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

TitlePotentiating antibody-dependent killing of cancers with CAR T cells secreting CD47-SIRPα checkpoint blocker.
Publication TypeJournal Article
Year of Publication2023
AuthorsDacek MM, Kurtz K, Wallisch P, Pierre SA, Khayat SShiraz, Bourne CM, Gardner TJ, Vogt KC, Aquino N, Younes A, Scheinberg DA
JournalBlood
Date Published2023 Jan 25
ISSN1528-0020
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.

DOI10.1182/blood.2022016101
Alternate JournalBlood
PubMed ID36696633

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