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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Acknowledgements

We would like to acknowledge Y. Iragashi and A. Rookard for technical assistance with in vivo experiments and the MSKCC Molecular Cytogenetics Core and NIH Cancer Center support grant P30 CA008748 for karyotyping of the ID8 and SKOV3 cells. The authors thank the following for financial support: US National Institutes of Health grants 5 P01 CA190174-03 and 5 P50 CA192937-02 (R.J.B.), The Annual Terry Fox Run for Cancer Research organized by the Canada Club of New York (R.J.B.), Kate's Team (R.J.B.), Carson Family Charitable Trust (R.J.B.), the Leukemia & Lymphoma Society Specialized Center of Research Program (7014) (R.J.B.), William Lawrence and Blanche Hughes Foundation (R.J.B.), the ARD Foundation (R.J.B.), and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center (Innovations in the structures, functions and targets of monoclonal antibody-based drugs for cancer) (R.J.B.).

Author information

Author notes

    • Sarwish Rafiq
    • , Oladapo O Yeku
    •  & Hollie J Jackson

    These authors contributed equally to this work.

Affiliations

  1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Sarwish Rafiq
    • , Oladapo O Yeku
    • , Hollie J Jackson
    • , Terence J Purdon
    • , Dayenne G van Leeuwen
    •  & Renier J Brentjens
  2. Cellular Therapeutics Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Sarwish Rafiq
    •  & Renier J Brentjens
  3. Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.

    • Dylan J Drakes
    •  & Renier J Brentjens
  4. Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA.

    • Mei Song
    •  & Xiaojing Ma
  5. Proteomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Matthew M Miele
    • , Zhuoning Li
    •  & Ronald C Hendrickson
  6. Eureka Therapeutics Inc., Emeryville, California, USA.

    • Pei Wang
    • , Su Yan
    • , Jingyi Xiang
    •  & Cheng Liu
  7. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Venkatraman E Seshan
  8. Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Ronald C Hendrickson

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Contributions

S.R., O.O.Y., H.J.J. and R.J.B. designed the experiments, interpreted the results and wrote the manuscript. T.J.P., D.G.v.L., D.J.D., M.S., M.M.M., Z.L., P.W., S.Y. J.X. X.M., R.C.H. and C.L. designed, performed and/or analyzed the experiments. V.E.S. performed the statistical analysis.

Competing interests

R.J.B. is a co-founder and receives royalties from Juno Therapeutics. R.J.B., S.R., H.J.J., O.Y. and C.L. have submitted a patent related to this work.

Corresponding author

Correspondence to Renier J Brentjens.

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DOI

https://doi.org/10.1038/nbt.4195

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