Project 3: Hedgehog Inhibition to Enhance Response to ICI Therapy

摘要/摘要-项目3

SUMMARY/ABSTRACT – PROJECT 3 When effective, immune checkpoint inhibitor (ICI) therapy can significantly improve the outcome of patients with ovarian cancer (OvCa). However, only 10-20% of OvCa patients respond to ICI therapy. One reason for the low ICI response rate of OvCa may be OvCa’s unique immunosuppressive tumor microenvironment (TME), which is typified by a dense stroma infiltrated by immunosuppressive ‘M2’ tumor associated macrophages (TAMs). We recently found that ovarian carcinoma-associated mesenchymal stem cells (CA-MSC) orchestrate an immunosuppressive OvCa TME; differentiating into BIGH3 expressing fibroblast/tumor stroma, recruiting monocytes to the stroma, and promoting the differentiation of immunosuppressive BIGH3 expressing ‘M2’ TAMs. The combined effect is that CA-MSC drive tumor immune exclusion and a resultant resistance to ICI therapy. Importantly, we find that hedgehog inhibitors (HHi) reverse CA-MSC-driven immune exclusion, promote M2 to M1 TAM conversion, and restore response to ICI therapy. HHi therapy down-regulates BIGH3 in CA-MSC and TAMs, and promotes the conversion of TAMs from an M2 to and M1 phenotype. Our studies are consistent with numerous recent reports that HHi promote M1 macrophage polarization and promote anti-tumor immunity. Based on these results, we hypothesize that CA-MSC create an immunosuppressive OvCa TME and that HHi will reverse CA-MSC mediated immune-suppression and enhance patient response to ICI therapy. To test our hypothesis, we propose the following specific aims: SA1. Conduct a single arm Phase-II clinical trial evaluating Atezolizumab (aPD-L1) combined with Vismodegib (HHi) in patients with platinum resistant recurrent ovarian cancer. Primary endpoints will be efficacy and safety. Secondary endpoints will be duration of response, PFS, OS and translational correlatives. SA2: Evaluate the impact of HHi on patients’ tumor immune infiltrates and peripheral chemokines and determine if changes predict response to therapy. SA3: To assess BIGH3 as a driver of tumor immune exclusion and immunotherapeutic target. Using murine models of OvCa, we will assess the impact of BIGH3 on immune effector migration and function and determine if anti-BIGH3 therapy can enhance ICI response in murine tumor models. IMPACT: This will be the first clinical trial in OvCa to determine (i) the impact of HHi on ICI therapy in patients with epithelial cancer, and (ii) the role of targeting CA-MSCs to overcome the immunosuppressive OvCa TME. Correlative translational studies will reveal potential predictive biomarkers of response to therapy. Finally, we will evaluate BIGH3 as an immune regulator and novel therapeutic target. Ultimately, we believe these studies will impact OvCa patient’s response to ICI therapy and will improve outcomes.