γδT cells are an essential part of daily cancer immune surveillance by sensing cancer mediated metabolic changes through defined γδT cell receptors (TCRs). This metabolic immune surveillance does not depend on classical antigen presentation, making these innate-like receptors valuable additions to current treatment strategies. However, γδT cells have failed so far in clinical trials, most likely due to their rapid exhaustion and large diversity. Therefore we propose to generate the next generation of genetically engineered immune cells using the highly proliferative αβT cells as carriers for defined highly tumor reactive γδTCRs.
Results: γ9δ2T cells were isolated from healthy donor PBMCs, cloned by limiting dilution and tested against a broad panel of hematological tumor cell lines and primary leukemic blasts. High variability in tumor cell recognition and functional avidity was observed between the individual γ9δ2T cell clones. The individual γ9δ2TCRs were isolated and expressed in αβT cells and again functionally analyzed, which confirmed that tumor reactivity and functional avidity were mediated by the individual γ9δ2TCRs. One particular γ9δ2TCR, isolated from “clone 5”, showed a high and broad tumor specific recognition and has been selected as the candidate for clinical testing (TEG001).
Conclusions: TEGs are a promising addition to the currently available immune therapeutic strategies as they target cancer as a metabolic disorder. TEG001 will be evaluated in a phase I open label dose escalation study to assess the safety of γ9δ2TCR transduced αβT cells in patients with primary refractory or relapsed acute myeloid leukemia as well as in patients with multiple myeloma.
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