Phase II Clinical Development of Galectin-3 Inhibition and Anti-PD-1: Immune Monitoring and Tumor Response

Galectin-3抑制和抗PD-1的II期临床开发：免疫监测和肿瘤反应

• 批准号: 10460646
• 负责人: BRENDAN D CURTI
• 金额: $ 58.29万
• 依托单位: PROVIDENCE PORTLAND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-02 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460646
• 关键词: Advanced Malignant Neoplasm; Antitumor Response; Biopsy; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Clinical; Combination immunotherapy; Combined Modality Therapy; Data; Disease; Double-Blind Method; Environment; Flow Cytometry; Frequencies; Funding; Galectin 3; Goals; Head and Neck Squamous Cell Carcinoma; Immune; Immune signaling; Immune system; Immunologic Monitoring; Immunologics; Immunosuppression; Immunotherapy; Incidence; Knowledge; Leukocytes; Malignant Neoplasms; Mediating; Metastatic Melanoma; Molecular; Monoclonal Antibodies; Myeloid-derived suppressor cells; PD-1 blockade; PD-1/PD-L1; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Population; Prognostic Factor; Proteins; Randomized; Regimen; Regulatory Pathway; Research; Systemic Therapy; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Time; Tumor Immunity; United States National Institutes of Health; anti-PD-1; anti-PD1 therapy; antitumor effect; cancer cell; candidate marker; clinical care; clinical development; clinical efficacy; disorder control; effector T cell; efficacy evaluation; experience; immune checkpoint blockade; immune-related adverse events; improved; inhibitor; innovation; insight; molecular marker; monocyte; neoplastic cell; novel; objective response rate; pembrolizumab; phase I trial; polarized cell; potential biomarker; programmed cell death ligand 1; programmed cell death protein 1; resistance mechanism; responders and non-responders; response; response biomarker; side effect; standard of care; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

Project Summary/Abstract Due to recent advances, immunotherapy is now part of the standard of care for patients with metastatic melanoma (MM) and head and neck squamous cell carcinoma (HNSCC). Immune checkpoint blockade with drugs such as pembrolizumab (pembro; anti-PD-1) release the brakes on specialized white blood cells (T cells) to boost anti-tumor immunity. Unfortunately, anti-PD-1 monotherapy infrequently cures patients with advanced malignancy, thus curative regimens are still critically needed for these patients. There are many mechanisms of resistance to immunotherapy, but tumor-induced immune suppression is likely one of the most important. Two ways anti-tumor immunity is suppressed are through PD-1/PD-L1 interactions and the secretion of an inhibitory protein called galectin-3 (Gal-3) by the tumor. Given the ability of PD-1/PD-L1 and Gal-3 to suppress anti-tumor immunity, the central hypothesis of this proposal is that relieving two mechanisms of immune suppression by treatment with a novel Gal-3 inhibitor (GR-MD-02; belapectin) plus PD-1 blockade will enhance tumor regression in patients with MM and HNSCC. This innovative approach targets a unique regulatory pathway capable of changing the tumor microenvironment (TME) and enhancing T cell activity. Importantly, our recent phase 1 trial (NCT02575404) provided evidence of clinical benefit in patients with MM (ORR 50%) and HNSCC (ORR 33%) following GR-MD-02+aPD-1 therapy, which compared favorably with the 15-20% (10% in HNSCC) response rate expected in this population of heavily pre-treated patients. Moreover, combination therapy was associated with significantly fewer immune-mediated adverse events than anticipated with pembro monotherapy. Responding patients experienced significantly increased effector memory T cell activation and reduced monocytic myeloid-derived suppressor cells (M-MDSCs) compared to non-responding patients, leading us to hypothesize that combination therapy increases responses by boosting the function of tumor-reactiveT cells and diminishing M-MDSC-mediated immune suppression. These data provide a strong rationale for comparing the clinical and immunological activity of GR-MD-02+pembro vs. pembro monotherapy in patients with MM or HNSCC. This research is significant because improvement to the ORR and reduction of potential side effects associated with pembro monotherapy will considerably enhance clinical care. Our objective is to perform a randomized phase II clinical trial to evaluate the efficacy of GR-MD-02 plus pembro compared to pembro monotherapy in patients with MM or HNSCC. Our goals are to: 1) Determine the objective response of this novel combination for patients with MM or HNSCC; and 2) Elucidate the underlying molecular mechanisms by which combined GR-MD-02+pembro immunotherapy augments anti-tumor immunity and influences galectin-3-induced immune suppression. These studies will help elucidate the mechanisms for the anti-tumor effect of GR-MD- 02+pembro therapy, which will provide critical insight into the underlying mechanisms by which combination therapy, in comparison to anti-PD-1 monotherapy, supports anti-tumor immunity.

项目总结/摘要 由于最近的进展，免疫疗法现在是转移性肝癌患者的标准治疗的一部分。 黑色素瘤（MM）和头颈部鳞状细胞癌（HNSCC）。免疫检查点阻断， pembrolizumab（pembro;抗PD-1）等药物释放了对特化白色血细胞（T细胞）的抑制作用 增强抗肿瘤免疫力不幸的是，抗PD-1单一疗法很少治愈晚期PD患者。 恶性肿瘤，因此这些患者仍然迫切需要治疗方案。有许多机制 免疫治疗的抵抗，但肿瘤诱导的免疫抑制可能是最重要的。两 抗肿瘤免疫被抑制的方式是通过PD-1/PD-L1相互作用和抑制剂的分泌， 一种叫做半乳糖凝集素-3（Gal-3）的蛋白质。鉴于PD-1/PD-L1和Gal-3抑制抗肿瘤活性的能力， 免疫，该建议的中心假设是，通过以下方式缓解免疫抑制的两种机制： 用新型Gal-3抑制剂（GR-MD-02; belapectin）加PD-1阻断剂治疗将增强肿瘤消退 在MM和HNSCC患者中。这种创新的方法针对一种独特的调控途径， 改变肿瘤微环境（TME）和增强T细胞活性。重要的是，我们最近的一期试验 （NCT 02575404）提供了MM（ORR 50%）和HNSCC（ORR 33%）患者的临床获益证据 GR-MD-02+aPD-1治疗后，与15-20%（HNSCC中为10%）的缓解相比， 这是该接受过大量预先治疗的患者人群的预期发生率。此外，联合治疗与 与pembro单药治疗相比，免疫介导的不良事件显著减少。 应答患者的效应记忆T细胞活化显著增加， 单核细胞骨髓源性抑制细胞（M-MDSC）相比，无反应的患者，导致我们， 假设联合治疗通过增强肿瘤反应性T细胞的功能来增加应答， 减少M-MDSC介导的免疫抑制。这些数据为比较 GR-MD-02+pembro与pembro单药治疗在MM患者中的临床和免疫活性，或 HNSCC。这项研究具有重要意义，因为ORR的改善和潜在副作用的减少 与pembro单药治疗相关的药物组合将显著增强临床护理。我们的目标是执行一个 评价GR-MD-02加pembro与pembro相比的疗效的随机II期临床试验 MM或HNSCC患者的单药治疗。我们的目标是：1）确定这部小说的客观反应 联合治疗MM或HNSCC患者;和2）阐明以下潜在的分子机制： 联合GR-MD-02+pembro免疫疗法增强抗肿瘤免疫力并影响半乳糖凝集素-3诱导的 免疫抑制这些研究将有助于阐明GR-MD抗肿瘤作用的机制。 02+pembro治疗，这将提供关键的洞察，通过组合的潜在机制 与抗PD-1单一疗法相比，抗PD-1治疗支持抗肿瘤免疫。