Targeting head and neck cancer cells and the adverse tumor microenvironment with a novel small-molecule STAT3 inhibitor

University Of Tx Md Anderson Can Ctr, Houston TX

Investigators

Abstract

Most patients with head and neck squamous cell carcinoma (HNSCC) present with locally advanced disease and are treated with a combination of surgery, radiotherapy, and chemotherapy; however, recurrences occur in about half. Despite recent success with immune checkpoint inhibitors, 82% of patients with recurrent or metastatic (RM) disease do not respond to immunotherapy and only a very small subset have complete responses. Therefore, there is an urgent need for new approaches to treat RM HNSCC, including approaches that can be combined with anti-PD-1 therapy to increase durable responses. Increased levels of activated STAT3 (pY-STAT3) or nuclear STAT3 have been reported in 37-75% of HNSCC tumor samples, which correlated with poor prognosis. STAT3 contributes to cancer cell proliferation and immune resistance in HNSCC by promoting the development and function of several immunosuppressive cells, most notably myeloid derived suppressor cells (MDSC), within the tumor microenvironment (TME). Importantly, resistance to immune checkpoint inhibitor (ICI) therapy in HNSCC patients is linked to increased numbers of MDSC; the addition of danvatirsen (STAT3 anti-sense oligonucleotide) enhanced ICI responses in HNSCC patients but was associated with episodes of severe thrombocytopenia and liver injury. Of note, targeting of STAT3 also may reduce immune-related severe adverse events (irSAE) of ICI therapy. The Tweardy group, working with a clinical-stage biotechnology company (Tvardi Therapeutics, Inc.), used computer-based docking and lead-compound optimization strategies to identify TTI-101, a potent, non-toxic and orally bioavailable inhibitor of STAT3 that in a Phase I study in patients with solid tumors at MD Anderson Cancer Center determined an RP2D and showed no TTI-101-attributable adverse events; TTI-101 administration reduced levels of pY-STAT3 within tumors and was beneficial in 9 of 18 evaluable patients, with two patients having partial responses of 40% and 62%. Thus, TTI-101 is the most promising smallmolecule STAT3 inhibitor currently in clinical development for cancer treatment. The main objective of this proposal is to determine if STAT3 targeting with TTI-101 is beneficial in treatment of RM HNSCC. The specific aims are: 1) to determine the effects of TTI-101 alone and in combination with anti-PD-1 therapy in syngeneic mouse models of HNSCC, and 2) to determine the effects of STAT3 inhibition on the TME and STAT3 gene targets in a window-of-opportunity (WOO) clinical trial of TTI-101 in HNSCC patients undergoing surgical resection. We will obtain tumor biopsies pre- and post-treatment in the WOO and Phase II trials and perform correlative studies in the two Aims that include determining the relationships between pharmacokinetics, pharmacodynamics, the TME, and clinical responses in patients and mice with HNSCC treated with TTI-101 alone or in combination with anti-PD-1 therapy. If successful, our research will lead to improved survival and decreased toxicity for patients with advanced HNSCC.