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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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Additional file 3 of Contextual reprogramming of CAR-T cells for treatment of HER2+ cancers
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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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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