The long range goal of our studies is to generate durable CD8+ T cell responses against epithelial ovarian cancer (EOC) for extending remission rates. We have demonstrated a role for the immunoregulatory enzyme, indoleamine 2,3 dioxygenase (IDO) in restricting effector CD8+ expansion and augmenting expansion of CD4+CD25+FOXP3+Treg cells in human and murine ovarian cancer. In turn, we have shown that Treg cells suppress polyfunctional high avidity effector T cells derived from vaccinated patients. Consequently, we hypothesize that blockade of IDO activity by a novel IDO inhibitor, INCB024360 will (i) abrogate differentiation of CD4+ T cells into Treg cells, (ii) reverse IDO mediated arrest of T cell proliferation, (iii) unmask vaccine induced high avidity polyfunctional effector CD8+ T cells and thereby potentiate vaccine efficacy against EOC in a clinical trial. To test our hypotheses, we propose: SA1 To test whether the combinatorial regimen of IDO inhibition and rCNP-NY-ESO-1/TRICOM immunization is safe, and produces clinical efficacy in a phase I/IIb trial;SA2: To test whether INCB024360 mediated IDO blockade favors generation of high avidity polyfunctional effector CD8+ T cells;SA3: To determine the impact of IDO blockade on vaccine induced CD4+ T cell response for high avidity CD8+ Effector/Memory generation. The experimental plan is designed to test whether vaccine efficacy will be enhanced by blocking IDO mediated immune tolerance in a clinical trial. Mechanistically, because our phase II study design is randomized with a 2X2 factorial design, we will be able to delineate the impact of IDO blockade on promoting vaccine induced T cell clonal expansion and effector/memory differentiation, and whether this is mediated by relieving inhibition of high avidity polyfunctional antigen specific T cells by Tregs. The successful completion of our proposed studies will result in the generation of critical data that will facilitate Phase III evaluation of IDO blockade to relieve Treg mediated immune tolerance, promote conditions that favor durable host immunity and prolong disease free survival in ovarian cancer patients.

Public Health Relevance

The goal of this project is to optimize and test a multi-modal approach consisting of vaccine therapy and blockade of IDO enzyme activity, which promotes accumulation regulatory T cells (Tregs) in ovarian cancer. This approach would greatly enhance the anti-tumor efficacy of the vaccination and potentially prolong the duration of remission in ovarian cancer patients who are in second remission.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA159981-02
Application #
8754344
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
$656,160
Indirect Cost
$216,167
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Szender, J Brian; Eng, Kevin H; Matsuzaki, Junko et al. (2016) HLA superfamily assignment is a predictor of immune response to cancer testis antigens and survival in ovarian cancer. Gynecol Oncol 142:158-62
Kohrt, Holbrook E; Tumeh, Paul C; Benson, Don et al. (2016) Immunodynamics: a cancer immunotherapy trials network review of immune monitoring in immuno-oncology clinical trials. J Immunother Cancer 4:15
Chen, Yichao; Xia, Rui; Huang, Yixian et al. (2016) An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy. Nat Commun 7:13443
Wong, Jeffrey L; Obermajer, Nataša; Odunsi, Kunle et al. (2016) Synergistic COX2 Induction by IFNγ and TNFα Self-Limits Type-1 Immunity in the Human Tumor Microenvironment. Cancer Immunol Res 4:303-11
Shi, Liangrong; Chen, Lujun; Wu, Changping et al. (2016) PD-1 Blockade Boosts Radiofrequency Ablation-Elicited Adaptive Immune Responses against Tumor. Clin Cancer Res 22:1173-84
Cuellar-Partida, Gabriel; Lu, Yi; Dixon, Suzanne C et al. (2016) Assessing the genetic architecture of epithelial ovarian cancer histological subtypes. Hum Genet 135:741-56
Winham, Stacey J; Pirie, Ailith; Chen, Yian Ann et al. (2016) Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer. Cancer Epidemiol Biomarkers Prev 25:446-54
Præstegaard, Camilla; Kjaer, Susanne K; Nielsen, Thor S S et al. (2016) The association between socioeconomic status and tumour stage at diagnosis of ovarian cancer: A pooled analysis of 18 case-control studies. Cancer Epidemiol 41:71-9
Earp, Madalene; Winham, Stacey J; Larson, Nicholas et al. (2016) A targeted genetic association study of epithelial ovarian cancer susceptibility. Oncotarget 7:7381-9
Zhao, Wenyuan; Chen, Beibei; Guo, Xin et al. (2016) A rank-based transcriptional signature for predicting relapse risk of stage II colorectal cancer identified with proper data sources. Oncotarget 7:19060-71

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