Harnessing the Immunotherapeutic Potential of TYK2 Inhibitor SAR-20351 in Tumor Models

The study focuses on the role of TYK2, a non-receptor tyrosine kinase, in the signaling pathways of type I interferons and cytokines IL-12 and IL-23, which are significant in T-ALL cases. It explores the impact of STAT3 signaling on the balance between IL-12 and IL-23, and its implications in tumor and microenvironment interactions. The research also discusses the role of TYK2 in CTLA-4 STAT3 signal transduction in B cell lymphomas and melanoma. The investigation centers on SAR-20347, a TYK2 inhibitor, and its analog, SAR-20351, which has been shown to reduce STAT phosphorylation and IFNγ production in response to IL-12.

In this research, the efficacy of SAR-20351 is evaluated in various syngeneic tumor models, both as a monotherapy and in combination with standard treatments. The use of FACS analysis helps identify changes in immune cell populations within tumor tissues and assesses the expression levels of PD-1 and PD-L1. The results indicate that SAR-20351 significantly reduces tumor growth in multiple models, and its combination with other treatments enhances this effect.

The mechanism of action of SAR-20351 is suggested to be through immunotherapy, as evidenced by increased efficacy in immunocompetent animals and reduced myeloid and Treg cell infiltration in tumors. Additionally, the compound is found to decrease PD-1 expression on TIL and TAMs and reduce PD-L1 expression by tumor cells, potentially reversing the exhaustion phenotype induced by certain therapies. The study also notes a reduction in pTYK2, pSTAT3, and cMYC levels in B cells.

Importantly, SAR-20351 is well-tolerated, with no significant changes in animal bodyweight, behavior, or blood parameters observed post-treatment. The findings suggest that SAR-20351 could be a promising therapeutic agent for controlling solid tumor growth through immunotherapeutic mechanisms.