The goal of our studies is to generate durable CD8+ T cell responses against epithelial ovarian cancer (EOC) for extending remission rates. However, major obstacles to the development of effective immunotherapy exist including (i) inability to induce expansion of high avidity, tumor-antigen specific effector CD8+ T cells (ii) lack of tumor-antigen specific memory CD8+ T cells, and (iii) presence of CD4+CD25+FOXP3+ regulatory T cells. In previous studies, we have observed that although vaccine induced tumor antigen specific effector CD8+ T cells can provide tumor protection, they do not provide durable tumor immunity, which is typically afforded by memory T cells. We have also noted that rapamycin mediated inhibition of mammalian target of rapamycin (mTOR) switches effector CD8+ T cells to memory via regulation of transcriptional factors T-bet and Eomesodermin. Moreover, in our murine model, varying the duration (0-8, 0-20 or 0-40 days) of mTOR inhibition after immunization produces memory CD8+ T cells with varying extent of type 1 effector functions. Consequently, we hypothesize that by changing the regimen (dose and duration) of rapamycin administration in immunized ovarian cancer patients, we will generate high avidity CD8+ T cells with varying extent of effector functions for durable ovarian tumor immunity. Therefore, our objectives are to determine the regimen of mTOR inhibition, that in combination with viral vector immunization does not produce toxicity but generates optimal durable CD8+ T cell responses in a phase I clinical trial. Second, by varying the timing of rapamycin administration, we will determine the mechanisms by which mTOR inhibition produces functionally distinct memory CD8+ T cells of high avidity. To test our hypotheses, we propose: SA1: To determine the regimen (dose and duration) of mTOR inhibition that in combination with rCNP-NY-ESO-1/TRICOM immunization is safe and produces durable CD8+ T cell responses in a phase I clinical trial. SA2: To test whether the regimen of rapamycin administration after rCNP-NY-ESO-1/TRICOM immunization generates memory CD8+ T cells with varying extent of effector functions and antigen avidity. SA3: To determine the impact of rapamycin treatment regime on rCNP-NY-ESO-1/TRICOM induced CD4+ T cell response for CD8+ T cell memory generation. The successful completion of our proposed studies will result in the generation of critical data that will facilitate Phase II evaluation of mTOR inhibition to generate high avidity memory T cells, promote conditions that favor durable host immunity, and prolong disease free survival in ovarian cancer patients.
There is increasing evidence that the immune system has the ability to recognize and kill ovarian and other human cancers. However, attempts at using cancer vaccines to engage the immune system to fight cancer cells have been disappointing because of (i) inability to generate long lasting immune responses (ii) suppression of immune cells by a specialized population of cells called regulatory T cells. In this study proposed, we plan to test a multi-modal approach of immunizing ovarian cancer patients by (i) using a viral based vaccine expressing three specialized molecules (TRICOM) to enhance immune reaction to NY-ESO-1 antigen, that is frequently expressed in ovarian cancers (ii) rapamycin to promote generation of memory immune cells that persist for a long time and thereby prevent relapse of ovarian cancer.
|Daudi, Sayeema; Eng, Kevin H; Mhawech-Fauceglia, Paulette et al. (2014) Expression and immune responses to MAGE antigens predict survival in epithelial ovarian cancer. PLoS One 9:e104099|
|Liao, Jianqun; Qian, Feng; Tchabo, Nana et al. (2014) Ovarian cancer spheroid cells with stem cell-like properties contribute to tumor generation, metastasis and chemotherapy resistance through hypoxia-resistant metabolism. PLoS One 9:e84941|
|Odunsi, Kunle; Matsuzaki, Junko; James, Smitha R et al. (2014) Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer. Cancer Immunol Res 2:37-49|
|Matsuzaki, Junko; Tsuji, Takemasa; Luescher, Immanuel et al. (2014) Nonclassical antigen-processing pathways are required for MHC class II-restricted direct tumor recognition by NY-ESO-1-specific CD4(+) T cells. Cancer Immunol Res 2:341-50|
|Godoy, Heidi E; Khan, A Nazmul H; Vethanayagam, R Robert et al. (2013) Myeloid-derived suppressor cells modulate immune responses independently of NADPH oxidase in the ovarian tumor microenvironment in mice. PLoS One 8:e69631|