Human double negative T cells target lung cancer via ligand-dependent mechanisms that can be enhanced by IL-15

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Abstract

Background

The advents of novel immunotherapies have revolutionized the treatment of cancer. Adoptive cellular therapies using chimeric antigen receptor T (CAR-T) cells have achieved remarkable clinical responses in B cell leukemia and lymphoma but the effect on solid tumors including lung cancer is limited. Here we present data on the therapeutic potential of allogeneic CD3 ⁺CD4 ⁻CD8 ⁻ double negative T (DNT) cells as a new cellular therapy for the treatment of lung cancer and underlying mechanisms.

Methods

DNTs were enriched and expanded ex vivo from healthy donors and phenotyped by flow cytometry. Functionally, their cytotoxicity was determined against primary and established non-small-cell lung cancer (NSCLC) cell lines in vitro or through in vivo adoptive transfer into xenograft models. Mechanistic analysis was performed using blocking antibodies against various cell surface and soluble markers. Furthermore, the role of IL-15 on DNT function was determined.

Results

We demonstrated that ex vivo expanded DNTs can effectively lyse various human NSCLC cells in vitro and inhibit tumor growth in xenograft models. Expanded DNTs have a cytotoxic phenotype, as they express NKp30, NKG2D, DNAM-1, membrane TRAIL (mTRAIL), perforin and granzyme B, and secrete IFNγ and soluble TRAIL (sTRAIL). DNT-mediated cytotoxicity was dependent on a combination of tumor-expressed ligands for NKG2D, DNAM-1, NKp30 and/or receptors for TRAIL, which differ among different NSCLC cell lines. Furthermore, stimulation of DNTs with IL-15 increased expression of effector molecules on DNTs, their TRAIL production and cytotoxicity against NSCLC in vitro and in vivo.

Conclusion

Healthy donor-derived DNTs can target NSCLC in vitro and in vivo . DNTs recognize tumors via innate receptors which can be up-regulated by IL-15. DNTs have the potential to be used as a novel adoptive cell therapy for lung cancer either alone or in combination with IL-15.

Electronic supplementary material

The online version of this article (10.1186/s40425-019-0507-2) contains supplementary material, which is available to authorized users.

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Most cited references 33

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Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer.

Kevin Conlon, Enrico Lugli, Hugh C. Welles … (2015)

Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy.

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Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity.

Prasad Adusumilli, Leonid Cherkassky, Jonathan Villena-Vargas … (2014)

Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intrapleurally administered CAR T cells vastly outperformed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. After intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced antitumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4(+) T cell activation associated with a higher intratumoral CD4/CD8 cell ratios and CD28-dependent CD4(+) T cell-mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor, did not achieve comparable activation, tumor eradication, or persistence. The ability of intrapleurally administered T cells to circulate and persist supports the concept of delivering optimal CAR T cell therapy through "regional distribution centers." On the basis of these results, we are opening a phase 1 clinical trial to evaluate the safety of intrapleural administration of mesothelin-targeted CAR T cells in patients with primary or secondary pleural malignancies.

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Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial.

Johan Vansteenkiste, Byoung Cho, Tonu Vanakesa … (2016)

Fewer than half of the patients with completely resected non-small-cell lung cancer (NSCLC) are cured. Since the introduction of adjuvant chemotherapy in 2004, no substantial progress has been made in adjuvant treatment. We aimed to assess the efficacy of the MAGE-A3 cancer immunotherapeutic in surgically resected NSCLC.

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Author and article information

Contributors

Li Zhang: 416-581-7521 , lzhang@uhnresearch.ca

Journal

Journal ID (nlm-ta): J Immunother Cancer

Journal ID (iso-abbrev): J Immunother Cancer

Title: Journal for Immunotherapy of Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 2051-1426

Publication date (Electronic): 22 January 2019

Publication date PMC-release: 22 January 2019

Publication date Collection: 2019

Volume: 7

Electronic Location Identifier: 17

Affiliations

[1 ]ISNI 0000 0004 0474 0428, GRID grid.231844.8, Toronto General Hospital Research Institute, , University Health Network, ; Toronto, Ontario Canada

[2 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Immunology, , University of Toronto, ; Toronto, Ontario Canada

[3 ]ISNI 0000 0004 0474 0428, GRID grid.231844.8, Princess Margaret Cancer Centre, , University Health Network, ; Toronto, Ontario Canada

[4 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Sir Run Run Shaw Hospital, College of Medicine, , Zhejiang University, ; Hangzhou, China

[5 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Laboratory Medicine and Pathobiology, , University of Toronto, ; Toronto, Ontario Canada

[6 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Present address: Sir Run Run Shaw Hospital, College of Medicine, , Zhejiang University, ; Hangzhou, China

[7 ]ISNI 0000 0004 0473 9881, GRID grid.416166.2, Present address: Department of Systems Biology, Mount Sinai Hospital, ; Toronto, Ontario Canada

[8 ]University Health Network, Princess Margaret Cancer Research Tower, 101 College St. Rm 2-807, Toronto, Ontario M5G 1L7 Canada

Article

Publisher ID: 507

DOI: 10.1186/s40425-019-0507-2

PMC ID: 6343266

PubMed ID: 30670085

SO-VID: 8c8df098-a77b-49cd-9129-55e5f6fd16c7

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 23 July 2018

Date accepted : 13 January 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;

Funded by: Ontario Research Fund Research Excellence (ORF-RE)

Award ID: RE-03-020

Award Recipient : Ming-Sound Tsao

Custom metadata

Keywords: adoptive cellular therapy,double negative t cells,lung cancer,il-15

Data availability:

Keywords: adoptive cellular therapy, double negative t cells, lung cancer, il-15

Human double negative T cells target lung cancer via ligand-dependent mechanisms that can be enhanced by IL-15

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Most cited references 33

Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer.

Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity.

Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial.

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