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: 10889412
• 负责人: Yaguang Xi
• 金额: $ 56.3万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10889412
• 关键词: Address; Affect; Animal Model; Antibodies; Binding; Biological Markers; Body Weight decreased; CD8B1 gene; CT26; Cancer Model; Cells; Chemopreventive Agent; Chromosomal Instability; Circulation; 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; Mismatch Repair Deficiency; 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; Signal Transduction; Solid Neoplasm; Sulindac; Survival Rate; Tandem Repeat Sequences; Testing; Therapeutic; Toxic effect; Translating; Tumor Tissue; Tumor Volume; Tumor-Infiltrating Lymphocytes; United States; Woman; advanced disease; anti-CTLA4; anti-PD-1; anti-PD-L1; anti-PD-L1 antibodies; anti-PD-L1 therapy; cancer type; cell transformation; checkpoint therapy; clinically relevant; colon cancer patients; colorectal cancer metastasis; colorectal cancer progression; colorectal cancer treatment; efficacy evaluation; efficacy study; exosome; experimental study; glycosylation; implantation; improved; in vivo; innovation; interest; ipilimumab; male health; metastatic colorectal; mouse model; patient derived xenograft model; pembrolizumab; posttranscriptional; 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.

项目摘要： 在过去的几十年中，结直肠癌（CRC）患者的总体生存率显着改善， 但是IV期CRC患者的5年生存率仍低于14％。因此，有一个紧急的 需要对CRC开发更有效，更安全的治疗方法。新的免疫检查点抑制剂（ICI） 疗法已经迎来了免疫疗法的新时代，并成为一种重要的治疗选择 实体瘤。但是，ICI仅在缺乏不匹配维修（DMMR）和 微卫星不稳定性高（MSI-H）。大约有85％的CRC患者携带熟练不匹配的患者 维修（PMMR）和微卫星稳定（MSS）或不稳定性（MSI-L）CRC，ICIS几乎没有临床益处。在 一项初步研究，我们检查了低剂量苏琳克在增强PMMR/MSS响应方面的疗效 CRC至抗PD-L1免疫疗法。利用合成小鼠肿瘤模型和人源化的患者衍生 异种移植（PDX）小鼠模型，我们比较了PD-L1抗体（ABS），Sulindac在低的抑制作用 剂量及其在PMMR/MSS CRC上的组合。我们的结果表明，用 联合疗法显示肿瘤体积显着减少，并且CD8+肿瘤的增加 肿瘤组织中浸润淋巴细胞（TILS）。在研究作用机理时，我们发现苏琳克 可以转录抑制PD-L1表达，并最终减少外泌体PD-L1的释放 循环。由于外泌体PD-L1通常与循环PD-L1 ABS结合并耗尽，因此 Sulindac和PD-L1 AB可以潜在地增强抗体募集。因此，我们假设低 - Sulindac剂量可以使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，严格地研究苏莱达克的这一新活动。在AIM 1中，我们将通过 Sulindac将CRC敏感到抗PD-L1治疗，特别是Sulindac如何调节PD-L1表达。在 AIM 2，我们将使用创新且健壮的人源性PDX模型来研究低剂量苏莱达克的体内功效 在增强抗PD-L1治疗方面。将测试MSS和MSI CRC模型。在AIM 3中，我们将调查 Sulindac和抗PD-L1治疗的结合是否可以阻止CRC的转移性进展。自从 Sulindac和Pd-L1抗体是FDA批准的药物，其安全性和毒性曲线已经很好 记录到，我们希望我们的研究成功将迅速促进II期临床试验，以调查 CRC中硫酸增强抗PD-L1治疗的效用 大多数CRC患者对ICI治疗的反应。