Sulindac sensitizes colorectal cancer to anti-PD-L1 therapy

舒林酸使结直肠癌对抗 PD-L1 疗法敏感

基本信息

批准号：
10538823
负责人：
Yaguang Xi
金额：
$ 55.38万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10538823
关键词：
Address Affect Animal Model Antibodies Binding Biological Markers Blood Circulation Body Weight decreased CD8B1 gene CT26 Cancer Model Cells Chemopreventive Agent Chromosomal Instability Clinic Clinical Clinical Research Colorectal Cancer Combined Modality Therapy DNA DNA Repair DNA Sequence Data Development Dose FDA approved Gene Expression Genetic Transcription Growth Human Immune checkpoint inhibitor Immunotherapy MC38 Malignant - descriptor MicroRNAs Microsatellite Instability Microsatellite Repeats Mismatch Repair Modeling Molecular Mus Mutation Nivolumab Non-Steroidal Anti-Inflammatory Agents Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase II Clinical Trials Production Publications Reporting Research Safety Short Tandem Repeat Signal Transduction Solid Neoplasm Sulindac Survival Rate Testing Therapeutic Toxic effect Translating Tumor Tissue Tumor Volume Tumor-Infiltrating Lymphocytes United States Woman advanced disease anti-CTLA-4 therapy anti-PD-1 anti-PD-L1 anti-PD-L1 antibodies anti-PD-L1 therapy base cancer type cell transformation checkpoint therapy clinically relevant colon cancer patients colorectal cancer metastasis colorectal cancer progression colorectal cancer treatment efficacy evaluation efficacy study experimental study glycosylation implantation improved in vivo innovation interest ipilimumab male health metastatic colorectal mouse model patient derived xenograft model pembrolizumab programmed cell death ligand 1 recruit response success transcription factor tumor tumor xenograft

项目摘要

Project Summary: The overall survival of colorectal cancer (CRC) patients has improved significantly over the past few decades, but the 5-year survival rate for patients with stage IV CRC remains below 14%. Therefore, there is an urgent need to develop more effective and safer treatments against CRC. New immune checkpoint inhibitor (ICI) therapies have ushered in a new era of immunotherapy and emerged as important treatment options for a variety of solid tumors. However, ICIs are only effective in CRC patients with deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H). For the approximately 85% of CRC patients who carry proficient mismatch repair (pMMR) and microsatellite stable (MSS) or instability-low (MSI-L) CRCs, ICIs show little clinical benefit. In a preliminary study, we examined the efficacy of low-dose sulindac in enhancing the response of pMMR/MSS CRC to anti-PD-L1 immunotherapy. Utilizing a syngeneic mouse tumor model and a humanized patient-derived xenograft (PDX) mouse model, we compared the inhibitory effects of PD-L1 antibodies (Abs), sulindac at low doses, and their combination on pMMR/MSS CRC. Our results demonstrated that the mice treated with the combination therapy showed a significant reduction in tumor volume, along with an increase of CD8+ tumor- infiltrating lymphocytes (TILs) in tumor tissues. While studying the mechanism of action, we found that sulindac could transcriptionally inhibit PD-L1 expression and ultimately reduce the release of exosomal PD-L1 into the circulation. As exosomal PD-L1 normally binds to and depletes circulating PD-L1 Abs, the combination of sulindac and the PD-L1 Ab can potentially enhance antibody recruitment. Therefore, we hypothesize that low- dose sulindac can sensitize CRC to anti-PD-L1 therapy. In this application, we propose three specific aims to systematically and rigorously investigate this new activity of sulindac. In Aim 1, we will study the mechanisms by which sulindac sensitizes CRC to anti-PD-L1 therapy, specifically how sulindac regulates PD-L1 expression; in Aim 2, we will use innovative and robust humanized PDX models to study the in vivo efficacy of low-dose sulindac in enhancing anti-PD-L1 therapy. Both MSS and MSI CRC models will be tested. In Aim 3, we will investigate whether the combination of sulindac and anti-PD-L1 therapy can block the metastatic progression of CRC. Since sulindac and PD-L1 antibodies are FDA-approved drugs and their safety and toxicity profiles have been well- documented, we hope that the success of our study will rapidly facilitate Phase II clinical trials to investigate the utility of sulindac-enhanced anti-PD-L1 therapy in CRC and address the important clinical challenge of poor response to ICI therapy in the majority of CRC patients.

项目概要：在过去的几十年里，结直肠癌（CRC）患者的总体生存率显着提高，但 IV 期 CRC 患者的 5 年生存率仍低于 14%。因此，当务之急是需要开发更有效、更安全的 CRC 治疗方法。新型免疫检查点抑制剂（ICI）疗法开创了免疫疗法的新时代，并成为多种疾病的重要治疗选择实体瘤。然而，ICIs 仅对错配修复缺陷 (dMMR) 的 CRC 患者有效，并且微卫星不稳定性高（MSI-H）。大约 85% 的 CRC 患者存在严重错配修复 (pMMR) 和微卫星稳定 (MSS) 或低不稳定性 (MSI-L) CRC，ICIs 几乎没有临床益处。在在一项初步研究中，我们检查了低剂量舒林酸在增强 pMMR/MSS 反应方面的功效 CRC 到抗 PD-L1 免疫治疗。利用同基因小鼠肿瘤模型和人源化患者肿瘤模型在异种移植（PDX）小鼠模型中，我们比较了PD-L1抗体（Abs）、舒林酸在低浓度下的抑制效果。剂量及其组合对 pMMR/MSS CRC 的影响。我们的结果表明，接受过治疗的小鼠联合治疗显示肿瘤体积显着减小，同时 CD8+ 肿瘤 - 肿瘤组织中的浸润淋巴细胞（TIL）。在研究其作用机制时，我们发现舒林酸可以转录抑制 PD-L1 表达并最终减少外泌体 PD-L1 释放到循环。由于外泌体 PD-L1 通常会结合并消耗循环 PD-L1 Ab，因此舒林酸和 PD-L1 Ab 可以潜在地增强抗体募集。因此，我们假设低一定剂量的舒林酸可以使 CRC 对抗 PD-L1 治疗敏感。在此应用中，我们提出了三个具体目标系统而严格地研究了舒林酸的这一新活性。在目标 1 中，我们将通过以下方式研究其机制：哪种舒林酸使 CRC 对抗 PD-L1 治疗敏感，特别是舒林酸如何调节 PD-L1 表达；在目标2，我们将使用创新且稳健的人源化PDX模型来研究低剂量舒林酸的体内功效增强抗 PD-L1 治疗。 MSS 和 MSI CRC 模型都将进行测试。在目标 3 中，我们将调查舒林酸与抗 PD-L1 联合治疗是否可以阻止 CRC 的转移进展。自从舒林酸和 PD-L1 抗体是 FDA 批准的药物，其安全性和毒性特征已得到充分证实。有据可查，我们希望我们研究的成功将迅速促进 II 期临床试验，以调查舒林酸增强抗 PD-L1 疗法在 CRC 中的效用，并解决贫困患者的重要临床挑战大多数 CRC 患者对 ICI 治疗的反应。