Estabelecimento de uma nova terapia antitumoral utilizando parasito transgênico expressando NY-ESO-1 associado ao bloqueio de CTLA-4

Abstract

The development of immunotherapy for cancer has long been a challenge. Although multiple clinical trials have resulted in the development of measurable immune responses only a minority of patients has experienced clinical benefit, such as tumor regression. The use of a transgenic attenuated Trypanosoma cruzi strain (CL-14) as a vaccine vector expressing the cancer testis antigen NY-ESO-1 (CL-14-NY-ESO-1), proposed by our group, was able to prevent tumor growth in a vaccine model. Here we report that CL-14-NY-ESO-1 induces both memory effector and effector CD8+ T lymphocytes that efficiently prevent tumor development. Additionally, the better prognosis correlates with the high production of cytokines IFN- and IL-2 and the presence of greater numbers of specific cells against tumor including cells with cytotoxic profile. However, the therapeutic effect of such vaccine is rather limited. To increase T cell response induced by transgenic parasite we propose, in therapeutic protocol, the blockade of inhibitory signals mediated by Cytotoxic T Lymphocyteassociated Antigen 4 (CTLA-4). The results show the enhanced of the frequency of NY-ESO- 1-specific effector CD8+ T cells producing IFN-, and promote lymphocyte migration to the tumor infiltrate. As a result, therapy with CL-14-NY-ESO-1 associated with anti-CTLA-4 is highly effective in controlling the development of an ongoing melanoma.