Neoadjuvant PD-1 blockade in mismatch repair deficient rectal cancer

新辅助 PD-1 阻断治疗错配修复缺陷型直肠癌

基本信息

批准号：
10199521
负责人：
Andrea Cercek
金额：
$ 24.82万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2021-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199521
关键词：
Address Adenocarcinoma Adjuvant Aftercare Antigens Antitumor Response Biology Biopsy Cancer Patient Clinical Clinical Trials Cohort Studies Colorectal Adenocarcinoma Data Diagnosis Disease Enrollment Evolution Excision Fluorouracil Genomics Goals Hereditary Nonpolyposis Colorectal Neoplasms Image Immunotherapy Incidence Inherited Life Malignant Neoplasms Metastatic/Recurrent Methods Mismatch Repair Mismatch Repair Deficiency Monitor Morbidity - disease rate Mutation Neoadjuvant Therapy Operative Surgical Procedures Organ Preservation Outcome PD-1 blockade Pathologic Patient Care Patient-Focused Outcomes Patients Population Proteins Protocols documentation Rectal Adenocarcinoma Rectal Cancer Rectal Neoplasms Rectum Refractory Relapse Residual Tumors Resistance Sampling Sequential Treatment Solid Neoplasm Somatic Mutation Specimen Testing Tissues Tumor Markers Tumor-infiltrating immune cells Visualization anti-PD1 antibodies base burden of illness cancer therapy cancer type checkpoint inhibition chemoradiation chemotherapy design gastrointestinal immune checkpoint immunogenic improved improved outcome interest neoantigens non-invasive monitor novel pembrolizumab potential biomarker programmed cell death protein 1 rectal response response biomarker standard of care targeted sequencing therapy resistant treatment guidelines treatment response tumor tumor DNA young adult

项目摘要

ABSTRACT Rectal cancer is treated with induction chemotherapy followed by chemoradiationand subsequentsurgery. Most patients who have undergone this sequential treatment approach have significant tumor downstaging , and up to 30% achieve complete clinical and pathologic responses. Approximately 5-10%of all rectal cancers are deficient in mismatch repair (dMMR) and tumors with this genetic defect respond poorly to standard therapy. Studies in metastatic patients with dMMR have demonstrated durable response to checkpoint inhibition, with nearly 20% achieving a complete clinical response with PD-1 blockade. We seek to improve outcomes in dMMR rectal cancers by treatment with upfront PD-1 blockade with or without standard chemoradiotherapy, with the goal of increasing the number of complete clinical responses and improving the chances of organ preservation and reduction in morbidity. Our proposed clinical trial incorporates neoadjuvant PD-1 blockade in patients with dMMR locally advanced rectal cancer. Utilizing collected biospecimens from patients enrolled in this trial we will use genomic assessments to determine if the intrinsic features of these dMMR rectal tumors can predict for resistance or response to PD-1 blockade (Aim 1) and determine if we can predict which patients will achieve long-term benefit from neoadjuvant PD-1 blockade using circulating tumor DNA (ctDNA) to monitor tumor response (Aim 2).

抽象的直肠癌的治疗方法是诱导化疗，然后是放化疗和随后的手术。最多接受这种序贯治疗方法的患者的肿瘤降期显着，并且高达 30% 达到完全的临床和病理反应。大约 5-10% 的直肠癌存在缺陷错配修复（dMMR）和具有这种遗传缺陷的肿瘤对标准治疗反应不佳。研究于 dMMR 转移性患者已表现出对检查点抑制的持久反应，其中近 20% 通过 PD-1 阻断实现完全临床缓解。我们寻求改善 dMMR 直肠治疗的结果通过前期 PD-1 阻断治疗（联合或不联合标准放化疗）来治疗癌症，目标是增加完整临床反应的数量并提高器官保存和治疗的机会发病率降低。我们提议的临床试验在 dMMR 患者中纳入新辅助 PD-1 阻断局部晚期直肠癌。利用从参加本试验的患者收集的生物样本，我们将使用基因组评估以确定这些 dMMR 直肠肿瘤的内在特征是否可以预测对 PD-1 阻断的耐药性或反应（目标 1），并确定我们是否可以预测哪些患者将实现使用循环肿瘤 DNA (ctDNA) 监测肿瘤的新辅助 PD-1 阻断的长期益处响应（目标 2）。