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Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice.

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Affiliations

  • 1. Department of Oncology, University Hospital Zurich, Zurich, Switzerland.
      Authors
    • Gulati P 1, 2
    • Pircher M 1
    • Schuberth P 1
    • Winder T 1
    • Samaras P 1
    • Stupp R 1
    • Petrausch U 1, 2
    (7 authors)
  • 2. Institute for Experimental Immunology, University of Zurich, Zurich, Switzerland.
      Authors
    • Gulati P 1, 2
    • Rühl J 2
    • Münz C 2
    • Petrausch U 1, 2
    (4 authors)
  • 3. Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
      Authors
    • Kannan A 3
    (1 author)
  • 4. Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland.
      Authors
    • Nytko KJ 4
    • Pruschy M 4
    (2 authors)
  • 5. Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland.
      Authors
    • Sulser S 5
    (1 author)
    • Show all (13)

ORCIDs linked to this article

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Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 10 May 2018, 24(16):3981-3993
https://doi.org/10.1158/1078-0432.ccr-17-1788 PMID: 29748183 

Abstract 

Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed.Experimental Design: Fibroblast activation protein (FAP)-specific CARs with different costimulatory domains, including CD28, Δ-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the Δ-CD28 CAR was tested clinically in a patient with MPM.Results: All the three CARs demonstrated FAP-specific functionality in vitro Gene expression data indicated a distinct activity profile for the Δ-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the Δ-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the Δ-CD28 CAR could be detected for up to 21 days and showed functionality.Conclusions: Overall, anti-FAP-Δ-CD28/CD3ζ CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981-93. ©2018 AACR.

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Read article at publisher's site: https://doi.org/10.1158/1078-0432.ccr-17-1788

Read article for free, from open access legal sources, via Unpaywall: https://clincancerres.aacrjournals.org/content/clincanres/24/16/3981.full.pdfUnpaywall

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Funding 

Funders who supported this work.

Swiss Cancer League (1)

University of Zurich (1)