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 放射疗法（RT）通常用于局部复发的头颈部鳞状细胞癌（HNSCCS），但不存在标准伴随的全身治疗，RT阻力率很高。抗体针对编程的死亡1（PD-1），FDA已批准用于处理传递/经常性HNSCCS，但回应率很低。 RT通过引起DNA损伤和肿瘤杀死该释放来诱导抗肿瘤免疫力新抗原触发“原位肿瘤疫苗”和刺激（IFN基因刺激剂）的局部和激活全身免疫激活。相反，RT还诱导转化生长因子-β1（TGFβ1），一种免疫抑制剂和PD-L1，PD-1的配体。这些RT效应使双TGFβ/PD-L1抑制有理在这个项目中测试了组合。我们报告说，在烟草相关的60％中，TGFβ1升高 HNSCCS。 TGFβ1介导的DNA修复有助于RT电阻。 TGFβ1也有助于RT诱导的毒性，例如口服粘膜炎和纤维化。使用我们的小鼠HNSCC模型，我们发现TGFβ/PD-L1双重在TGFβ1水平高且数量高的肿瘤中，抑制放射性的SCC比单独的抗PD-L1更好 PD-L1+/CD11b+细胞。我们还发现，TGFβ降低了与无胸腺小鼠的转移酶减少CD11b+髓样细胞。我们假设在高级HNSCC中，TGFβ/PD-L1双重抑制增强RT引起的原位疫苗接种，逆转免疫抑制并克服RT电阻通过T细胞依赖性和非依赖性机制。我们将通过实验检验该假设 HNSCC患者标本的治疗，机理研究和分析。 AIM 1将确定TGFβ/PD-是否是否 L1双抑制增强RT诱导的原位疫苗接种和全身免疫激活在口服SCC小鼠中型号。 RT加TGFβ/PD-L1双重抑制的实验疗法将使用小鼠SCC进行原始小鼠的线直接移植的线，依赖于T细胞的抗肿瘤机制是在细胞和分子水平上进行分析。 AIM 2将确定RT方案如何与在小鼠和人HNSCC模型中，TGFβ/PD-L1抑制靶向肿瘤上皮死亡和髓样细胞。 t 将分析RT与TGFβ/PD-L1结合使用的细胞非依赖性治疗益处。目标3 将使用M7824（TGFβ/PD-L1双向抑制剂）进行RT的IB期试验。寡聚HNSCC患者，并将细胞和分子标记鉴定为治疗靶标。经过进行拟议的研究，我们旨在实时进行治疗干预，以简单地增强免疫疗法并降低预后不良的HNSCC患者的RT耐药性。此外，确定拟议治疗的预测标记将导致真正的生物标志物II期试验预先选择的患者。