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Engineering Cancer Antigen-Specific T Cells to Overcome the Immunosuppressive Effects of TGF-β

Jonathan D. Silk, Rachel J. M. Abbott, Katherine J. Adams, Alan D. Bennett, Sara Brett, Terri V. Cornforth, Katherine L. Crossland, David J. Figueroa, Junping Jing, Caitriona O’Connor, Annette Pachnio, Lea Patasic, Carlos E. Peredo, Adriano Quattrini, Laura L. Quinn, Alistair G. Rust, Manoj Saini, Joseph P. Sanderson, Dylan Steiner, Barbara Tavano, Preetha Viswanathan, Guy E. Wiedermann, Ryan Wong, Bent K. Jakobsen, Cedrik M. Britten, Andrew B. Gerry and Joanna E. Brewer
J Immunol January 1, 2022, 208 (1) 169-180; DOI: https://doi.org/10.4049/jimmunol.2001357
Jonathan D. Silk
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Rachel J. M. Abbott
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Katherine J. Adams
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Alan D. Bennett
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Sara Brett
†Oncology Research and Development, GlaxoSmithKline, Stevenage Herts, United Kingdom; and
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Terri V. Cornforth
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Katherine L. Crossland
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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David J. Figueroa
†Oncology Research and Development, GlaxoSmithKline, Stevenage Herts, United Kingdom; and
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Junping Jing
†Oncology Research and Development, GlaxoSmithKline, Stevenage Herts, United Kingdom; and
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Caitriona O’Connor
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Annette Pachnio
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Lea Patasic
†Oncology Research and Development, GlaxoSmithKline, Stevenage Herts, United Kingdom; and
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Carlos E. Peredo
‡Cell and Gene Therapy Product Development and Supply, Analytical Development, GlaxoSmithKline, Collegeville, PA
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  • ORCID record for Carlos E. Peredo
Adriano Quattrini
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Laura L. Quinn
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Alistair G. Rust
†Oncology Research and Development, GlaxoSmithKline, Stevenage Herts, United Kingdom; and
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Manoj Saini
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Joseph P. Sanderson
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Dylan Steiner
†Oncology Research and Development, GlaxoSmithKline, Stevenage Herts, United Kingdom; and
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Barbara Tavano
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Preetha Viswanathan
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Guy E. Wiedermann
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Ryan Wong
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Bent K. Jakobsen
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Cedrik M. Britten
†Oncology Research and Development, GlaxoSmithKline, Stevenage Herts, United Kingdom; and
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Andrew B. Gerry
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Joanna E. Brewer
*Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
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Key Points

  • Active TGF-β is present in many cancer indications.

  • dnTGFβRII can be coexpressed in T cells with engineered TCRs.

  • dnTGFβRII–expressing T cells are resistant to inhibition by TGF-β.

Abstract

Adoptive T cell therapy with T cells expressing affinity-enhanced TCRs has shown promising results in phase 1/2 clinical trials for solid and hematological tumors. However, depth and durability of responses to adoptive T cell therapy can suffer from an inhibitory tumor microenvironment. A common immune-suppressive agent is TGF-β, which is secreted by tumor cells and cells recruited to the tumor. We investigated whether human T cells could be engineered to be resistant to inhibition by TGF-β. Truncating the intracellular signaling domain from TGF-β receptor (TGFβR) II produces a dominant-negative receptor (dnTGFβRII) that dimerizes with endogenous TGFβRI to form a receptor that can bind TGF-β but cannot signal. We previously generated specific peptide enhanced affinity receptor TCRs recognizing the HLA-A*02–restricted peptides New York esophageal squamous cell carcinoma 1 (NY-ESO-1)157–165/l-Ag family member-1A (TCR: GSK3377794, formerly NY-ESO-1c259) and melanoma Ag gene A10254–262 (TCR: ADP-A2M10, formerly melanoma Ag gene A10c796). In this article, we show that exogenous TGF-β inhibited in vitro proliferation and effector functions of human T cells expressing these first-generation high-affinity TCRs, whereas inhibition was reduced or abolished in the case of second-generation TCRs coexpressed with dnTGFβRII (e.g., GSK3845097). TGF-β isoforms and a panel of TGF-β–associated genes are overexpressed in a range of cancer indications in which NY-ESO-1 is commonly expressed, particularly in synovial sarcoma. As an example, immunohistochemistry/RNAscope identified TGF-β–positive cells close to T cells in tumor nests and stroma, which had low frequencies of cells expressing IFN-γ in a non–small cell lung cancer setting. Coexpression of dnTGFβRII may therefore improve the efficacy of TCR-transduced T cells.

