A PHASE I/II STUDY USING ALLOGENEIC TUMOR CELL VACCINATION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 神经母细胞瘤是一种儿科癌症，可导致严重的发病率和死亡率。作为第二大最常见的恶性实体肿瘤，占所有儿童癌症死亡的10%以上。在目前的治疗下，4期高危疾病患者的总体存活率仍然不到30%-40%，迫切需要改善这些儿童的治疗方案。我们和其他小组已经通过使用神经母细胞瘤特异性免疫疗法显示了免疫学和临床疗效。由于神经母细胞瘤的异质性，教导免疫系统以不同的肿瘤抗原库为靶点，并使用更广泛的宿主效应机制，使用肿瘤细胞疫苗，与过继细胞和单抗治疗相比，可能提供更高的抗肿瘤疗效。在我们上一次的同种异体肿瘤细胞疫苗试验中，我们能够诱导复发/难治性疾病患者的临床反应，包括完全缓解。然而，总体结果可能受到呈现的肿瘤抗原数量和肿瘤抑制微环境的限制。在这项临床研究中，我们建议通过1)修改疫苗产品以增加呈递给免疫系统的肿瘤相关抗原的数量，以及2)将疫苗接种与节律口服环磷酰胺相结合来解决这些障碍，环磷酰胺已被证明通过抗血管生成和抑制T调节细胞来改变肿瘤微环境。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Neuroblastoma is a form of pediatric cancer that leads to significant morbidity and mortality. As the 2nd most common malignant solid tumor, it accounts for greater than 10% of all pediatric cancer deaths. With current therapy, overall survival remains less than 30-40% for patients with stage 4 high-risk disease and there is an urgent need for improved treatments options for these children. We and other groups have show immunological and clinical efficacy with the use of neuroblastoma-specific immunotherapy. Due to the heterogeneous nature of neuroblastoma, teaching the immune system to target a diverse tumor antigen repertoire and use a broader array of host effector mechanisms with the use of tumor cell vaccines may provide increased anti-tumor efficacy when compared to adoptive cellular and monoclonal antibody therapy. During our last allogeneic tumor cell vaccine trial, we were able to induce clinical responses, including complete remissions, in patients with relapsed/refractory disease. However, the overall results were likely limited by the number of tumor antigens presented and the inhibitory microenvironment of the tumor. In this clinical study, we propose to address these obstacles by 1) modifying the vaccine product to increase the number of tumor associated antigens presented to the immune system, and 2) combine vaccination with metronomic oral cytoxan which has been show to alter the tumor microenvironment via anti-angiogenesis and suppression of T regulatory cells.