OPS-γδ: allogeneic opsonin-secreting γδT cell immunotherapy for solid tumours mediates direct and bystander immunity

Abstract

AbstractT cell-based cancer immunotherapy has typically relied on membrane-bound cytotoxicity enhancers such as chimeric antigen receptors expressed in autologous αβT cells. These approaches are limited by tonic signalling of synthetic constructs and costs associated with manufacture of bespoke patient products. γδT cells are an emerging alternative chassis for cellular therapy, possessing innate anti-tumour activity, potent antibody-dependent cytotoxicity (ADCC) and minimal alloreactivity. We present an immunotherapeutic platform technology built around the Vγ9Vδ2 γδT cell chassis, harnessing specific characteristics of this cell type and offering an allo-compatible means of delivering cellular therapy that recruits bystander immunity. We engineered γδT cells to secrete synthetic opsonins and stabilized IL15 (stIL15). Using GD2 as a model antigen we show how opsonin-secreting Vγ9Vδ2 (OPS-γδ) have enhanced cytotoxicity and also confer this benefit on lymphoid and myeloid bystander cells. Reflecting the secreted nature of the engineered efficacy modules, the entire product rather than just the gene-modified fraction exhibited enhanced activation and cytotoxic profiles, superior persistence and proliferative capacity even upon repeated tumour challenge. Secretion of stIL15 abrogated the need for exogenous cytokine supplementation during expansion and further mediated functional licensing of bystander NK cells. Compared to unmodified γδT cells, stIL15-OPS-γδ cells exhibited superiorin-vivocontrol of subcutaneous tumour and persistence in the blood. stIL15-OPS-γδ cells were further efficacious in 3D patient-derived osteosarcoma models, where efficacy could be boosted with the addition of immunomodulatory aminobisphosphonate drug, zoledronic acid. Together the data identify stIL15-OPS-γδ cells as a novel allogeneic platform combining direct cytolysis with bystander activation to effect solid tumour control.One Sentence SummaryArmoured, opsonin-secreting OPS-γδ cell immunotherapy is built on the innate strengths of the Vγ9Vδ2 cell chassis for allogeneic solid tumour targeting.