Combinational Immunotherapies to Amplify Vaccine Induced Immunity

描述（由申请方提供）：T细胞代表治疗性癌症疫苗产生的抗肿瘤免疫应答中的关键免疫效应物。参与这项NCDDG资助的研究人员都参与了利用当前分子技术开发诱导T细胞介导的抗肿瘤免疫应答的新方法。此外，他们最近发现了一种新的候选肿瘤抗原，该抗原在大多数胰腺癌和卵巢癌中过表达。间皮素是一大类鉴定的肿瘤相关的非突变自身抗原之一，其相对于正常组织由肿瘤细胞过表达。尽管存在诱导针对这类抗原（包括间皮素）的T细胞应答的实例，但目前采用的疫苗方法不足以克服这些自身抗原发生的外周耐受性机制。因此，有必要利用相关的动物模型来确定最有效的组合疫苗方法，这些方法可以克服肿瘤微环境内的外周耐受、全身耐受和局部耐受的天然机制，从而值得临床试验。Jaffee和Wu博士正在开发试剂，并分别在两种表达间皮素的小鼠肿瘤模型（胰腺和卵巢肿瘤模型）中测试间皮素靶向疫苗方法。利用与Pardoll博士和Chen博士在过去10年中进行的积极科学合作，NCDDG小组现在建议利用这两种小鼠模型来评估和开发更有效的抗原特异性疫苗策略，结合生物制剂形式的免疫调节剂，可以克服对肿瘤相关自身抗原的耐受性。该开发将遵循四个步骤的过程：1）NCDDG项目领导人正在开发的个体疫苗策略将针对使用可移植胰腺和卵巢肿瘤的许多参数进行优化。每个模型都提供了独特的机会来了解肿瘤微环境中的局部T细胞耐受性。2)将测量基线免疫效应子功能，作为鉴定最有效疫苗方法的额外参数。3)然后将对优化的疫苗方法根除自然发展的肝转移（胰腺肿瘤模型）和腹膜转移（卵巢肿瘤模型）的能力进行头对头比较。4)基于体内研究的数据和测量的免疫参数，将使用针对肝胰腺肿瘤转移和腹膜卵巢肿瘤转移的效力作为最终结果，对不同疫苗策略之间的潜在协同作用进行有针对性的评价。

DESCRIPTION (provided by applicant): T cells represent critical immunologic effectors in the anti-tumor immune response produced by therapeutic cancer vaccines. The investigators participating in this NCDDG grant have all been involved in utilizing current molecular technology to develop novel approaches for inducing T cell-mediated anti-tumor immune responses. In addition, they recently identified a new candidate tumor antigen that is overexpressed by the majority of pancreatic and ovarian cancers. Mesothelin is one of a large category of identified tumor-associated, non-mutated self-antigens which is overexpressed by tumor cells relative to normal tissue. Although there are examples of the induction of T cell responses against this category of antigens, including mesothelin, currently employed vaccine approaches are not potent enough to overcome the mechanisms of peripheral tolerance that occur to these self-antigens. Therefore, it is necessary to utilize relevant animal models for identifying the most potent combinatorial vaccine approaches that can overcome natural mechanisms of peripheral tolerance, systemic and locally within the tumor's micro-environment, and thus be worthy of clinical testing. Drs. Jaffee and Wu are developing the reagents and testing mesothelin-targeted vaccine approaches, in two mesothelin-expressing, murine tumor models, a pancreatic and ovarian tumor model, respectively. Taking advantage of active scientific collaborations with Drs. Pardoll and Chen, which have been ongoing over the past 10 years, the NCDDG group now proposes to utilize these two mouse models to evaluate and develop more potent antigen-specific vaccine strategies combined with immune modulators in the form of biologics, that can overcome tolerance to tumor-associated self antigens. This development will follow a four step process: 1) Individual vaccine strategies under development by the NCDDG project leaders will be optimized for a number of parameters using transplantable pancreas and ovarian tumors. Each model provides unique opportunities to understand local T cell tolerance in the tumor's micro-environment. 2) Baseline immunologic effector functions will be measured as an additional parameter for identifying the most potent vaccine approaches. 3) Optimized vaccine approaches will then be compared head-to-head for the ability to eradicate naturally developing hepatic metastases (pancreatic tumor model) and peritoneal metastases (ovarian tumor model). 4) Based on data from the in vivo studies and the measured immune parameters, a targeted evaluation of potential synergies between different vaccine strategies will be evaluated using potency against hepatic pancreatic tumor metastases and peritoneal ovarian tumor metastases as the final outcome.