This article is featured in Top Reads, p.

Footnotes

  • This work was supported by Adaptimmune and GlaxoSmithKline.

  • A.D.B. conceived the project. J.D.S., K.J.A., T.V.C., K.L.C., J.J., C.O., D.J.F., A.P., L.P., C.E.P., L.L.Q., A.G.R., M.S., D.S., B.T., G.E.W., and R.W. performed experiments. A.D.B., A.Q., and P.V. provided key reagents. J.D.S., R.J.M.A., K.J.A., A.D.B., S.B., T.V.C., K.L.C., C.O., D.J.F., A.P., L.L.Q., M.S., J.P.S., B.T., G.E.W., R.W., B.K.J., C.M.B., A.B.G., and J.E.B. contributed to the conception and design of the studies. J.D.S., R.J.M.A., and S.B. prepared the manuscript. A.D.B., J.P.S., C.M.B., A.B.G., J.E.B., and K.L.C. provided critical review.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    ACT
    adoptive T cell therapy
    AUC
    area under the curve
    CTS
    Cell Therapy Systems
    3D
    three-dimensional
    dnTGFβRII
    dominant-negative TGF-β receptor II
    FPKM
    fragments per kilobase million
    GZMB
    granzyme B
    IHC
    immunohistochemistry
    ISH
    in situ hybridization
    LAGE
    l-Ag-family member
    LUAD
    lung adenocarcinoma
    MAGE
    melanoma Ag gene
    MFI
    median fluorescence intensity
    NSCLC
    non–small cell lung cancer
    NTD
    nontransduced
    NY-ESO-1
    New York esophageal squamous cell carcinoma 1
    PD-L1
    programmed death-ligand 1
    PPIB
    peptidylprolyl isomerase B
    rhIL-2
    recombinant human IL-2
    SARC
    synovial sarcoma
    SMAD
    similar to mothers against decapentaplegic
    TCGA
    The Cancer Genome Atlas
    TGFβR
    TGF-β receptor
    TNFR
    TNF receptor
    Treg
    regulatory T cell
    Vβ
    β-chain V region

  • Received December 2, 2020.
  • Accepted October 20, 2021.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (1)
The Journal of Immunology
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1 Jan 2022
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Engineering Cancer Antigen-Specific T Cells to Overcome the Immunosuppressive Effects of TGF-β
Jonathan D. Silk, Rachel J. M. Abbott, Katherine J. Adams, Alan D. Bennett, Sara Brett, Terri V. Cornforth, Katherine L. Crossland, David J. Figueroa, Junping Jing, Caitriona O’Connor, Annette Pachnio, Lea Patasic, Carlos E. Peredo, Adriano Quattrini, Laura L. Quinn, Alistair G. Rust, Manoj Saini, Joseph P. Sanderson, Dylan Steiner, Barbara Tavano, Preetha Viswanathan, Guy E. Wiedermann, Ryan Wong, Bent K. Jakobsen, Cedrik M. Britten, Andrew B. Gerry, Joanna E. Brewer
The Journal of Immunology January 1, 2022, 208 (1) 169-180; DOI: 10.4049/jimmunol.2001357

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Engineering Cancer Antigen-Specific T Cells to Overcome the Immunosuppressive Effects of TGF-β
Jonathan D. Silk, Rachel J. M. Abbott, Katherine J. Adams, Alan D. Bennett, Sara Brett, Terri V. Cornforth, Katherine L. Crossland, David J. Figueroa, Junping Jing, Caitriona O’Connor, Annette Pachnio, Lea Patasic, Carlos E. Peredo, Adriano Quattrini, Laura L. Quinn, Alistair G. Rust, Manoj Saini, Joseph P. Sanderson, Dylan Steiner, Barbara Tavano, Preetha Viswanathan, Guy E. Wiedermann, Ryan Wong, Bent K. Jakobsen, Cedrik M. Britten, Andrew B. Gerry, Joanna E. Brewer
The Journal of Immunology January 1, 2022, 208 (1) 169-180; DOI: 10.4049/jimmunol.2001357
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