Immunogenomic predictors of outcomes in patients with locally advanced cervical cancer treated with immunotherapy and chemoradiation

接受免疫治疗和放化疗的局部晚期宫颈癌患者结果的免疫基因组预测因子

• 批准号: 10908093
• 负责人: Dmitriy Zamarin
• 金额: $ 59.54万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10908093
• 关键词: Address; Affect; Aftercare; Antigen-Presenting Cells; Bioinformatics; Biological Assay; Biological Markers; Biopsy; Blood; Blood specimen; Cancer Patient; Cells; Cessation of life; Chemotherapy and/or radiation; Cisplatin; Clinical; Clinical Trials; Clonality; Collection; Combination Drug Therapy; Combination immunotherapy; DNA; DNA copy number; Data; Disease; Disease Marker; Disease-Free Survival; Drug Targeting; Early identification; Evolution; Exhibits; Financial Hardship; Fluorescence Microscopy; Freezing; Funding; Genetic; Genomics; Goals; Head and Neck Cancer; Human Papillomavirus; Human papilloma virus infection; Immunofluorescence Microscopy; Immunogenomics; Immunotherapy; In complete remission; Knowledge; Maintenance; Maintenance Therapy; Malignant neoplasm of cervix uteri; Measures; Metastatic Neoplasm to Lymph Nodes; Molecular Profiling; Morbidity - disease rate; Outcome; PD-1 inhibitors; PDL1 inhibitors; PET/CT scan; Paraaortic; Pathologic; Patient Selection; Patient-Focused Outcomes; Patients; Peripheral; Phenotype; Plasma; Positron-Emission Tomography; Predictive Value; Prognosis; Radiation; Radiation therapy; Randomized; Recurrence; Relapse; Risk; Source; Specimen; T cell receptor repertoire sequencing; T-Cell Activation; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Techniques; Tissues; Toxic effect; Tumor Tissue; United States; Viral; Woman; anti-tumor immune response; arm; biomarker identification; burden of illness; chemoradiation; digital; draining lymph node; experience; follow-up; high risk; immune checkpoint blockade; immunotherapy clinical trials; improved; mortality; neoplastic cell; novel therapeutic intervention; outcome prediction; partial response; patient stratification; pembrolizumab; peripheral blood; predicting response; predictive marker; programmed cell death ligand 1; programmed cell death protein 1; prospective; radiological imaging; response; risk stratification; spatial relationship; standard of care; treatment response; tumor; tumor microenvironment; tumor-immune system interactions; uptake

Project Summary/Abstract Locally advanced cervical cancer (LACC) associated with human papillomavirus (HPV) infection continues to be a significant source of morbidity and mortality in the US and globally. In particular, patients with evidence of metastases to lymph nodes have a dismal 3-year overall survival of 39%, despite treatment with the current standard of care of chemotherapy combined with radiation (CRT). There is thus a critical need to develop new therapeutic strategies for patients with high-risk LACC. Combinations of CRT with immune checkpoint blockade (ICB) drugs targeting PD-L1 (durvalumab) or PD-1 (pembrolizumab) are being studied in global prospective trials CALLA and KEYNOTE A18, respectively. Unfortunately, the results of the CALLA trial failed to demonstrate substantial improvement in 24-month survival with addition of durvalumab, highlighting several critical knowledge gaps in combination of CRT and ICB in LACC. First, optimal sequencing of CRT and ICB is unknown, and there are clear concerns that concurrent initiation of CRT and ICB carries a potential to kill activated proliferating T cells in tumors and tumor-draining lymph nodes, leading to tolerance. Second, predictors of long-term outcomes for the patients treated with ICB and CRT are unknown. In this application, our key study objectives are to examine the evolution of blood and tumor microenvironment (TME) immune parameters in response to differential ICB-CRT sequencing and to establish the predictors of long-term outcomes. To achieve these goals, we conducted and completed an NCI-sponsored clinical trial of PD-L1 inhibitor atezolizumab in combination with CRT in patients with high-risk LACC, randomizing patients to atezolizumab administration prior to and concurrent with CRT vs. concurrent with CRT in 36 patients. The study incorporated comprehensive collection of pre- and on-treatment tumor biopsies and blood and PET scans that will enable us to address the knowledge gaps above. In Aim 1 we will determine how the tumor immune microenvironment evolves as a function of differential immunotherapy and CRT sequencing. By using multi-parameter fluorescence microscopy, we will determine how activation of T cells and their interaction with other cells in the tumors change in response to therapy and how these changes predict long term outcomes. In Aim 2, we will take advantage of T cell receptor (TCR) repertoire sequencing as well as advanced bioinformatics techniques to evaluate how evolution of T cells in tumors and peripheral blood could serve as an indicator of anti-tumor immune response and long-term outcomes. In Aim 3 we will establish radiographic and blood biomarkers as predictors of outcomes in high-risk LACC patients by examining blood HPV DNA and post-treatment PET-CT as markers of disease burden pre- and post-therapy. Identification of early biomarkers predictive of outcomes will be critical for risk-stratification of patients with LACC in order to guide patient selection for clinical trials or maintenance therapy, while minimizing the potential clinical toxicities and financial burden in patients at low risk for recurrence.

