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Cancer Cell. 2019 Dec 9;36(6):613-629.e7. doi: 10.1016/j.ccell.2019.10.006. Epub 2019 Nov 21.

Intratumor Adoptive Transfer of IL-12 mRNA Transiently Engineered Antitumor CD8+ T Cells.

Author information

1
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Avenida de Pio XII, 55, 31008 Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
2
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Avenida de Pio XII, 55, 31008 Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain.
3
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Avenida de Pio XII, 55, 31008 Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain.
4
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Vall d'Hebron Institute of Oncology (V.H.I.O.), Barcelona, Spain.
5
Program against Cancer Therapeutic Resistance (ProCURE), IDIBELL, Catalan Institute of Oncology, L'hospitalet del Llobregat, Barcelona, Spain.
6
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Program against Cancer Therapeutic Resistance (ProCURE), IDIBELL, Catalan Institute of Oncology, L'hospitalet del Llobregat, Barcelona, Spain; Department of Medical Oncology, IDIBELL, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.
7
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Department of Pathology Hospital Universitari Arnau de Vilanova, University of Lleida, IRB-Lleida, Lleida, Spain; Department of Pathology, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain.
8
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Department of Pathology, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain.
9
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Avenida de Pio XII, 55, 31008 Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
10
Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain.
11
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Avenida de Pio XII, 55, 31008 Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, Pamplona, Spain; Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain. Electronic address: imelero@unav.es.

Abstract

Retroviral gene transfer of interleukin-12 (IL-12) into T cells markedly enhances antitumor efficacy upon adoptive transfer but has clinically shown unacceptable severe side effects. To overcome the toxicity, we engineered tumor-specific CD8+ T cells to transiently express IL-12. Engineered T cells injected intratumorally, but not intravenously, led to complete rejections not only of the injected lesion but also of distant concomitant tumors. Efficacy was further enhanced by co-injection with agonist anti-CD137 mAb or by transient co-expression of CD137 ligand. This treatment induced epitope spreading of the endogenous CD8+ T cell immune response in a manner dependent on cDC1 dendritic cells. Mouse and human tumor-infiltrating T lymphocyte cultures can be transiently IL-12 engineered to attain marked immunotherapeutic effects.

KEYWORDS:

CD137; IL-12; TILs; adoptive T cell therapy; cancer immunotherapy; epitope spreading; intratumor delivery; mRNA T cell engineering; monoclonal antibody

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