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: 10297549
• 负责人: BRENDAN D CURTI
• 金额: $ 59.31万
• 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/10297549
• 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; base; 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/antagonist; 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.

项目概要/摘要 由于最近的进展，免疫疗法现已成为转移性患者护理标准的一部分 黑色素瘤（MM）和头颈鳞状细胞癌（HNSCC）。免疫检查点封锁 帕博利珠单抗 (pembro；抗 PD-1) 等药物可以抑制特化白细胞（T 细胞） 以增强抗肿瘤免疫力。不幸的是，抗 PD-1 单一疗法很少能治愈晚期晚期患者 恶性肿瘤，因此这些患者仍然迫切需要治疗方案。有很多机制 对免疫治疗产生耐药性，但肿瘤引起的免疫抑制可能是最重要的原因之一。二 抗肿瘤免疫被抑制的方式是通过 PD-1/PD-L1 相互作用和抑制性物质的分泌 肿瘤产生一种称为半乳糖凝集素-3 (Gal-3) 的蛋白质。鉴于PD-1/PD-L1和Gal-3具有抑制抗肿瘤的能力 免疫，该提案的中心假设是通过缓解两种免疫抑制机制 使用新型 Gal-3 抑制剂（GR-MD-02；belapetin）联合 PD-1 阻断治疗将增强肿瘤消退 MM 和 HNSCC 患者。这种创新方法针对的是一种独特的监管途径，能够 改变肿瘤微环境（TME）并增强 T 细胞活性。重要的是，我们最近的第一阶段试验 (NCT02575404) 提供了对 MM (ORR 50%) 和 HNSCC (ORR 33%) 患者临床获益的证据 GR-MD-02+aPD-1 治疗后，与 15-20%（HNSCC 中为 10%）的缓解率相比，效果更好 在这一接受过大量治疗的患者群体中，预期发生率。此外，联合治疗与 免疫介导的不良事件明显少于 pembro 单一疗法的预期。 有反应的患者的效应记忆 T 细胞激活显着增加，并且效应记忆 T 细胞激活减少 与无反应患者相比，单核细胞骨髓源性抑制细胞（M-MDSC） 假设联合疗法通过增强肿瘤反应性 T 细胞的功能来增加反应， 减少 M-MDSC 介导的免疫抑制。这些数据为比较 GR-MD-02+ pembro 与 pembro 单一疗法在 MM 或 MM 患者中的临床和免疫学活性 HNSCC。这项研究意义重大，因为改善了 ORR 并减少了潜在的副作用 与 pembro 单一疗法相结合将大大增强临床护理。我们的目标是执行 评估 GR-MD-02 加 pembro 与 pembro 相比疗效的随机 II 期临床试验 MM 或 HNSCC 患者的单一疗法。我们的目标是：1）确定这部小说的客观反应 MM 或 HNSCC 患者的联合用药； 2) 阐明潜在的分子机制 GR-MD-02+pembro 联合​​免疫疗法增强抗肿瘤免疫并影响 Galectin-3 诱导的 免疫抑制。这些研究将有助于阐明GR-MD-的抗肿瘤作用机制 02+pembro 疗法，这将为了解组合的潜在机制提供重要的见解 与抗 PD-1 单一疗法相比，该疗法支持抗肿瘤免疫。