Intratumor adoptive transfer of il-12 MRNA transiently engineered antitumor CD8+ T cells

  1. Etxeberria Uriz, Iñaki
Dirigée par:
  1. Ignacio Melero Bermejo Directeur

Université de défendre: Universidad de Navarra

Fecha de defensa: 04 juin 2020

Jury:
  1. Sandra Hervás Stubbs President
  2. Fernando Pastor Rodríguez Secrétaire
  3. Francisco de Asís Palazón García Rapporteur
  4. Alena Gros Vidal Rapporteur
  5. David Escors Rapporteur
Département:
  1. (FM) Inmunología

Type: Thèses

Teseo: 152259 DIALNET

Résumé

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.