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：
10268846
负责人：
Xiao-Jing Wang
金额：
$ 35.28万
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/10268846
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/antagonist 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 true biomarker 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) 通常用于治疗局部复发性头颈部鳞状细胞癌（HNSCC），但尚无标准的伴随全身治疗，且 RT 耐药率很高。抗程序性死亡-1 (PD-1) 已被 FDA 批准用于治疗复发/复发性 HNSCC，但 RT 通过引起 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 STING（干扰素基因刺激剂）以促进局部和离线时，RT 还会诱导转化生长因子-β1 (TGFβ1)，这是一种免疫系统。抑制剂和 PD-L1（PD-1 的配体）这些 RT 效应使 TGFβ/PD-L1 双重抑制成为合理。我们在该项目中测试了 TGFβ1 的组合，其在 60% 以上的烟草相关人群中升高。 HNSCC 介导的 DNA 修复有助于 RT 抵抗。使用我们的小鼠 HNSCC 模型，我们发现 TGFβ/PD-L1 具有双重作用。在具有高 TGFβ1 水平和大量我们还发现 TGFβ 抑制可减少无胸腺小鼠的转移。我们在晚期 HNSCC 中发现了 TGFβ/PD-L1 双重抑制。增强 RT 诱导的原位疫苗接种、逆转免疫抑制并克服 RT 耐药性我们将通过实验验证这一假设。 HNSCC 患者标本的治疗、机制研究和分析目标 1 将确定 TGFβ/PD- 是否存在。 L1 双重抑制增强口腔 SCC 小鼠 RT 诱导的原位疫苗接种和全身免疫激活 RT 加 TGFβ/PD-L1 双重抑制的实验治疗将使用小鼠 SCC 进行。将细胞系原位移植到同基因小鼠中，T细胞依赖性抗肿瘤机制将被目标 2 将确定如何将 RT 方案与细胞和分子水平相结合。 TGFβ/PD-L1 抑制作用针对小鼠和人类 HNSCC T 模型中的肿瘤上皮死亡和骨髓细胞。将分析 RT 与 TGFβ/PD-L1 抑制相结合的细胞依赖性治疗益处。将针对 M7824（TGFβ/PD-L1 双向抑制剂）在局部复发性和寡转移 HNSCC 患者并确定细胞和分子标记作为治疗靶点。进行拟议的研究，我们的目标是同时进行实时治疗干预加强免疫治疗并降低预后不良的 HNSCC 患者的 RT 抵抗。确定拟议治疗的预测标记将导致真正的生物标记驱动的 II 期试验预先选定的患者。