Estudios de orientación terapéutica sobre la biología de la estimulación de cd137 y la transferencia génica de interleukina-15

Resumen

There is an ongoing explosion of knowledge in immunological sciences following the discovery of many agents that have the potential to serve as immunotherapeutic drugs. These agents include interleukin-15 (IL-15) and agonistic anti-CD137 monoclonal antibodies (mAbs). In animal models, both IL-15 and anti-CD137 mAbs have been shown to promote powerful anti-tumor responses capable of clearing established tumors, and they hold great expectations for cancer therapy in humans. However, for a rational design of treatments with these agents a fully understanding of the mechanisms behind their anti-tumor effects is needed. The driving force of the studies presented in this thesis has been the discovery of mechanistic aspects of IL-15 and anti-CD137 mAbs that could be suitable to improve cancer immunotherapy with these agents. In particular, our work has focused in three crucial points, to study: 1) the feasibility and mechanisms pertaining therapy of myeloma with anti-CD137 mAbs, 2) the mechanisms of antigen presentation underlying immunotherapy with anti-CD137 mAbs, and 3) the effects of hydrodynamically-delivered IL-15 on NK cells and IKDCS, two immune cell subsets involved in tumor surveillance. This study demonstrates that anti-CD137 mAb treatment shows benefit in various murine myeloma models and provides important clues on the involvement of CD8+ T lymphocytes and NK cells in the therapeutic immune response. In addition, our work provides evidence for an involvement of DC in the augmentation of anti-tumor CTL immunity by agonist anti-CD137 mAbs; however the presence of DC is not absolutely required for the therapeutic effects of this anti-tumoral agent. Finally, this thesis proves the concept that liver gene transfer in mice provides a source of IL-15 that thereby impacts the biology of IKDCS and NK cells up-regulating both their numbers and their cytolytic function.