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

使用放射和双重 TGF-Beta/PD-L1 治疗复发性 HNSCC。

基本信息

批准号：
10477461
负责人：
Xiao-Jing Wang
金额：
$ 32.81万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10477461
关键词：
Affect Aftercare Antibodies Attenuated Biopsy Blood Cells CCL4 gene CD8B1 gene Cancer Biology Catchment Area Cell Death Cells Cessation of life Clinical Colorado DNA DNA Damage DNA Repair Epithelial Epithelial Cells FDA approved Fibrosis Future Genes Growth Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human Human Papillomavirus ITGAM gene Immune Immunocompetent Immunosuppression Immunosuppressive Agents Immunotherapy Individual Infiltration Interferons Investigational Therapies Mediating Medical Oncology Metastatic Neoplasm to the Lung Modeling Molecular Mus Mutant Strains Mice Myeloid Cells Neoplasm Metastasis Nitroquinolines Nude Mice Oral Oral mucous membrane structure Outcome Oxides Pathway interactions Patients Phase Ib Clinical Trial Phase Ib Trial Prediction of Response to Therapy Prognosis Radiation Radiation Oncology Radiation therapy Recurrence Regimen Relapse Reporting Resistance Safety Sampling Science Serum Signal Transduction Specimen Systemic Therapy T cell receptor repertoire sequencing T-Cell Receptor T-Lymphocyte Testing Therapeutic Therapeutic Intervention Time Tobacco Toxic effect Transforming Growth Factor beta Transforming Growth Factors Transplantation Tumor Antigens Tumor Immunity Tumor-Infiltrating Lymphocytes antitumor effect biomarker-driven candidate validation cell injury cell killing head and neck cancer patient immune activation in situ cancer vaccine in situ vaccination inhibitor molecular marker mouse model neoantigens neoplastic cell novel oral mucositis patient derived xenograft model phase II trial predictive marker programmed cell death ligand 1 programmed cell death protein 1 radiation effect radiation response recruit response small molecule targeted agent therapeutic target therapy outcome treatment response tumor tumor immunology tumor microenvironment vaccine efficacy vaccine response

项目摘要

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.

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。