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.

项目概要/摘要 与人乳头瘤病毒（HPV）感染相关的局部晚期宫颈癌（LACC）持续存在 是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 年总生存率仅为 39%，尽管采用了治疗 目前化疗联合放疗（CRT）的护理标准。因此迫切需要 为高危 LACC 患者开发新的治疗策略。 CRT 的组合 针对 PD-L1（durvalumab）或 PD-1（pembrolizumab）的免疫检查点阻断（ICB）药物正在研发中 分别在全球前瞻性试验 CALLA 和 KEYNOTE A18 中进行了研究。不幸的是，结果 CALLA 试验未能证明添加 durvalumab 可显着改善 24 个月生存率， 强调了 LACC 中 CRT 和 ICB 组合的几个关键知识差距。一、最优测序 CRT 和 ICB 的作用尚不清楚，并且明显担心同时启动 CRT 和 ICB 会带来副作用 具有杀死肿瘤和肿瘤引流淋巴结中激活的增殖T细胞的潜力，从而产生耐受性。 其次，接受 ICB 和 CRT 治疗的患者长期结果的预测因素尚不清楚。在这个 应用程序，我们的主要研究目标是检查血液和肿瘤的进化 微环境（TME）免疫参数响应差异ICB-CRT测序和 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 NCI 赞助的 PD-L1 抑制剂 atezolizumab 联合 CRT 治疗高危患者的临床试验 LACC，将患者随机分配到在 CRT 之前和同时给予阿替利珠单抗与同时给予 36 名患者接受 CRT 治疗。该研究综合收集了治疗前和治疗中的肿瘤 活检、血液和 PET 扫描将使我们能够解决上述知识差距。在目标 1 中，我们将 确定肿瘤免疫微环境如何随着差异免疫治疗的功能而演变， CRT 测序。通过使用多参数荧光显微镜，我们将确定 T 的激活如何 细胞及其与肿瘤中其他细胞的相互作用因治疗而发生变化以及这些变化是如何发生的 预测长期结果。在目标 2 中，我们将利用 T 细胞受体 (TCR) 库测序： 以及先进的生物信息学技术来评估肿瘤和外周血中 T 细胞的进化 可以作为抗肿瘤免疫反应和长期结果的指标。在目标 3 中，我们将建立 通过检查血液，将放射学和血液生物标志物作为高危 LACC 患者预后的预测因子 HPV DNA 和治疗后 PET-CT 作为治疗前后疾病负担的标记。鉴定 预测结果的早期生物标志物对于 LACC 患者的风险分层至关重要 以指导患者选择临床试验或维持治疗，同时最大限度地减少 低复发风险患者的潜在临床毒性和经济负担。