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Comparison of IL-2 vs IL-7/IL-15 for the generation of NY-ESO-1-specific T cells

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Abstract

The anti-tumor efficacy of TCR-engineered T cells in vivo depends largely on less-differentiated subsets such as T cells with naïve-like T cell (TN) phenotypes with greater expansion and long-term persistence. To increase these subsets, we compared the generation of New York esophageal squamous cell carcinoma-1 (NY-ESO-1)-specific T cells under supplementation with either IL-2 or IL-7/IL-15. PBMCs were transduced with MS3II-NY-ESO-1-siTCR retroviral vector. T cell generation was adapted from a CD19-specific CART cell production protocol. Comparable results in viability, expansion and transduction efficiency of T cells under stimulation with either IL-2 or IL-7/IL-15 were observed. IL-7/IL-15 led to an increase of CD4+ T cells and a decrease of CD8+ T cells, enriched the amount of TN among CD4+ T cells but not among CD8+ T cells. In a 51Cr release assay, similar specific lysis of NY-ESO-1-positive SW982 sarcoma cells was achieved. However, intracellular cytokine staining revealed a significantly increased production of IFN-γ and TNF-α in T cells generated by IL-2 stimulation. To validate these unexpected findings, NY-ESO-1-specific T cell production was evaluated in another protocol originally established for TCR-engineered T cells. IL-7/IL-15 increased the proportion of TN. However, the absolute number of TN did not increase due to a significantly slower expansion of T cells with IL-7/IL-15. In conclusion, IL-7/IL-15 does not seem to be superior to IL-2 for the generation of NY-ESO-1-specific T cells. This is in sharp contrast to the observations in CD19-specific CART cells. Changes of cytokine cocktails should be carefully evaluated for individual vector systems.

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Abbreviations

51Cr:

Chromium-51

ACD-A:

Anticoagulant citrate dextrose solution

ACT:

Adoptive cell therapy

HDs:

Healthy donors

NY-ESO-1:

New York esophageal squamous cell carcinoma-1

TCM :

Central memory-like T cell(s)

TE :

Effector-like T cell(s)

TEM :

Effector memory-like T cell(s)

Th cells:

T helper cells

TN :

Naïve-like T cell(s)

TSCM :

Stem cell memory T cell(s)

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Funding

This work was funded in part by the Government of Baden-Württemberg (Anschubfinanzierung zur Etablierung eines Netzwerks “Brückeninstitutionen für die Regenerative Medizin in Baden-Württemberg”, Kapitel 1403 Tit.Gr. 74), by the DKTK (Deutsches Konsortium für Translationale Krebsforschung) and by the NCT-HD-CAR-1 Grant from the German Cancer Research Center (DKFZ). Leopold Sellner was supported by the “Physician Scientist-Programm” of the Medical Faculty of Heidelberg, the NCT Heidelberg School of Oncology (HSO) and the “Clinician Scientist Programm” of the German Society of Internal Medicine (DGIM).

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Authors and Affiliations

  1. Cellular Immunotherapy Unit, Department of Internal Medicine V, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Wenjie Gong, Jean-Marc Hoffmann, Sophia Stock, Lei Wang, Yibin Liu, Maria-Luisa Schubert, Brigitte Neuber, Angela Hückelhoven-Krauss, Ulrike Gern, Anita Schmitt, Carsten Müller-Tidow, Michael Schmitt & Leopold Sellner

  2. National Center for Tumor Diseases (NCT), German Cancer Consortium (DKTK), Heidelberg, Germany

    Carsten Müller-Tidow, Michael Schmitt & Leopold Sellner

  3. Department of Immuno-Gene Therapy, Mie University, Tsu, Japan

    Hiroshi Shiku

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  1. Wenjie Gong
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Contributions

WG and LS designed the study; WG, JMH and YL performed experiments; WG and LS analyzed the data and wrote the manuscript; MS edited the manuscript; MS, LW, MLS, WG, SS, BN, AHK, UG and AS discussed the experimental design; CMT and HS read the manuscript and gave comments; HS provided essential materials; all authors reviewed the manuscript.

Corresponding author

Correspondence to Leopold Sellner.

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Conflict of interest

The authors declare that there are no conflicts of interest.

Ethical approval and ethical standards

The research was approved by the Ethics Committee of the University of Heidelberg (S-254/2016). All studies involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent for the use of their blood for research purposes was obtained from all healthy donors by the Blood Bank Heidelberg.

Cell line authentication

The soft-tissue sarcoma cell lines SW982 (HLA-A2-positive NY-ESO-1-positive), SYO-1 (HLA-A2-negative NY-ESO-1-negative), Fuji (HLA-A2-positive NY-ESO-1-negative) and MLS-1765-92 (HLA-A2-negative NY-ESO-1-positive) were provided by Prof. H. Shiku (Mie University, Tsu, Japan). All cell lines were authenticated at DSMZ (German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany).

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Gong, W., Hoffmann, JM., Stock, S. et al. Comparison of IL-2 vs IL-7/IL-15 for the generation of NY-ESO-1-specific T cells. Cancer Immunol Immunother 68, 1195–1209 (2019). https://doi.org/10.1007/s00262-019-02354-4

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