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. 2024 May 29;16(749):eadg9814.
doi: 10.1126/scitranslmed.adg9814. Epub 2024 May 29.

Payload-delivering engineered γδ T cells display enhanced cytotoxicity, persistence, and efficacy in preclinical models of osteosarcoma

Daniel Fowler  1 , Marta Barisa  1 , Alba Southern  1 , Callum Nattress  2 , Elizabeth Hawkins  1 , Eleni Vassalou  1 , Angeliki Kanouta  1 , John Counsell, Enrique Rota  2 , Petra Vlckova  2 , Benjamin Draper  1 , Tessa De Mooij  1 , Andrea Farkas  1 , Helena Brezovjakova  1 , Alfie T Baker  1 , Katia Scotlandi  3 , Maria C Manara  3 , Chris Tape  2 , Kerry Chester  2 , John Anderson  1 , Jonathan Fisher  1
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Payload-delivering engineered γδ T cells display enhanced cytotoxicity, persistence, and efficacy in preclinical models of osteosarcoma

Daniel Fowler et al. Sci Transl Med. .

Abstract

T cell-based cancer immunotherapy has typically relied on membrane-bound cytotoxicity enhancers such as chimeric antigen receptors expressed in autologous αβ T cells. These approaches are limited by tonic signaling of synthetic constructs and costs associated with manufacturing. γδ T cells are an emerging alternative for cellular therapy, having innate antitumor activity, potent antibody-dependent cellular cytotoxicity, and minimal alloreactivity. We present an immunotherapeutic platform technology built around the innate properties of the Vγ9Vδ2 T cell, harnessing specific characteristics of this cell type and offering an allocompatible cellular therapy that recruits bystander immunity. We engineered γδ T cells to secrete synthetic tumor-targeting opsonins in the form of an scFv-Fc fusion protein and a mitogenic IL-15Rα-IL-15 fusion protein (stIL15). Using GD2 as a model antigen, we show that GD2-specific opsonin-secreting Vγ9Vδ2 T cells (stIL15-OPS-γδ T cells) have enhanced cytotoxicity and promote bystander activity of other lymphoid and myeloid cells. Secretion of stIL-15 abrogated the need for exogenous cytokine supplementation and further mediated activation of bystander natural killer cells. Compared with unmodified γδ T cells, stIL15-OPS-γδ T cells exhibited superior in vivo control of subcutaneous tumors and persistence in the blood. Moreover, stIL15-OPS-γδ T cells were efficacious against patient-derived osteosarcomas in animal models and in vitro, where efficacy could be boosted with the addition of zoledronic acid. Together, the data identify stIL15-OPS-γδ T cells as a candidate allogeneic cell therapy platform combining direct cytolysis with bystander activation to promote tumor control.

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