Abstract C086: Immunotherapeutic effects of the TYK2 inhibitor SAR-20351 in syngeneic tumor models

Abstract

Abstract Background: TYK2 (tyrosine kinase 2) is a member of the Janus family of non-receptor tyrosine kinases and has been shown to play an important role in the signalling of type I interferons, as well as IL-12 and IL-23, via phosphorylation of downstream STATs. The TYK2/STAT1/BCL-2 pathway is implicated in the survival of leukemic cells in a proportion of T-ALL cases. It has been reported that STAT3 signalling in both the tumor, and microenvironment, is critical in shifting the balance from IL-12, a central cytokine in antitumor and antiviral immunity, to potentially pro-carcinogenic IL-23 production. Furthermore there is increasing evidence that chronic tumor interferon signalling leads to multigenic T cell exhaustion and resistance to immune checkpoint blockade. Additionally, TYK2 has been suggested to play a key role in CTLA-4 STAT3 signal transduction in B cell lymphomas and in melanoma associated B cells. We have previously reported on SAR-20347, a 1,3-oxazole-4 carboxamide, which is an orally bioavailable potent and selective inhibitor of TYK2, which causes tumor regression in in vivo models of T-ALL, and which has shown striking reductions in STAT phosphorylation downstream of IFNα signalling, and IFNγ production in response to IL-12 both in vitro and in vivo. Here we report the effects of SAR-20351, an orally bioavailable optimised analog of SAR-20347, on tumor cell viability and components of the tumor microenvironment in immunocompetent mouse models. Methods: A range of syngeneic tumor models were used to establish SAR-20351 efficacy as both a monotherapy and in combination with standards of care. FACS analysis was used to identify immune cell sub-populations within tumor tissue and measure PD-1 and PD-L1 expression levels on appropriate cell types. Results: Reduced tumor growth was observed following SAR-20351 treatment as a monotherapy in the Panc02, CT26, MC38, B16F10, Renca and A20 models, and in combination with 5-FU or anti-CTLA-4 in the colon CT26 model. Similar effects were seen in the MC38 model when SAR-20351 was combined with 5-FU and in the Renca model when SAR-20351 was combined with everolimus. To elucidate mechanism of action in these models, tumors were grown in immunocompetent and immunodeficient animals and efficacy compared. Increased efficacy of SAR-20351 in an immunocompetent background compared to immunodeficient animals indicated immunotherapy as a mechanism of action. FACS analysis identified reduced myeloid and Treg cell infiltration in tumor tissue and reduced PD-1 expression was observed on TIL and TAMs, indicative of a less-exhausted phenotype. SAR-20351 was seen to reduce levels of PD-L1 expression by tumor cells, and reversed the increase in PD-L1 levels induced by certain chemotherapy or targeted agents. Reduction of pTYK2, pSTAT3 and cMYC was observed in B cells derived from the A20 model. No changes in animal bodyweight or behavior, and no significant differences in complete blood counts and blood chemistry parameters following treatment with SAR-20351 demonstrated that treatment was well-tolerated during these studies. Conclusions: The TYK2 inhibitor, SAR-20351 results in significant control of solid tumor growth and the mechanism of action involves immunotherapy, with reductions in myeloid and Treg cell infiltration in a range of tumor models. Citation Format: John Reader, Nicole Williams, James Bojdo, Jenny Worthington, Tim Mitchell. Immunotherapeutic effects of the TYK2 inhibitor SAR-20351 in syngeneic tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C086. doi:10.1158/1535-7163.TARG-19-C086