Impact of Vaccination against GM2, GD2 and GD3 on Disease Free Survival in Resect

描述(由申请人提供)：这项用于临床开发治疗肉瘤患者的新型疫苗的SBIR赠款申请是基于纪念斯隆·凯特琳癌症中心(MSKCC)30年的研究基础上提出的。在这30年中，各种癌症(神经母细胞瘤、肉瘤、乳腺癌、卵巢癌、黑色素瘤等)表达的抗原。免疫组织学定义，小细胞肺癌和肉瘤被确定为免疫原性抗原表达最强的肿瘤，肉瘤被选为最初概念验证随机试验的最合适环境。与肉瘤疫苗最相关且在所有类型的肉瘤中唯一过表达的三种细胞表面抗原被鉴定为神经节苷脂GM2、GD2和GD3。临床前研究证明了使用神经节苷脂-KLH结合疫苗免疫或使用针对这些神经节苷脂的单抗治疗的好处，当靶点是微转移或循环中的肿瘤细胞时，产生的最显著的好处是；这种设置与临床上的佐剂设置相当。在临床前研究和临床试验中，都可以看到针对这些抗原的鼠源单抗治疗的反应。针对所有三种神经节苷脂的结合疫苗也已用于临床试验。在迄今进行的临床试验中，单价(GM2)或双价(GM2/GD2或GD2/GD3)神经节苷脂接种显示出非常轻微的毒性特征和一致的高滴度抗体。第一阶段和第二阶段SBIR联合拨款申请的目的是首次评估三价神经节苷脂疫苗加免疫佐剂在肉瘤患者中的临床疗效。在这项STTR提案的最初6个月的第一阶段中，将扩大最终成分(GD2-KLH)的生产，并将接种和释放三价疫苗。与我们之前所做的相比，这将涉及到GD2和三价疫苗复杂准备的显著扩大。此外，在11个医疗中心中，至少有5个的方案将获得IRB批准，研究人员培训将开始，为启动第二阶段试验做准备。该提案的第二阶段部分将支持进行随机、多中心的第二阶段试验。希望这项双盲试验将被证明对肉瘤患者群体至关重要，并将促进随后在神经母细胞瘤和儿童肉瘤患者中使用相同疫苗的试验。这里提出的转化性研究目标将加深我们对抗体在这一背景下的作用的理解，同时它们验证了基于PCR的循环肿瘤细胞(CTC)分析用于预后和可能的分期目的的使用，以及作为疫苗有效性的替代标记。 公共卫生相关性：建议的针对肉瘤神经节苷脂GM2、GD2和GD3的三价疫苗诱导的抗体非常适合于根除游离肿瘤细胞和微转移。如果能诱导出针对这些抗原的足够效价的抗体，以消除血液中的肉瘤细胞和微转移，这将极大地改变我们治疗肉瘤患者的方法。建立新的转移瘤将不再可能，因此更积极的局部治疗(包括手术或放射治疗)可能导致转移肉瘤的长期控制。这项关键的多中心随机试验的主要终点是改善一年的无进展存活率。

DESCRIPTION (provided by applicant): This SBIR grant application for the clinical development of a novel vaccine to treat patients with sarcoma is based on a foundation of 30 years of studies at Memorial Sloan Kettering Cancer Center (MSKCC). During these 30 years, the antigens expressed by various cancers (neuroblastoma, sarcoma, breast, ovarian, melanoma, etc.) were defined using Immunohistology, SCLC and sarcomas were identified as having the most intense expression of immunogenic antigens, and sarcomas selected as the most suitable setting for the initial proof of concept randomized trial. Three cell surface antigens most relevant for a sarcoma vaccine and uniquely over-expressed in all types of sarcomas were identified as the gangliosides GM2, GD2 and GD3. The benefit of immunization with ganglioside-KLH conjugate vaccines or treatment with monoclonal antibodies against these gangliosides was demonstrated in preclinical studies, with the most striking benefit resulting when the targets were micrometastases or circulating tumor cells; a setting comparable to the adjuvant setting in the clinic. Responses to treatment with murine mAbs against each of these antigens have been seen in both preclinical studies and clinical trials. Conjugate vaccines against all three gangliosides have also been used in clinical trials. Vaccination with either the monovalent (GM2) or bivalent (GM2/GD2 or GD2/GD3) gangliosides has demonstrated very mild toxicity profiles and consistent high titer antibodies in the clinical trials conducted to date. The objective of this combined Phase I and II SBIR grant application is to evaluate for the first time the clinical efficacy of a trivalent ganglioside vaccine plus immunological adjuvant in sarcoma patients. Over the initial 6 month Phase I portion of this STTR proposal, scale-up of production of the final component (GD2-KLH) will be performed, and the trivalent vaccine will be vialed and released. This will involve a significant scale up in the complex preparation of GD2 and trivalent vaccine compared to what we have previously undertaken. Also, protocols in at least 5 of the 11 medical centers will be IRB approved and investigator training will be started in preparation for initiation of the Phase 2 trial. The Phase II portion of this proposal will support conduct of the randomized, multi-center Phase 2 trial. It is hoped that this double-blind trial will prove pivotal for this sarcoma population of patients and that it will facilitate subsequent trials with this same vaccine in patients with neuroblastoma and pediatric sarcomas. The translational research objectives proposed here will add depth to our understanding of the role of antibodies in this setting while they validate the use of a PCR based circulating tumor cell (CTC) assay for prognostic and possibly staging purposes, and as a surrogate marker for vaccine efficacy. PUBLIC HEALTH RELEVANCE: Antibodies induced by the proposed trivalent vaccine against sarcoma gangliosides GM2, GD2 and GD3 are ideally suited for eradication of free tumor cells and micrometastases. If antibodies of sufficient titer can be induced against these antigens to eliminate these sarcoma cells from the blood and to eradicate micrometastases, this would dramatically change our approach to treating sarcoma patients. Establishment of new metastases would no longer be possible, so more aggressive local therapies (including surgery or radiation therapy) might result in long term control of metastatic sarcoma. The primary endpoint for this pivotal multicenter randomized trial is improvement in progression-free survival at one year.