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Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo.

TitleTargeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo.
Publication TypeJournal Article
Year of Publication2018
AuthorsRafiq S, Yeku OO, Jackson HJ, Purdon TJ, van Leeuwen DG, Drakes DJ, Song M, Miele MM, Li Z, Wang P, Yan S, Xiang J, Ma X, Seshan VE, Hendrickson RC, Liu C, Brentjens RJ
JournalNat Biotechnol
Volume36
Issue9
Pagination847-856
Date Published2018 10
ISSN1546-1696
KeywordsAnimals, Humans, Mice, Programmed Cell Death 1 Receptor, Receptors, Chimeric Antigen, Single-Chain Antibodies, T-Lymphocytes, Tumor Microenvironment, Xenograft Model Antitumor Assays
Abstract

The efficacy of chimeric antigen receptor (CAR) T cell therapy against poorly responding tumors can be enhanced by administering the cells in combination with immune checkpoint blockade inhibitors. Alternatively, the CAR construct has been engineered to coexpress factors that boost CAR-T cell function in the tumor microenvironment. We modified CAR-T cells to secrete PD-1-blocking single-chain variable fragments (scFv). These scFv-secreting CAR-T cells acted in both a paracrine and autocrine manner to improve the anti-tumor activity of CAR-T cells and bystander tumor-specific T cells in clinically relevant syngeneic and xenogeneic mouse models of PD-L1 hematologic and solid tumors. The efficacy was similar to or better than that achieved by combination therapy with CAR-T cells and a checkpoint inhibitor. This approach may improve safety, as the secreted scFvs remained localized to the tumor, protecting CAR-T cells from PD-1 inhibition, which could potentially avoid toxicities associated with systemic checkpoint inhibition.

DOI10.1038/nbt.4195
Alternate JournalNat Biotechnol
PubMed ID30102295
PubMed Central IDPMC6126939
Grant ListP01 CA190174 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
P50 CA192937 / CA / NCI NIH HHS / United States

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