Intratumoral Injection of a-gal Glycolipids in Stage IV Melanoma: Phase I Trial

描述（由申请人提供）：我们的目标是在一项I期临床试验中研究一种新的免疫治疗方法，在该临床试验中，化疗难治性黑色素瘤患者的病变注射1-gal糖脂。这种治疗方法利用了天然抗gal抗体的治疗潜力。Anti-Gal占人体免疫球蛋白的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-Gal糖脂具有1-Gal表位覆盖的碳水化合物链。当注射到肿瘤中时，1-半乳糖糖脂的脂质尾部会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，这种注射破坏了治疗的病变，并将其转化为内源性的自体肿瘤疫苗。肿瘤内注射1-gal糖脂结合抗gal并诱导局部炎症。具有插入1-gal糖脂的肿瘤细胞被抗gal破坏，其方式类似于抗gal介导的异种移植排斥反应。Anti-Gal进一步靶向肿瘤细胞，插入1-gal糖脂，使APC有效摄取，APC作为炎症反应的一部分被募集到治疗的病变中。这种摄取是由APC上的Fc3受体介导的，该受体有效地结合抗gal IgG的Fc部分，使肿瘤细胞活化。APC运输内化自体黑色素瘤相关抗原（MAA）至引流淋巴结，加工并呈递MAA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。我们的目标是在标准治疗难治性易注射黑色素瘤病变的IV期患者中完成该治疗的I期临床试验（FDA-IND 12946）。我们的具体目标是：主要目的是在剂量递增研究中评估1-半乳糖糖脂瘤内注射的毒性并确定最大耐受剂量（MTD）。2. 确定治疗后患者的肿瘤反应。3. 评价常见MAA免疫反应的发展。如果成功，这些研究将使1-半乳糖糖脂在转移性黑色素瘤患者以及其他类型的标准治疗难治性实体瘤患者的II期研究中评估治疗效果成为可能。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，这是我们为标准治疗无效的癌症患者开发的一种新疗法。建议的治疗包括将一种称为1-半乳糖糖脂的物质直接注射到肿瘤病变处。在注射的肿瘤内，1-gal糖脂插入肿瘤细胞膜，并与人类天然存在的最丰富的抗体相互作用，称为“抗gal”。抗gal和注射的1-gal糖脂之间的相互作用可能达到两个目的：1。它会引起肿瘤内炎症，破坏已治疗的病变。它将治疗过的病变转化为疫苗，使患者对其肿瘤产生免疫。这种免疫导致免疫反应的发展，破坏不可见的转移性肿瘤细胞。在拟议的I期研究中，我们计划确定癌症患者可以安全使用的最大剂量，测量治疗对治疗病变的影响，并评估治疗患者在瘤内注射1-gal糖脂后对黑色素瘤的免疫反应。这项I期研究将使我们将来能够将这种治疗应用于有转移和对标准治疗没有反应的癌症患者。

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.