Ipilimumab plus a galectin-3 inhibitor for metastatic melanoma

 描述(申请人提供)：尽管最近取得了进展，但对于转移性黑色素瘤患者来说，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摧毁癌细胞。像抗CTLA-4(Ipilimumab)这样的药物会释放对特殊白细胞(T细胞)的“刹车”，以增强抗肿瘤免疫。不幸的是，单一疗法通常只使一小部分患者受益，这可能是由于肿瘤诱导的免疫反应抑制。肿瘤抑制免疫系统的一种方式是通过分泌一种被称为Galectin-3(Gal-3)的抑制蛋白。GAL-3可以促进肿瘤的生长和转移，也可以抑制肿瘤特异性T细胞的功能。鉴于CTLA-4和Gal-3具有抑制抗肿瘤免疫的能力，该建议的中心假设是，使用新型Gal-3抑制剂(GR-MD-02)和CTLA-4阻滞剂(Ipilimumab)联合治疗将通过增强肿瘤特异性T细胞的功能来促进晚期黑色素瘤患者的肿瘤消退。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，临床前研究表明，GR-MD-02/抗CTLA-4联合治疗显著促进了肿瘤的消退，并增加了荷瘤小鼠的存活率。这些数据为测试ipilimumab加GR-MD-02在转移性黑色素瘤患者中的临床和免疫学活性提供了强有力的理论依据。这项拟议的研究意义重大，因为如果临床前模型的免疫增强和抗肿瘤效果也在人类身上观察到，那么临床护理将得到相当大的改善。这项应用的目的是在I期临床试验中调查GR-MD-02/ipilimumab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。目的是：1)确定这种新型联合疗法对转移性黑色素瘤患者的安全性和有效性；2)阐明GR-MD-02/ipilimumab联合疗法增强抗肿瘤免疫的机制。

 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.