- [IMMUNOLOGY AND IMMUNOTHERAPY]
- [COMBINATION STRATEGIES FOR TRANSLATIONAL IMMUNOTHERAPY]
- [ADOPTIVE CELLULAR THERAPY]
Intratumor Adoptive Transfer of IL-12 mRNA Transiently Engineered Antitumor CD8 + T Cells
Iñaki Etxeberria, Elixabet Bolaños, Jose I Quetglas, Alena Gros, Alberto Villanueva, Jara Palomero, Alfonso R Sánchez-Paulete, Jose María Piulats, Xavier Matias-Guiu, Irene Olivera, Maria C Ochoa, Sara Labiano, Saray Garasa, Inmaculada Rodriguez, August Vidal, Uxua Mancheño, Sandra Hervás-Stubbs, Arantza Azpilikueta, Itziar Otano, M Angela Aznar, Miguel F Sanmamed, Susana Inogés, Pedro Berraondo, Álvaro Teijeira, Ignacio Melero
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.