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Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo
Open accessAbstract
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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“Moreover, modified CAR-T cells, which secret PD-1-blocking single-chain variable fragments (scFv), had improved antitumor activity by an autocrine and paracrine manner [345].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [345]
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Metadata
- 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
- Venue
- Nature Biotechnology
- Published
- 2018-08-13
- Volume
- 36
- Issue
- 9
- Pages
- 847-856
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- 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
- 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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