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

• Published in: Science translational medicine Vol. 16; no. 749; p. eadg9814
• Main Authors: Fowler, Daniel, Barisa, Marta, Southern, Alba, Nattress, Callum, Hawkins, Elizabeth, Vassalou, Eleni, Kanouta, Angeliki, Counsell, John, Rota, Enrique, Vlckova, Petra, Draper, Benjamin, De Mooij, Tessa, Farkas, Andrea, Brezovjakova, Helena, Baker, Alfie T, Scotlandi, Katia, Manara, Maria C, Tape, Chris, Chester, Kerry, Anderson, John, Fisher, Jonathan
• Format: Journal Article
• Language: English
• Published: United States 29-05-2024
• Subjects: Animals; Bystander Effect; Cell Engineering; Cell Line, Tumor; Cytotoxicity, Immunologic; Humans; Interleukin-15; Mice; Osteosarcoma - immunology; Osteosarcoma - pathology; Osteosarcoma - therapy; Receptors, Antigen, T-Cell, gamma-delta - immunology; Receptors, Antigen, T-Cell, gamma-delta - metabolism; T-Lymphocytes - immunology; Zoledronic Acid - pharmacology
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.adg9814

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.