Ror Gamma Agonists As A Novel Immunotherapy Approach For Cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAAgents that enhance activation or release suppression of the immune system could form the basis of new treatments for cancer. RORγt is the key transcription factor controlling the development and function of CD4+ Th17, CD8+ Tc17 and IL-17+ innate immune cells. RORγγmodulates expression of genes involved in multiple anti-tumor mechanisms and in some cancers Th17/Tc17 cells are reported to mediate potent and durable anti-cancer efficacy. To further enhance these responses, we designed small molecule RORγ agonists and characterized their activities on immune cells and utility in murine tumor models.Synthetic agonists activate an RORγ-dependent reporter construct and when present during activation of murine or human T cells in vitro, increase production of IL-17A, IL-17F, IL-22 and GM-CSF without negatively impacting IFNγ production. Th17 and Tc17 cells differentiated in the presence of RORγ agonists exhibit decreased expression of inhibitory molecules such as PD-1, TIGIT, CD160, CD73 and increased expression of costimulatory molecules including CD137 (4-1BB) and CD226 (DNAM-1). Stimulation of CD4+ T cells with cytokine cocktails including TGFβ in vitro can generate Th17 and Treg cells; addition of RORγ agonists improves the Teff/Treg ratio via decreased FOXP3 and increased IL-17 expression. Functionally, RORγ agonist treatment reprograms cells to resist PD-1:PD-L1 mediated inhibition of proliferation and cytokine production. In vitro activation of OT-1 Tc17 cells with RORγ agonists generates potent effector cells that control the growth of large EG7 tumors when transferred into non-irradiated mice. The tumor-infiltrating lymphocytes from this model have enhanced survival, increased IL-17 production and decreased PD-1 expression. Oral administration of RORγ agonists to C57BL/6 mice significantly inhibits the growth of established, subcutaneous MC38 colon carcinoma tumors. The anti-tumor activity of RORγ agonists is dependent on T cells, as growth of MC38 cells implanted into scid mice is not affected by agonist treatment. RORγ agonists also inhibit growth of established, subcutaneous 4T1 mammary carcinoma tumors in Balb/c mice. In the tumors from agonist-treated animals there is significantly elevated expression of RORγ and IL-17 as well as decreased CD73 expression with evidence of decreased metastases.As a transcription modulator, RORγ agonists increase immune activation and decrease immune suppression. These activities translate into robust anti-tumor effects in syngeneic tumor models and represent a promising approach for the treatment of cancer.Citation Format: Xiao Hu, Jacques Moisan, Charles Lesch, Yahong Wang, Xikui Liu, Rodney Morgan, David Mertz, Brian Sanchez, Dick Bousley, Clark Taylor, Chad Van Huis, Thomas Aicher, Peter Toogood, Weiping Zou, Gary Glick, Laura L. Carter. RORγ agonists as a novel immunotherapy approach for cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4273. doi:10.1158/1538-7445.AM2015-4273