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Etxeberria, Iñaki; Bolaños, Elixabet; Quetglas, Jose I.; Gros, Alena; Villanueva, Alberto; Palomero, Jara; Sánchez-Paulete, Alfonso R.; Piulats, Jose María; Matias-Guiu, Xavier; Olivera, Irene; Ochoa, Maria C.; Labiano, Sara; Garasa, Saray; Rodriguez, Inmaculada; Vidal, August; Mancheño, Uxua; Hervás-Stubbs, Sandra; Azpilikueta, Arantza; Otano, Itziar; Aznar, M. Angela; Sanmamed, Miguel F.; Inogés, Susana; Berraondo, Pedro; Teijeira, Álvaro; Melero, Ignacio
Cancer cell, 12/2019, Letnik: 36, Številka: 6Journal Article
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. Display omitted •mRNA electroporation engineers T cells to transiently produce single-chain IL-12•IL-12-engineered T cells injected intratumorally reject local and distant tumors•Co-injection of anti-CD137 mAb or co-electroporation of CD137L enhances efficacy•IL-12-engineered TIL cultures successfully treat autologous engrafted tumors Etxeberria et al. engineer tumor-specific CD8+ T cells that transiently express IL-12 to mitigate toxicity and show that intratumoral injection of these engineered T cells in conjunction with local CD137 co-stimulation leads to epitope spreading and regression of injected and distant lesions in solid tumor models.
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