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 the antibody had an additive effect in xenograft models, and this effect was potentiated by CAR T-cell local CV1 secretion. Furthermore, OrexiCAR-secreted CV1 reversed the 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 monotherapy.

Automated summary

Chimeric antigen receptor (CAR) T-cell therapy combined with local CD47 blockade and an orthogonal antibody may be a promising combinatorial strategy to enhance the effectiveness of hematopoietic malignancy treatment. In this study, Orexi CAR T cells were engineered to secrete a high-affinity CD47 blocker, CV1, at the tumor site, leading to an additive effect in xenograft models when combined with an orthogonally targeted monoclonal antibody. Furthermore, the local secretion of CV1 reversed the immunosuppression of myelomonocytoid cells in both in vitro and tumor microenvironment settings.