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

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 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 转移到淋巴结的人的3年总存活率只有39%，尽管接受了 目前的护理标准为放化疗(CRT)。因此，有一个迫切的需要 为高危LACC患者开发新的治疗策略。CRT与 针对PD-L1(Duvalumab)或PD-1(Pembrolizumab)的免疫检查点阻断(ICB)药物正在研制中 分别在全球前瞻性试验CALLA和Keynote A18中进行研究。不幸的是， Calla试验未能证明添加杜伐单抗可显著改善24个月的存活率， 在LACC中突出了CRT和ICB结合的几个关键知识差距。第一，优化排序 CRT和ICB的关系尚不清楚，人们明显担心同时启动CRT和ICB会带来 有可能杀死肿瘤和肿瘤引流淋巴结中激活的增殖T细胞，导致耐受性。 其次，接受ICB和CRT治疗的患者的长期结果的预测因素是未知的。在这 应用，我们的主要研究目标是检查血液和肿瘤的演变 微环境(TME)免疫参数对ICB-CRT差异测序的响应 建立长期结果的预测值。为了达到这些目标，我们进行并完成了一项 NCI赞助的PD-L1抑制剂阿替唑单抗联合CRT治疗高危患者的临床试验 LACC，随机将患者在CRT之前和同时给药与同期给药 CRT治疗36例。这项研究纳入了治疗前和治疗中肿瘤的全面收集 活组织检查、血液和正电子发射计算机断层扫描，这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作为差异免疫治疗的函数而演变 CRT测序。通过使用多参数荧光显微镜，我们将确定T细胞的激活 肿瘤中的细胞及其与其他细胞的相互作用随着治疗的反应而变化，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)谱系测序作为 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 可作为抗肿瘤免疫反应和长期疗效的指标。在目标3中，我们将建立 放射学和血液生物标志物通过检查血液来预测高危LACC患者的预后 HPVDNA和治疗后PET-CT作为治疗前后疾病负担的标志物。身份识别 早期预测预后的生物标志物将是LACC患者风险分层的关键 以指导临床试验或维持治疗的患者选择，同时将 复发风险低的患者的潜在临床毒性和经济负担。

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.