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

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          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.

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          Author and article information

          Journal
          Cancer Cell
          Cancer cell
          Elsevier BV
          1878-3686
          1535-6108
          Dec 09 2019
          : 36
          : 6
          Affiliations
          [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.
          Article
          S1535-6108(19)30480-5
          10.1016/j.ccell.2019.10.006
          31761658
          c101101c-42ac-4b47-b64f-431ceca153eb
          History

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

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