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

By S. Rafiq, O. Yeku, H. J. Jackson, Terence J. Purdon, Dayenne G van Leeuwen, Dylan J Drakes, Mei Song, Matthew M. Miele, Zhuoning Li, Pei Wang and 7 more. Nature Biotechnology, 2018

723 citations recorded by the source corpus.

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.

Subfields: Electrical and Electronic Engineering, Oncology

View Paper: https://www.semanticscholar.org/paper/de48ec6472462110dde1fcc23347fe69e5151147

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In Oncology

1. Christopher S. Hackett
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Citations in the corpus

• Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, background): “CAR T cells have also been engineered to counter the actions of adenosine in the TME, which can activate adenosine receptor A 2A and thereby inhibit T cell function, through expression of a small-peptide disrupter of the interaction between the A 2A - activated kinases PKA and ezrin 173 , siRNA sile”
• Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022, background): “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].”
• CAR-NK cells: A promising cellular immunotherapy for cancer (2020, background): “[106] Recent reports have shown that local secretion of anti-PD1 antibodies [107] or scFv [108] at the tumour site by engineered CAR-T cells achieved superior anti-tumour activity and reduced adverse effect compared with systemic therapy.”
• CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment (2019, methodology): “A similar study also used MUC16-ecto targeting CARs secreting anti-PD-1 scFvs in syngeneic and xenograft mouse models of PD-L1metastatic ovarian cancers, and showed superiority over CAR T cells plus PD-1 checkpoint inhibitors (134).”