项目摘要/摘要 与人乳头瘤病毒（HPV）感染相关的局部晚期宫颈癌（LACC）继续 成为美国和全球发病率和死亡率的重要来源。特别是有证据的患者 淋巴结转移的3年总生存率为39％，尽管 当前的化学疗法护理标准与辐射（CRT）结合使用。因此有急需 为高危LACC患者制定新的治疗策略。 CRT与 靶向PD-L1（Durvalumab）或PD-1（Pembrolizumab）的免疫检查点阻滞（ICB）药物正在 分别研究了全球前瞻性试验Calla和Keynote A18。不幸的是， Calla试验未能证明24个月生存期的重大改善，加上Durvalumab， 在LACC中，强调了CRT和ICB组合的几个关键知识差距。首先，最佳测序 CRT和ICB的尚不清楚，并且有明确的担忧CRT和ICB的同时启动 在肿瘤和肿瘤淋巴结中杀死活化的增殖T细胞的潜力，从而导致耐受性。 其次，尚不清楚接受ICB和CRT治疗的患者长期结局的预测因子。在这个 应用，我们的关键研究目标是检查血液和肿瘤的演变 微环境（TME）免疫参数响应差异ICB-CRT测序和至 建立长期结果的预测因素。为了实现这些目标，我们进行并完成了 PD-L1抑制剂Atezolizumab的NCI赞助的临床试验与CRT结合使用高危患者 LACC，将患者随机与CRT与并发同时发生之前的atezolizumab给药 与36例患者一起使用CRT。该研究纳入了预处理和治疗肿瘤的综合收集 活检，血液和PET扫描将使我们能够解决上面的知识差距。在目标1中，我们将 确定肿瘤免疫微环境如何演变为差异免疫疗法和 CRT测序。通过使用多参数荧光显微镜，我们将确定T 细胞及其与肿瘤中其他细胞的相互作用会随着治疗的响应而发生变化，以及这些如何变化 预测长期结果。在AIM 2中，我们将利用T细胞受体（TCR）曲目测序作为 以及高级生物信息学技术，以评估肿瘤和外周血中T细胞的演变 可以用作抗肿瘤免疫反应和长期结局的指标。在目标3中，我们将建立 射线照相和血液生物标志物作为高危LACC患者预后的预测指标，通过检查血液 HPV DNA和治疗后PET-CT是疾病负担前后疗法的标志。识别 早期的生物标志物预测结果对LACC患者的风险分层至关重要 为了指导患者选择临床试验或维持治疗，同时最大程度地减少 潜在的临床毒性和低复发风险患者的经济负担。