Potentiating antibody-dependent killing of cancers with CAR T cells secreting CD47-SIRPα checkpoint blocker Journal Article
| Authors: | Dacek, M. M.; Kurtz, K. G.; Wallisch, P.; Pierre, S. A.; Khayat, S.; Bourne, C. M.; Gardner, T. J.; Vogt, K. C.; Aquino, N.; Younes, A.; Scheinberg, D. A. |
| Article Title: | Potentiating antibody-dependent killing of cancers with CAR T cells secreting CD47-SIRPα checkpoint blocker |
| 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. © 2023 The American Society of Hematology |
| Keywords: | controlled study; unclassified drug; nonhuman; rituximab; neoplasm; neoplasms; t lymphocyte; t-lymphocytes; mouse; cancer immunotherapy; neoplasm recurrence, local; dendritic cell; animal experiment; animal model; in vivo study; antineoplastic activity; in vitro study; pathology; monoclonal antibody; antibodies, monoclonal; tumor recurrence; cell activation; adoptive immunotherapy; immunotherapy, adoptive; cd19 antigen; antibody production; cell killing; nuclear reprogramming; tumor microenvironment; cd47 antigen; humans; human; article; raji cell line; chimeric antigen receptor t-cell immunotherapy; additive effect; cell therapy agent; m2 macrophage; cv1 monoclonal antibody; cd47 protein, human |
| Journal Title: | Blood |
| Volume: | 141 |
| Issue: | 16 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2023-04-20 |
| Start Page: | 2003 |
| End Page: | 2015 |
| Language: | English |
| DOI: | 10.1182/blood.2022016101 |
| PUBMED: | 36696633 |
| PROVIDER: | scopus |
| PMCID: | PMC10163312 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is David Scheinberg -- Export Date: 1 May 2023 -- Source: Scopus |
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