Intratumoral injection of a-gal glycolipids in stage IV melanoma: Phase I Trial

描述(申请人提供)：我们的目标是在I期临床试验中研究一种新的免疫疗法，在该试验中，化疗难治性黑色素瘤患者的皮损被注射1-半乳糖脂。这种治疗方法利用了天然抗Gal抗体的治疗潜力。抗-Gal占人类免疫球蛋白的1%，与1-Gal表位(Gal11-3Gal21-4GlcNAc-R)相互作用。从兔红细胞膜中提取的1-半乳糖脂具有被1-半乳糖表位覆盖的碳水化合物链。当注射到肿瘤中时，1-半乳糖脂的脂尾自发地插入病变内的肿瘤细胞膜。我们在小鼠模型中的初步数据表明，这种注射可以破坏治疗的病变，并将它们转化为内源性自体肿瘤疫苗。瘤内注射1-半乳糖脂结合抗半乳糖并引起局部炎症。插入了1-半乳糖脂的肿瘤细胞被抗-Gal以类似于抗-Gal介导的异种移植排斥反应的方式破坏。抗-Gal进一步靶向插入1-半乳糖脂的肿瘤细胞，使其被APC有效摄取，作为炎症反应的一部分被招募到治疗的病变中。这种摄取是由APC上的Fc3受体介导的，它有效地结合了抗Gal抗体的Fc部分，对肿瘤细胞起调理作用。APC将内化的自体黑色素瘤相关抗原(MAA)转运到引流淋巴结，处理并呈递MAA多肽以激活黑色素瘤特异性T细胞，最终引发针对黑色素瘤微转移的保护性免疫反应。我们的目标是在对标准治疗无效的易注射黑色素瘤皮损的IV期患者中完成这种治疗的I期临床试验(FDA-IND 12946)。我们的具体目标是：1.主要目的是在剂量递增研究中评估肿瘤内注射1-半乳糖脂的毒性并确定最大耐受量(MTD)。2.测定治疗后患者的肿瘤反应。3.评价普通MAA免疫应答的动态变化。如果成功，这些研究将使今后能够在转移性黑色素瘤患者以及标准治疗难治的其他类型实体肿瘤患者的第二阶段研究中评估1-半乳糖脂的治疗效果。公共卫生相关性：我们的目标是在黑色素瘤患者的I期临床试验中进行研究，这是我们为对标准治疗无效的癌症患者开发的一种新疗法。建议的治疗方法包括将一种名为1-半乳糖脂的物质直接注射到肿瘤病变中。在注射的肿瘤内，1-半乳糖脂插入肿瘤细胞膜，并与自然存在于人类中最丰富的抗体相互作用，称为“抗半乳糖”。抗Gal和注射1-Gal糖脂之间的这种相互作用可能达到两个目的：1.它诱导瘤内炎症，破坏治疗的病变；2.它将治疗的病变转化为疫苗，使患者对他/她的肿瘤免疫。这种免疫会产生一种免疫反应，摧毁看不见的转移肿瘤细胞。在拟议的第一阶段研究中，我们计划确定癌症患者可以安全使用的最大剂量，测量治疗对治疗皮损的影响，并评估治疗患者在肿瘤内注射1-半乳糖脂后对黑色素瘤的免疫反应。这项第一阶段研究将使我们能够在未来将这种治疗应用于有转移且对标准治疗无效的癌症患者。

DESCRIPTION (provided by applicant): Our objective is to study a novel immunotherapy treatment in a Phase I clinical trial in which lesions of chemotherapy refractory melanoma patients are injected with 1-gal glycolipids. This treatment exploits the therapeutic potential of the natural anti-Gal antibody. Anti-Gal constitutes 1% of immunoglobulins in humans and interacts with 1-gal epitopes (Gal11-3Gal21-4GlcNAc-R). 1-Gal glycolipids extracted from rabbit RBC membranes have carbohydrate chains capped with 1-gal epitopes. When injected into tumors, the lipid tails of 1-gal glycolipids insert spontaneously into tumor cell membranes within the lesion. Our preliminary data in a mouse model have indicated that such injection destroys the treated lesions and converts them into endogenous autologous tumor vaccines. Intratumoral injected 1-gal glycolipids bind anti-Gal and induce local inflammation. Tumor cells with the inserted 1-gal glycolipids are destroyed by anti-Gal in a manner similar to anti-Gal mediated xenograft rejection. Anti-Gal further targets the tumor cells with inserted 1-gal glycolipids for effective uptake by APC that are recruited into the treated lesion as part of the inflammatory response. This uptake is mediated by Fc3 receptors on APC that bind effectively the Fc portion of anti-Gal IgG opsonizing the tumor cells. The APC transport internalized autologous melanoma associated antigens (MAA) to draining lymph nodes, process and present the MAA peptides for the activation of melanoma specific T cells, ultimately eliciting a protective immune response against melanoma micrometastases. We aim to complete a Phase I clinical trial of this treatment in stage IV patients with readily injectible melanoma lesions, refractory to standard therapy (FDA-IND 12946). Our specific objectives are: 1. the primary objective is to evaluate toxicity and determine the maximum tolerated dose (MTD) of 1-gal glycolipids injected intratumorally in a dose escalation study. 2. To determine tumor response in treated patients. 3. To evaluate development of immune response to common MAA. If successful, these studies will enable future evaluation of 1-gal glycolipids therapy efficacy in Phase II studies in patients with metastatic melanoma, as well as in patients with other types of solid tumors that are refractory to standard therapy. PUBLIC HEALTH RELEVANCE: We aim to study in a Phase I clinical trial in melanoma patients, a novel treatment that we have developed for cancer patients who do not responds to standard treatment. The proposed treatment includes the direct injection of a substance called 1-gal glycolipids into the tumor lesion. Within the injected tumor, 1-gal glycolipids insert into the tumor cell membranes and interact with the most abundant antibody naturally present in humans, called "anti-Gal". This interaction between anti-Gal and injected 1-gal glycolipids is likely to achieve two objectives: 1. it induces intratumoral inflammation which destroys the treated lesion, and 2. it converts the treated lesion into a vaccine that immunizes the patient against his/her tumor. This immunization results in the development of an immune response that destroys invisible metastatic tumor cells. In the proposed Phase I study we plan to determine the maximum dose which can be safely administered to cancer patients, measure the effect of the treatment on the treated lesion and evaluate the immune response against melanoma, induced in treated patients following intratumoral injection of 1-gal glycolipids. This Phase I study will enable us in the future to apply this treatment to cancer patients that have metastases and who do not respond to standard treatment.