Engineering T cells to prevent graft-versus-host disease and leukemia relapse following allogeneic stem cell transplantation

Abstract

Abstract Acute graft-versus-host disease (aGvHD) and leukemia relapse remain major causes of mortality after allogeneic hematopoietic stem cell transplantation (alloHSCT). Prophylaxis and treatment of aGvHD rely on generalized immunosuppression, increasing the risk of tumor relapse and opportunistic infections and emphasizing the need for more targeted therapies. Alloreactive donor CD4+ T cells play a central role in aGvHD pathogenesis, we thus hypothesized that elimination of activated CD4+ T cells with engineered T cells would mitigate aGvHD while preserving protective CD8+ T cell immunity post alloHSCT. We developed an alloimmune defense receptor (ADR) targeting OX40, a surface marker predominantly upregulated on activated CD4+ T cells. OX40 ADR-expressing T cells eliminated activated CD4+ T cells during coculture but spared the majority of activated CD8+ T cells, including virus-specific T cells, and had no discernible activity against resting lymphocytes. A single infusion of ADR T cells fully protected mice from fatal xenogeneic aGvHD induced by intravenous injection of human PBMC, minimizing signs of aGvHD and maximizing survival. To enable simultaneous activity of engineered T cells against aGvHD and leukemia relapse, we further armed ADR T cells with a CD19-directed chimeric antigen receptor (CAR). In a mouse model of residual leukemia post alloHSCT, administration of T cells co-expressing OX40 ADR and CD19 CAR mediated dual protection against tumor relapse and aGvHD. These results support the feasibility of a bi-functional CAR.ADR T cell product to improve outcomes post alloHSCT and reduce transplant-related mortality. Supported by grant from Leukemia & Lymphoma Society.