Combining the anti-CD20 mAb rituximab with CD19-CAR T cells treated mouse models of lymphoma and leukemia more effectively than either therapy alone. To disrupt CD47 signaling and enhance antibody-dependent phagocytosis, Dacek and Kurtz et al. further modified CAR T cells to secrete the SIRPα variant CV1. These CAR T cells concentrated CV1 at the tumor site and, compared to regular CAR T cells, improved survival in a mixed-antigen (CD19+/-) tumor model, better synergized with rituximab, and reduced macrophage immunosuppression in vitro. CV1-secreting PMEL T cells increased DC activation and macrophage proportion in B16F10 tumors.
Contributed by Alex Najibi
ABSTRACT: 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.
Author Info: (1) Memorial Sloan Kettering, United States. (2) Memorial Sloan Kettering, United States. (3) Memorial Sloan Kettering, United States. (4) Memorial Sloan Kettering. (5) Weill Corne
Author Info: (1) Memorial Sloan Kettering, United States. (2) Memorial Sloan Kettering, United States. (3) Memorial Sloan Kettering, United States. (4) Memorial Sloan Kettering. (5) Weill Cornell Medicine, New York, New York, United States. (6) Memorial Sloan Kettering, United States. (7) Memorial Sloan Kettering Cancer Center, New York, New York, United States. (8) Memorial Sloan Kettering, United States. (9) Memorial Hospital, New York, New York, United States. (10) AstraZeneca, New York, New York, United States. (11) Weill Cornell Medicine, United States.
