Treating recurrent HNSCC with radiation and dual TGF-Beta/PD-L1.

摘要，项目2 放射治疗(RT)通常用于局部复发的头颈部鳞状细胞癌 (HNSCCs)，但没有标准的伴随系统治疗，RT耐药率很高。抗体 FDA批准用于治疗复发/复发的HNSCC的抗程序性死亡-1(PD-1)，但 应答率很低。RT通过导致DNA损伤和释放的肿瘤细胞杀伤来诱导抗肿瘤免疫 新抗原触发“原位肿瘤疫苗”并激活局部和 系统免疫激活。相反，RT也能诱导转化生长因子-β-1(转化生长因子-β-1)，一种免疫 抑制子和PD-L1，PD-1的配体。这些RT效应使得双重转化生长因子β/PD-L1抑制成为一种合理的 这一组合在本项目中进行了试验。我们已经报道，转化生长因子β-1在60%的烟草相关患者中升高。 HNSCC。转化生长因子β1介导的DNA修复参与了RT耐药。转化生长因子β-1也参与了RT诱导 毒性，例如口腔粘膜炎和纤维化。使用我们的小鼠肝细胞癌模型，我们发现转化生长因子β/PD-L1双重 在高转化生长因子β1水平和高数量的肿瘤中，抑制比单独使用抗PD-L1更好地根除SCC PD-L1+/CD11b+细胞。我们还发现，抑制转化生长因子β减少无瘤小鼠的转移与 CD11b+髓系细胞减少。我们推测，在晚期HNSCCs中，转化生长因子β/PD-L1双重抑制 增强RT诱导的原位免疫，逆转免疫抑制，克服RT耐药性 通过T细胞依赖和非依赖机制。我们将通过实验来验证这一假设 HNSCC患者标本的治疗学、机制研究和分析。AIM 1将确定转化生长因子β/PD- L1双重抑制增强口腔鳞状细胞癌小鼠RT诱导的原位免疫和全身免疫激活 模特们。RT加转化生长因子β/PD-L1双重抑制对小鼠鳞状细胞癌的实验治疗 将细胞系原位移植到同基因小鼠，并将T细胞依赖的抗肿瘤机制 在细胞和分子水平上进行分析。目标2将确定RT方案如何与 转化生长因子β/PD-L1抑制小鼠和人鼻咽癌模型中肿瘤上皮细胞和髓系细胞的死亡。T 我们将分析RT联合抑制转化生长因子β/PD-L1对细胞非依赖性治疗的益处。目标3 将进行M7824(转化生长因子β/PD-L1双向抑制剂)治疗局部复发和 并确定细胞和分子标记物作为治疗靶点。通过 在进行拟议的研究时，我们的目标是将实时治疗干预带到同时 加强免疫治疗，减少预后不良的HNSCC患者的RT抵抗。另外， 确定拟议治疗的预测性标记将导致真正的生物标记驱动的II期试验 预先挑选的病人。

SUMMARY, Project 2 Radiation therapy (RT) is commonly used for locally recurrent head and neck squamous cell carcinoma (HNSCCs), yet no standard concomitant systemic therapy exists, and RT resistance rates are high. Antibodies against programmed death-1 (PD-1) are FDA approved for treating relapsed/recurrent HNSCCs, but the response rate is low. RT induces anti-tumor immunity by causing DNA damage and tumor cell killing that release neoantigens to trigger an “in situ tumor vaccine” and activation of STING (stimulator of IFN genes) for local and systemic immune activation. Conversely, RT also induces transforming growth factor-β1 (TGFβ1), an immune suppressor, and PD-L1, a ligand of PD-1. These RT effects make dual TGFβ/PD-L1 inhibition a rational combination being tested in this project. We have reported that TGFβ1 is elevated in >60% of tobacco-associated HNSCCs. TGFβ1-mediated DNA repair contributes to RT resistance. TGFβ1 also contributes to RT-induced toxicity, e.g., oral mucositis and fibrosis. Using our mouse HNSCC models, we found that TGFβ/PD-L1 dual inhibition eradicated SCCs better than anti-PD-L1 alone in tumors with high TGFβ1 levels and high numbers of PD-L1+/CD11b+ cells. We also found that TGFβ inhibition reduced metastases in athymic mice correlated with reduced CD11b+ myeloid cells. We hypothesize that in advanced HNSCCs, TGFβ/PD-L1 dual inhibition enhances RT-induced in situ vaccination, reverses immune suppression, and overcome RT resistance via T cell-dependent and -independent mechanisms. We will test this hypothesis with experimental therapeutics, mechanistic studies and analyses of HNSCC patient specimens. Aim 1 will determine if TGFβ/PD- L1 dual inhibition enhances RT-induced in situ vaccination and systemic immune activation in oral SCC mouse models. Experimental therapeutics of RT plus TGFβ/PD-L1 dual inhibition will be performed using mouse SCC lines transplanted orthotopically to syngeneic mice, and T-cell dependent anti-tumor mechanisms will be analyzed at the cellular and molecular levels. Aim 2 will determine how RT regimens in combination with TGFβ/PD-L1 inhibition target tumor epithelial death and myeloid cells in mouse and human HNSCC models. T cell-independent therapeutic benefit of RT in combination with TGFβ/PD-L1 inhibition will be analyzed. Aim 3 will conduct a Phase Ib trial for RT with M7824 (TGFβ/PD-L1 bidirectional inhibitor) in locally recurrent and oligometastatic HNSCC patients and identify cellular and molecular markers as therapeutic targets. By performing the proposed studies, we aim to bring a therapeutic intervention in real time to simultaneously enhance immunotherapy and reduce RT resistance in HNSCC patients with poor prognosis. Additionally, identifying predictive markers to the proposed treatment will lead to a true biomarker-driven Phase II trial with pre-selected patients.