Project 3: Hedgehog Inhibition to Enhance Response to ICI Therapy

总结/摘要-项目3 当有效时，免疫检查点抑制剂（ICI）治疗可以显著改善患者的结局， 卵巢癌（OvCa）。然而，只有10-20%的OvCa患者对ICI治疗有反应。低的原因之一 OvCa的ICI反应率可能是OvCa独特的免疫抑制肿瘤微环境（TME）， 典型的是被免疫抑制性“M2”肿瘤相关巨噬细胞（TAM）浸润的致密基质。我们 最近发现，卵巢癌相关的间充质干细胞（CA-MSC） 免疫抑制性OvCa TME;分化成表达BIGH 3的成纤维细胞/肿瘤基质，募集 单核细胞向基质的分化，并促进表达“M2”TAM的免疫抑制性BIGH 3的分化。 联合作用是CA-MSC驱动肿瘤免疫排斥和对ICI的抵抗 疗法重要的是，我们发现hedgehog抑制剂（HHi）逆转CA-MSC驱动的免疫排斥， 促进M2向M1 TAM转化，恢复对ICI治疗的应答。HHi疗法下调 BIGH 3在CA-MSC和TAM中的表达，并促进TAM从M2表型转化为M1表型。我们 研究与最近的许多报道一致，HHi促进M1巨噬细胞极化，并促进M1巨噬细胞分化。 抗肿瘤免疫基于这些结果，我们假设CA-MSC产生免疫抑制OvCa TME和HHi将逆转CA-MSC介导的免疫抑制并增强患者对ICI的反应 疗法为了验证我们的假设，我们提出了以下具体目标：SA 1。进行单臂第二阶段 评价Atezolizumab（aPD-L1）联合Vismodegib（HHi）治疗铂类药物患者的临床试验 耐药复发性卵巢癌主要终点为疗效和安全性。次要终点将是 缓解持续时间、PFS、OS和翻译相关因素。SA 2：评价HHi对患者的影响 肿瘤免疫浸润和外周趋化因子，并确定是否变化预测对治疗的反应。 SA 3：评估BIGH 3作为肿瘤免疫排斥和免疫靶点的驱动因素。使用 在OvCa的鼠模型中，我们将评估BIGH 3对免疫效应物迁移和功能的影响， 确定抗BIGH 3治疗是否可以增强鼠肿瘤模型中的ICI应答。 影响：这将是第一项OvCa临床试验，以确定（i）HHi对患者ICI治疗的影响 与上皮癌的关系，以及（ii）靶向CA-MSC克服免疫抑制性OvCa TME的作用。 相关翻译研究将揭示对治疗反应的潜在预测生物标志物。最后我们 将评估BIGH 3作为免疫调节剂和新的治疗靶点。最终，我们相信这些研究 将影响OvCa患者对ICI治疗的反应，并将改善结局。

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.