Validation of a PD-1/CD28 chimeric switch receptor to augment CAR-T function in dogs with spontaneous B cell lymphoma

Abstract

Chimeric antigen receptor (CAR) Tcell therapy has achieved unprecedented clinical outcomes in patientswith relapsed/refractory B cell leukemias; however, response rates in patients with large B cell lymphoma (LBCL) are less impressive. Expression of PD-1 on activated Tcells and PD-L1 on malignant, stromal, and immune cells within the tumor microenvironment (TME) contribute to CAR-T exhaustion, hypofunction, and treatment failures. Here, a comparative approach is taken to develop a chimeric switch receptor (CSR) with potential to augment CAR-T persistence, function, and clinical efficacy in immune competent, pet dogs with spontaneous B cell lymphoma (BCL). We show that similar to human CAR-T cells, expression of a PD-1/CD28 CSR in canine CAR-T cells results in enhanced function against PD-L1+ targets and preserves central memory phenotype. We also demonstrate that these effects depend upon active CSR signaling. This work paves the way for invivo studies in canine BCL patients to inform human trial design.