Cited by 833CAR-T cell therapy researchCancer Immunotherapy and BiomarkersImmunotherapy and Immune Responses

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

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Rafiq, Sarwish, Yeku, Oladapo O, Jackson, Hollie J, Purdon, Terence J, van Leeuwen, Dayenne G, Drakes, Dylan J, Song, Mei, Miele, Matthew M, Li, Zhuoning, Wang, Pei, Yan, Su, Xiang, Jingyi, Ma, Xiaojing, Seshan, Venkatraman E, Hendrickson, Ronald C, Liu, Cheng, Brentjens, Renier J·2018·Nature Biotechnology

DOI 10.1038/nbt.4195PMC PMC6126939

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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.

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Authors: Rafiq, S., Yeku, O. O., Jackson, H. J., Purdon, T. J., van Leeuwen, D. G., Drakes, D. J., Song, M., Miele, M. M., Li, Z., Wang, P., Yan, S., Xiang, J., Ma, X., Seshan, V. E., Hendrickson, R. C., Liu, C., & Brentjens, R. J.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Cornell University (US)
Weill Cornell Medicine (US)
Eureka Therapeutics (United States) (US)
Corresponding author: Brentjens, Renier J
ORCID: Rafiq, Sarwish
Yeku, Oladapo O
Purdon, Terence J
van Leeuwen, Dayenne G
Drakes, Dylan J
Song, Mei
Miele, Matthew M
Li, Zhuoning
Yan, Su
Xiang, Jingyi
Ma, Xiaojing
Seshan, Venkatraman E
Hendrickson, Ronald C
Brentjens, Renier J
Venue: Nature Biotechnology
Publisher: Springer Science and Business Media LLC
Published: 2018-08-13
Volume: 36
Issue: 9
Pages: 847-856
ISSN: 0733-222X (ISSN-L)
1087-0156
1546-1696
DOI: 10.1038/nbt.4195
PMC: PMC6126939
OpenAlex: W2886131798
Cited by: 833
References: 46
Citations by year: 2026: 78 · 2025: 94 · 2024: 91 · 2023: 114 · 2022: 123 · 2021: 121 · 2020: 122 · 2019: 72 · 2018: 14
FWCI: 31.01
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Biotechnology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (1s10od010598-01)
National Cancer Institute (P01CA190174, P50CA192937, P30CA008748)
Topics: Health Sciences › Medicine › Oncology › CAR-T cell therapy research
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: chimeric antigen receptor T cells, anti-PD-1 therapy, scFv, chimeric antigen receptor, immune checkpoint blockade, PD-L1, paracrine signaling, autocrine signaling, bystander T cells, tumor microenvironment, hematologic malignancies, solid tumors, CAR T cell safety
MeSH terms: Receptors, Chimeric Antigen, Animals, Humans, T-Lymphocytes, Xenograft Model Antitumor Assays, Mice, Single-Chain Antibodies, Tumor Microenvironment, Programmed Cell Death 1 Receptor

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

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