Abstract IA22: Reprogramming the tumor microenvironment and T cells for ovarian cancer immunotherapy

Immunologic destruction of tumors is a multistep, coordinated process that can be modulated or targeted at several critical points to elicit tumor rejection. These steps in the cancer immunity cycle include: (i) generation of sufficient numbers of effector T cells with high avidity recognition of tumor antigens in vivo; (ii) trafficking and infiltration into the tumor; (iii) overcoming inhibitory networks in the tumor microenvironment; (iv) direct recognition of tumor antigens and generation of an effector antitumor response; and (v) persistence of the antitumor T cells. Although several immune-based interventions have gained regulatory approval in many solid tumors and hematologic malignancies, there are currently no approved immune therapies for ovarian cancer. A major barrier to successful deployment of cancer immunotherapy for ovarian cancer patients is the immunosuppressive tumor microenvironment. Even if large numbers of tumor-specific T cells are generated in patients by active immunization or adoptive transfer, these T cells may not persist to readily destroy tumor targets in vivo. Previous studies by our group have defined some of the dominant immune resistance mechanisms in ovarian cancer to include extrinsic suppression of CD8+ effector cells by regulatory T cells (Tregs) (1, 2); metabolic deregulation via tryptophan catabolism by the immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO) (3, 4); engagement of inhibitory receptors such as PD-1 by the ligand PD-L1/B7-H1 (5-7); development of antigen loss variants (8); myeloid-derived suppressor cells (9); and inhibitory cytokines such as TGF-β. Collectively, this redundant immunosuppressive network facilitates tumor progression by actively restraining antitumor immunity and must be overcome in order to implement efficacious immunotherapeutic strategies. This presentation will be focused on our efforts at: (i) overcoming IDO-mediated innate and adaptive immune resistance as a strategy to reprogram the ovarian tumor microenvironment and (ii) novel “next-generation” strategies for reprograming T cells for adoptive immunotherapy of ovarian cancer. References: 1. Sato, E., et al.. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A, 2005;102(51):18538-43. 2. Nishikawa, H., et al. CD4+ CD25+ regulatory T cells control the induction of antigen-specific CD4+ helper T cell responses in cancer patients. Blood 2005. 3. Qian, F., et al. Efficacy of levo-1-methyl tryptophan and dextro-1-methyl tryptophan in reversing indoleamine-2,3-dioxygenase-mediated arrest of T-cell proliferation in human epithelial ovarian cancer. Cancer Res 2009;69(13):5498-504. 4. Qian, F., et al. Effects of 1-methyltryptophan stereoisomers on IDO2 enzyme activity and IDO2-mediated arrest of human T cell proliferation. Cancer Immunol Immunother 2012. 5. Matsuzaki, J., et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A 2010;107(17):7875-80. 6. Huang, R.Y., et al. LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model. Oncotarget 2015; 6(29):27359-77. 7. Huang, R., et al. Compensatory upregulation of PD-1, LAG-3 and CTLA-4 limits the efficacy of single agent checkpoint blockade in metastatic ovarian cancer. OncoImmunology 2017. 8. Odunsi, K., et al. Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer. Proc Natl Acad Sci U S A 2007;104(31):12837-42. 9. Khan, A.N., et al. Targeting myeloid cells in the tumor microenvironment enhances vaccine efficacy in murine epithelial ovarian cancer. Oncotarget 2015;6(13):11310-26. Citation Format: Kunle Odunsi. Reprogramming the tumor microenvironment and T cells for ovarian cancer immunotherapy. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA22.