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

描述（由申请人提供）：该SBIR资助申请用于治疗肉瘤患者的新型疫苗的临床开发，是基于纪念斯隆-凯特琳癌症中心（MSKCC）30年研究的基础。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）表达的抗原使用免疫组织学定义，SCLC和肉瘤被鉴定为具有免疫原性抗原的最强烈表达，并且肉瘤被选择为用于概念随机试验的初始证明的最合适的设置。三种与肉瘤疫苗最相关且在所有类型的肉瘤中唯一过表达的细胞表面抗原被鉴定为神经节苷脂GM 2、GD 2和GD 3。在临床前研究中证实了用神经节苷脂-KLH缀合物疫苗免疫或用抗这些神经节苷脂的单克隆抗体治疗的益处，当靶点是微转移或循环肿瘤细胞时产生最显著的益处;与临床中的辅助设置相当。在临床前研究和临床试验中均观察到对针对这些抗原中的每一种的鼠单克隆抗体治疗的应答。针对所有三种神经节苷脂的结合疫苗也已用于临床试验。在迄今为止进行的临床试验中，单价（GM 2）或二价（GM 2/GD 2或GD 2/GD 3）神经节苷脂疫苗接种显示出非常轻微的毒性特征和一致的高滴度抗体。这一合并的I期和II期SBIR资助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。在本STTR提案的最初6个月I期部分，将扩大最终组分（GD 2-KLH）的生产规模，并将三价疫苗装瓶和放行。这将涉及GD 2和三价疫苗的复杂制备与我们以前所做的相比的显著规模扩大。此外，11家医疗中心中至少有5家的方案将获得IRB批准，并将开始研究者培训，为启动II期试验做准备。本提案的II期部分将支持随机化、多中心II期试验的开展。希望这项双盲试验将证明对这一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。本文提出的转化研究目标将加深我们对抗体在这种情况下的作用的理解，同时验证基于PCR的循环肿瘤细胞（CTC）检测用于预后和可能的分期目的，并作为疫苗有效性的替代标志物。 公共卫生相关性：由针对肉瘤神经节苷脂GM 2、GD 2和GD 3的所提出的三价疫苗诱导的抗体理想地适合于根除游离肿瘤细胞和微转移。如果可以诱导足够滴度的抗体来对抗这些抗原，以从血液中消除这些肉瘤细胞并根除微转移，这将极大地改变我们治疗肉瘤患者的方法。新的转移瘤的建立将不再是可能的，因此更积极的局部治疗（包括手术或放射治疗）可能会导致转移性肉瘤的长期控制。这项关键性多中心随机试验的主要终点是1年无进展生存率的改善。

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.