Nuevas estrategias y aplicaciones en el tratamiento de modelos tumorales de ratón con anticuerpos monoclonales agonistas de cd137

Resumen

This thesis comprises three independent articles describing new findings in the biology of anti-CD137 monoclonal antibodies and its use for tumor immunotherapy. In the first part we test the synergistic effects of anti-CD13 mAbs and IFN- α. CD137 artificial co-stimulation results in complete tumor rejection in several mouse models. Type I interferons exert antitumor effects through an array of molecular functions on malignant cells, tumor stroma and immune system cells. Agonist anti-CD137 mAb induce tumor regressions in mice deficient in the receptor for type I IFNs (IFNAR-/-) indicating potential for treatment combinations. Intratumoral injections of mouse IFN-α and intraperitoneal injections of anti-CD137 mAb synergized in the treatment of subcutaneous lesions derived from the MC38 colon carcinoma, which is resistant to each treatment if given separately. In the second study, the encapsulation of antibody-producing hybridoma cells has been tested as an alternative for administration of monoclonal immunostimulatory antibodies. Hybridomas producing anti-CD137 and anti-OX40 mAb were encapsulated in alginate to generate microcapsules containing viable cells that secrete antibody, which pharmacokinetic profile was similar to that attained following an intraperitoneal administration of the purified antibodies. The antitumor therapeutic activity was studied on established transplanted CT26 colon carcinomas resulting in complete tumor eradication in an elevated fraction of cases with either anti-CD137 or anti-OX40 producing hybridomas. Previous reports indicated that CD137 stimulation induces polyclonal infiltrates of T lymphocytes in the liver. The third study characterizes the liver infiltrates, the target-dependency of the phenomena and addresses if tumors nested in the liver are a more favourable target for CD137-based immunotherapy. Mice implanted with MC38 colon carcinomas either subcutaneously or inside the liver were used for comparative studies under treatment with agonist anti-CD137 mAbs. These experiments showed that in spite of the tumor-independent accumulation of T cells in the liver, immunotherapeutic effects are not more prominent against tumors located in this organ.