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

细胞毒性 旁观者效应 免疫疗法 癌症研究 抗原 细胞毒性T细胞 嵌合抗原受体 癌症免疫疗法 T细胞 生物 免疫系统 免疫学 体外 生物化学
作者
Daniel Fowler,Marta Barisa,Alba Southern,Callum Nattress,Elizabeth Hawkins,Eleni Vassalou,Angeliki Kanouta,John R. Counsell,Enrique Miranda,Petra Vlckova,Benjamin Draper,Tessa De Mooij,A.M. Farkas,Helena Brezovjakova,Alfie T. Baker,Katia Scotlandi,Maria Cristina Manara,Christopher J. Tape,Kerry Chester,John Anderson,Jonathan Fisher
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science]
卷期号:16 (749) 被引量:3
标识
DOI:10.1126/scitranslmed.adg9814
摘要

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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