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

• 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
• 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

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： 结直肠癌（CRC）患者的总体生存率在过去几十年中显著提高， 但IV期CRC患者的5年生存率仍低于14%。因此迫切 需要开发更有效和更安全的治疗CRC的方法。新型免疫检查点抑制剂（ICI） 免疫疗法开创了免疫疗法的新时代，并成为各种疾病的重要治疗选择。 实体肿瘤的然而，ICI仅在错配修复缺陷（dMMR）的CRC患者中有效， 微卫星高不稳定性（MSI-H）。对于大约85%的CRC患者， 在pMMR和微卫星稳定（MSS）或不稳定性低（MSI-L）的CRC中，ICI显示出很少的临床益处。在 作为一项初步研究，我们检查了低剂量舒林酸在增强pMMR/MSS反应方面的疗效。 抗PD-L1免疫疗法。利用同基因小鼠肿瘤模型和人源化患者来源的 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作用。 剂量及其组合对pMMR/MSS CRC的影响。我们的结果表明， 联合治疗显示肿瘤体积显著减小，沿着CD 8+肿瘤细胞的增加。 肿瘤组织中的浸润淋巴细胞（TIL）。在研究作用机制时，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 流通由于外泌体PD-L1通常与循环PD-L1 Ab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- 剂量舒林酸可使CRC对抗PD-L1治疗敏感。在本申请中，我们提出了三个具体目标， 系统和严格地研究舒林酸的这种新活性。在目标1中，我们将通过以下方式研究机制： 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; 目的2，我们将使用创新和稳健的人源化PDX模型来研究低剂量舒林酸的体内功效 增强抗PD-L1治疗。将测试MSS和MSI CRC模型。在目标3中，我们将研究 舒林酸和抗PD-L1治疗的组合是否可以阻断CRC的转移进展。以来 舒林酸和PD-L1抗体是FDA批准的药物，它们的安全性和毒性特征已经得到很好的证实。 记录，我们希望我们的研究的成功将迅速促进II期临床试验，以调查 舒林酸增强的抗PD-L1治疗在CRC中的效用，并解决了不良反应的重要临床挑战 在大多数CRC患者中对ICI治疗的反应。