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

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.
Article Title: Targeted delivery of a PD-1-blocking scFV by CAR-T cells enhances anti-tumor efficacy in vivo
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. © 2018, Nature Publishing Group. All rights reserved.
Keywords: cytology; tumors; combination therapy; t-cells; tumor microenvironment; antigen receptors; targeted delivery; anti-tumor efficacy; single chain variable fragments; anti-tumor activities; autocrine manners
Journal Title: Nature Biotechnology
Volume: 36
Issue: 9
ISSN: 1087-0156
Publisher: Nature Publishing Group  
Date Published: 2018-09-01
Start Page: 847
End Page: 856
Language: English
DOI: 10.1038/nbt.4195
PROVIDER: scopus
PMCID: PMC6126939
PUBMED: 30102295
Notes: Article -- Export Date: 1 October 2018 -- Source: Scopus
Citation Impact
MSK Authors
  1. Venkatraman Ennapadam Seshan
    365 Seshan
  2. Renier J Brentjens
    281 Brentjens
  3. Hollie Jaine Pegram
    19 Pegram
  4. Sarwish Rafiq
    15 Rafiq
  5. Terence John Purdon
    60 Purdon
  6. Oladapo Olumoroti Yeku
    16 Yeku
  7. Matthew M Miele
    11 Miele
  8. Zhuoning Li
    8 Li