Article ; Online: Potentiating antibody-dependent killing of cancers with CAR T cells secreting CD47-SIRPα checkpoint blocker.
2023 Volume 141, Issue 16, Page(s) 2003–2015
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 ... ...
| 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 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. |
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| MeSH term(s) | Humans ; CD47 Antigen ; Neoplasm Recurrence, Local ; Neoplasms/pathology ; T-Lymphocytes ; Immunotherapy, Adoptive ; Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal/pharmacology ; Tumor Microenvironment | ||||||||||
| Chemical Substances | CD47 Antigen ; Antibodies, Monoclonal ; CD47 protein, human | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2023-01-10 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article | ||||||||||
| ZDB-ID | 80069-7 | ||||||||||
| ISSN | 1528-0020 ; 0006-4971 | ||||||||||
| ISSN (online) | 1528-0020 | ||||||||||
| ISSN | 0006-4971 | ||||||||||
| DOI | 10.1182/blood.2022016101 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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