Multicomponente particulates for immune modulation

Conniot, João Miguel de Oliveira, 1989-

http://hdl.handle.net/10451/33135

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Autores

Conniot, João Miguel de Oliveira, 1989-

Orientador(es)

Florindo, Helena Isabel Fialho, 1979-

Brocchini, Steve

Silva, Liana Casquinha da

Resumo(s)

Although immune checkpoint therapy improved the clinical outcomes of melanoma treatment, low response rate, severe side effects, and acquired resistance have been observed in patients. To overcome these limitations, complementary strategies that inhibit tumor immunosuppressive pathways and enhance immunity are urgently needed. We hypothesized that the anticancer activity of the combination of anti-PD-1, for immunosuppression blockade, with the monoclonal anti-OX40 agonist, for T-cell stimulation and expansion, could be improved by cancer vaccination. For this purpose, we designed, synthesized and characterized mannose-grafted poly(lactic coglycolic acid) and poly(lactic acid) (PLGA/PLA) nano-vaccines, containing both melan- A/MART-1 peptides and immune potentiators. These nanoparticle-based vaccines can amplify antitumor immune response by increasing tumor-associated antigen recognition, processing, and presentation to effector T cells. The nanoparticles were shown to have a spherical shape with an average diameter of 170 nm, displaying narrow polydispersity index and near-neutral surface charge. Immunization with these nano-vaccines induced splenocyte activation and antigen specific cytotoxic T-cell activity against melanoma cells ex vivo. Treatment with the combination of the prophylactic nano-vaccines and PD-1/OX40 antibodies in vivo led to maximal tumor growth inhibition, with minimal systemic toxicity. Whereas treatment with anti-PD-1/anti-OX40 alone led to 20% survival 42 days following tumor inoculation, the combination approach with the mannose-PLGA/PLA prophylactic nano-vaccine resulted in 100% survival for the same period. Moreover, the latter presented a survival rate of 50% two months following tumor inoculation and recapitulated a T-cell inflamed tumor microenvironment. On the other hand, the combination of therapeutic mannose-PLGA/PLA nanovaccines with PD-1/OX40 immune checkpoint therapy failed to show benefit in comparison with PD-1/OX40 immune checkpoint in monotherapy. This result seems to be related to infiltration of MDSC into the tumor microenvironment, over time, which may have overcome the effect of CD8+ T cell stimulation, inhibiting T cell infiltration and cytotoxic activity. Altogether, these findings reveal important aspects on the synergism of immune checkpoint targeting with polymeric cancer nano-vaccines, as well as the effect on the modulation of tumor-infiltrating immune cells in melanoma. Therefore, polymeric nanovaccines emerge as a potential strategy to improve clinical outcomes of melanoma treatment.