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

描述（由申请人提供）：我们的目的是在I期临床试验中研究一种新的免疫疗法治疗，其中化疗难治性黑色素瘤患者的病灶注射1-gal糖脂。这种治疗利用了天然抗Gal抗体的治疗潜力。抗Gal占人体免疫球蛋白的1%，与1-gal表位（Gal 11 - 3Gal 21 -4GlcNAc-R）相互作用。1-从兔RBC膜提取的Gal糖脂具有用1-gal表位封端的糖链。当注射到肿瘤中时，1-gal糖脂的脂质尾部自发地插入病变内的肿瘤细胞膜中。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自体肿瘤疫苗。瘤内注射的1-半乳糖糖脂结合抗半乳糖并诱导局部炎症。具有插入的1-gal糖脂的肿瘤细胞以类似于抗Gal介导的异种移植排斥的方式被抗Gal破坏。抗Gal进一步靶向具有插入的1-gal糖脂的肿瘤细胞，以被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。这种摄取由APC上的Fc 3受体介导，该受体有效地结合抗Gal IgG的Fc部分，调理肿瘤细胞。APC将内化的自体黑素瘤相关抗原（MAA）转运至引流淋巴结，加工并呈递MAA肽以活化黑素瘤特异性T细胞，最终引发针对黑素瘤微转移的保护性免疫应答。我们的目标是完成该治疗在IV期患者中的I期临床试验，这些患者患有易于注射的黑色素瘤病变，对标准治疗无效（FDA IND 12946）。我们的具体目标是：1。主要目的是评价毒性并确定在剂量递增研究中瘤内注射1-半乳糖脂的最大耐受剂量（MTD）。2.确定治疗患者的肿瘤缓解。3.评价对常见MAA的免疫应答的发展。如果成功，这些研究将使未来的1-gal糖脂治疗的疗效评估在II期研究中的转移性黑色素瘤患者，以及其他类型的实体瘤患者是难治性的标准治疗。公共卫生相关性：我们的目标是在黑色素瘤患者中进行I期临床试验，这是我们为标准治疗无效的癌症患者开发的一种新型治疗方法。拟议的治疗方法包括将一种称为1-gal糖脂的物质直接注射到肿瘤病变中。在注射的肿瘤中，1-gal糖脂插入肿瘤细胞膜，并与人体中天然存在的最丰富的抗体（称为“抗Gal”）相互作用。抗Gal和注射的1-gal糖脂之间的这种相互作用可能实现两个目的：1.它诱导肿瘤内炎症，其破坏治疗的损伤，和2.它将治疗的病变转化为疫苗，使患者对他/她的肿瘤免疫。这种免疫导致免疫反应的发展，破坏不可见的转移性肿瘤细胞。在拟定的I期研究中，我们计划确定可安全给予癌症患者的最大剂量，测量治疗对治疗病变的影响，并评估肿瘤内注射1-gal糖脂后治疗患者诱导的针对黑色素瘤的免疫应答。这项I期研究将使我们能够在未来将这种治疗方法应用于有转移并且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.