Ipilimumab plus a galectin-3 inhibitor for metastatic melanoma

Ipilimumab 加半乳糖凝集素 3 抑制剂治疗转移性黑色素瘤

• 批准号: 9105724
• 负责人: BRENDAN D CURTI
• 金额: $ 18.6万
• 依托单位: PROVIDENCE PORTLAND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-06 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105724
• 关键词: Aftercare; Cell physiology; Clinical; Combined Modality Therapy; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Disease; Dose; Drug Kinetics; FDA approved; Galectin 3; Goals; Growth; Health; Human; Immune; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Leukocytes; Malignant Neoplasms; Measures; Medicine; Metastatic Melanoma; Mus; Neoplasm Metastasis; New Agents; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Pre-Clinical Model; Prognostic Factor; Proteins; Regulatory Pathway; Research; Safety; Serum; Signal Transduction; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Treatment Efficacy; Tumor Immunity; antitumor effect; cancer cell; chemokine; clinical care; cytokine; fighting; improved; inhibitor/antagonist; innovation; leukocyte activation; leukocyte proliferation; melanoma; monocyte; novel; patient subsets; potential biomarker; preclinical study; response; tumor; tumor growth; tumor microenvironment

 DESCRIPTION (provided by applicant): Despite recent advances, more effective agents are critically needed for patients with metastatic melanoma. One exciting approach is immunotherapy, which utilizes the patient's immune system to destroy cancer cells. Drugs such as anti-CTLA-4 (ipilimumab) release the "brakes" on specialized white blood cells (T cells) to boost anti-tumor immunity. Unfortunately, monotherapy typically benefits only a subset of patients, which may be due to tumor-induced suppression of the immune response. One way tumors suppress the immune system is by secreting an inhibitory protein, called galectin-3 (Gal-3). Gal-3 enhances tumor growth and metastasis and can also suppress the function of tumor-specific T cells. Given the ability of CTLA-4 and Gal-3 to suppress anti- tumor immunity, the central hypothesis of this proposal is that treatment with a novel Gal-3 inhibitor (GR-MD- 02) plus CTLA-4 blockade (ipilimumab) will enhance tumor regression in patients with advanced melanoma by boosting the function of tumor-specific T cells. This is an innovative approach that targets two unique regulatory pathways to change the tumor microenvironment and enhance T cell activity. Importantly, pre- clinical studies revealed that combined GR-MD-02/anti-CTLA-4 therapy significantly boosted tumor regression and increased the survival of tumor-bearing mice. These data provide a strong rationale for testing the clinical and immunological activity of ipilimumab plus GR-MD-02 in patients with metastatic melanoma. The proposed research is significant because if the immune enhancing and anti-tumor effects from the pre-clinical models are also observed in humans, then clinical care will be considerably enhanced. The objective of this application is to investigate the safety and efficacy of combined GR-MD-02/ipilimumab therapy in a phase I clinical trial and identify the mechanisms by which these agents augment tumor-specific immunity. The goals are to: 1) Determine the safety and efficacy of this novel combination for patients with metastatic melanoma; and 2) Elucidate the mechanisms by which combined GR-MD-02/ipilimumab therapy boosts anti-tumor immunity.

 描述（由申请人提供）：尽管最近取得了进展，但转移性黑色素瘤患者迫切需要更有效的药物。一种令人兴奋的方法是免疫疗法，它利用患者的免疫系统来破坏癌细胞。抗CTLA-4（ipilimumab）等药物可以释放专门的白色血细胞（T细胞）的“刹车”，以增强抗肿瘤免疫力。不幸的是，单一疗法通常仅使一部分患者受益，这可能是由于肿瘤诱导的免疫应答抑制。肿瘤抑制免疫系统的一种方式是分泌一种抑制性蛋白质，称为半乳糖凝集素-3（Gal-3）。Gal-3促进肿瘤生长和转移，并且还可以抑制肿瘤特异性T细胞的功能。鉴于CTLA-4和Gal-3抑制抗肿瘤免疫的能力，该提议的中心假设是用新型Gal-3抑制剂（GR-MD- 02）加CTLA-4阻断剂（伊匹单抗）治疗将通过增强肿瘤特异性T细胞的功能来增强患有晚期黑素瘤的患者中的肿瘤消退。这是一种创新的方法，针对两种独特的调节途径来改变肿瘤微环境和增强T细胞活性。重要的是，临床前研究显示，组合的GR-MD-02/抗CTLA-4疗法显著促进肿瘤消退并增加荷瘤小鼠的存活。这些数据为在转移性黑色素瘤患者中测试易普利姆玛加GR-MD-02的临床和免疫活性提供了强有力的依据。这项研究具有重要意义，因为如果在人类中也观察到临床前模型的免疫增强和抗肿瘤作用，那么临床护理将大大加强。本申请的目的是在I期临床试验中研究GR-MD-02/伊匹单抗联合治疗的安全性和有效性，并确定这些药物增强肿瘤特异性免疫的机制。目标是：1）确定这种新型组合对转移性黑色素瘤患者的安全性和有效性; 2）阐明GR-MD-02/伊匹单抗联合治疗增强抗肿瘤免疫力的机制。

项目成果

The role of Galectin-3 in modulating tumor growth and immunosuppression within the tumor microenvironment.

• DOI: 10.1080/2162402x.2018.1434467
• 发表时间: 2018
• 期刊: Oncoimmunology
• 影响因子: 7.2
• 作者: Farhad M;Rolig AS;Redmond WL
• 通讯作者: Redmond WL

Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor.

• DOI: 10.1136/jitc-2021-002371
• 发表时间: 2021-04
• 期刊: Journal for immunotherapy of cancer
• 影响因子: 10.9
• 作者: Curti BD;Koguchi Y;Leidner RS;Rolig AS;Sturgill ER;Sun Z;Wu Y;Rajamanickam V;Bernard B;Hilgart-Martiszus I;Fountain CB;Morris G;Iwamoto N;Shimada T;Chang S;Traber PG;Zomer E;Horton JR;Shlevin H;Redmond WL
• 通讯作者: Redmond WL

Overcoming Tumor-Induced Immune Suppression: From Relieving Inhibition to Providing Costimulation with T Cell Agonists.

• DOI: 10.1007/s40259-018-0277-2
• 发表时间: 2018-06
• 期刊: BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy
• 作者: Emerson DA;Redmond WL
• 通讯作者: Redmond WL