Randomized Phase II Study of QS-DG +/- Trivalent Ganglioside Vaccine in Stage IV

描述(由申请人提供)：尽管有潜在的治愈方法，但大多数接受治疗的转移性肉瘤患者死于随后的疾病复发。成人肉瘤患者完全切除复发转移瘤后的一年无瘤生存率和儿童肉瘤患者综合治疗后3年的总生存率不到20%。鉴于这些患者的临床预后很差，迫切需要开发有效的辅助治疗来消除微转移疾病。神经节苷脂GM2、GD2和GD3是肉瘤上最常见的三种细胞表面抗原，已被证明是肿瘤免疫控制的有效靶点，特别是在佐剂环境下。在辅助试验中，主要靶点是单个循环肿瘤细胞或微转移，这些细胞或微转移在所有已知残留肿瘤治疗后可能会持续很长一段时间。由针对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。如果能针对这些抗原诱导出效价足够高的抗体，从而消除血液中的这些肿瘤细胞并消除微转移，我们治疗肉瘤患者的方法将发生巨大变化。MSKCC是唯一一个证明了在患者中持续诱导针对这些神经节苷脂抗体的能力的中心。疫苗的每个单独成分的安全性和免疫原性已经在患者身上得到证明。如果要测试疫苗接种对肉瘤临床病程的影响，则需要进行随机双盲临床试验。随着MSKCC这种三价神经节苷脂疫苗的开发和生产，我们现在能够评估这种疫苗在肉瘤患者中对无病生存和总体生存的影响。这项建议的主要目的是确定在转移性肉瘤患者中，三价神经节苷脂-KLH结合疫苗加免疫佐剂QS-DG(QS-21的合成版本)治疗后的中位无病存活率或3年存活率是否比单独使用QS-DG治疗更大，转移性肉瘤患者通过单一或多模式治疗获得了无病生存。140名患者将在两年内累积。在这项随机、双盲试验中，所有患者将在一年内接受8次疫苗接种，并将在MSKCC接受跟踪。次要目标是1)评估该方案在该患者群体中的毒性，2)分析接种患者的血清学反应，以确定疫苗随时间的稳定性，以及3)针对单个神经节苷脂的抗体反应与临床病程和复发时表达的抗原之间的关系。公共卫生相关性：这里提出的双盲随机临床试验将测试一种能诱导针对3种大量表达的肉瘤抗原的抗体的三价KLH结合疫苗是否能够防止循环中肉瘤细胞的生长和微转移。如果能针对这些抗原诱导出效价足够高的抗体，从而消除血液中的这些肿瘤细胞并消除微转移，我们治疗肉瘤患者的方法将发生巨大变化。新的转移瘤的建立将不再可能，所以积极的局部治疗，包括手术和放射治疗，可能会导致转移性肉瘤的长期控制甚至潜在治愈。

DESCRIPTION (provided by applicant): Despite potentially curative therapies, the majority of patients with treated metastatic sarcoma die as a result of subsequent disease relapse. The one-year disease-free survival rates and overall survival at 3 years following complete resection of recurrent metastatic disease in adult sarcoma patients or following combination therapy in pediatric sarcoma patients is less than 20%. Given the poor clinical outcome of these patients, the development of effective adjuvant therapy aimed at eliminating micrometastatic disease is desperately needed. The gangliosides GM2, GD2 and GD3 represent the three most prevalent cell surface antigens on sarcomas, and gangliosides have been shown to be effective targets for immune control of cancer, especially in the adjuvant setting. In adjuvant trials, the primary targets are individual circulating tumor cells or micrometastases which may persist for long periods after treatment of all known residual tumor. Antibodies induced by a trivalent vaccine against 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 such that they eliminate these tumor cells from the blood and eradicate micrometastases, our approach to treating the sarcoma patient would be dramatically changed. MSKCC is the only center that has demonstrated the ability to consistently induce antibodies against these gangliosides in patients. Safety and immunogenicity of each individual component of the vaccine has already been demonstrated in patients. If the impact of vaccination on the clinical course of sarcoma is to be tested, a randomized, double-blind clinical trial is required. With the development and production of this trivalent ganglioside vaccine at MSKCC, we are now in a position to evaluate the impact of this vaccine in sarcoma patients on disease free and overall survival. The primary aim of this proposal is to determine whether the median disease-free survival or survival at 3 years after treatment with a trivalent ganglioside-KLH conjugate vaccine plus immunological adjuvant QS-DG (a synthetic version of QS-21) is greater compared to treatment with QS-DG alone in patients with metastatic sarcoma rendered disease free by single- or multi-modality therapy. 140 patients will be accrued over 2 years. All patients in this randomized, double blind trial will receive 8 vaccinations over 1 year and will be followed at MSKCC. Secondary aims are 1) to evaluate the toxicity of this regimen in this patient population, 2) to analyze the serological response in vaccinated patients to confirm vaccine stability over time, and 3) to correlate antibody response against the individual gangliosides with clinical course and antigens expressed in recurrences. PUBLIC HEALTH RELEVANCE: The double blind, randomized clinical trial proposed here will test whether a trivalent KLH conjugate vaccine that induces antibodies against 3 abundantly expressed sarcoma antigens can prevent outgrowth of circulating sarcoma cells and micrometastases. If antibodies of sufficient titer can be induced against these antigens such that they eliminate these tumor cells from the blood and eradicate micrometastases, our approach to treating the sarcoma patient would be dramatically changed. The establishment of new metastases would no longer be possible, so aggressive local therapies including surgery and radiation therapy might result in long-term control or potential cure of even metastatic sarcoma.