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Published May 15, 2024 | Version v1
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Payload-delivering engineered γδ T cells display enhanced cytotoxicity, persistence, and efficacy in preclinical models of osteosarcoma

Authors/Creators

  • 1. University College London
  • 2. Istituto Ortopedico Rizzoli

Description

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, possessing innate anti-tumor 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 allo-compatible 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-15Ra–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 to 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.

Notes

Funding provided by: Academy of Medical Sciences
Crossref Funder Registry ID: https://ror.org/00c489v88
Award Number: SGL024\1022

Funding provided by: Great Ormond Street Hospital
Crossref Funder Registry ID: https://ror.org/00zn2c847
Award Number: VS0119

Funding provided by: National Institute for Health Research
Crossref Funder Registry ID: https://ror.org/0187kwz08
Award Number:

Funding provided by: UCL Technology Fund*
Crossref Funder Registry ID:
Award Number: UTF- 20-006/Fisher/UCL

Funding provided by: Children's Cancer and Leukaemia Group
Crossref Funder Registry ID: https://ror.org/057h5sf90
Award Number: CCLGA 2021 14 Fisher

Funding provided by: CRUK City of London Centre
Award Number: C7893/A26233

Funding provided by: UCL Technology Fund*
Crossref Funder Registry ID:
Award Number: UTF2- 22-002/Fisher/UCL

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