Potentiating antibody-dependent killing of cancers with CAR T cells secreting CD47-SIRPα checkpoint blocker.

Chimeric antigen receptor (CAR) T cell therapy has shown success in the treatment of hematopoietic malignancies; however, relapse remains a significant issue. To overcome this, we engineered "Orexi" CAR T cells to locally secrete a high affinity CD47-blocker, CV1, at the tumor, and treated tumors in combination with an orthogonally targeted monoclonal antibody. Traditional CAR T cells plus antibody were additive in effect in xenograft models and this effect was potentiated by CAR T cell local CV1 secretion. Furthermore, OrexiCAR-secreted CV1 reversed immunosuppression of myelomonocytoid cells, both in vitro and within the tumor microenvironment. Local secretion of the CD47 inhibitor bypasses the CD47 sink found on all cells in the body and may prevent systemic toxicities. This combination of CAR T cell therapy, local CD47 blockade, and orthogonal antibody may be a combinatorial strategy to overcome the limitations of each individual monotherapy.