Development of Immunotherapeutic Strategies in the Treatment of Lung Cancer

描述（由申请人提供）：鉴于许多癌症的常规治疗方式处于平台期，需要开发新的治疗方式。免疫疗法就是一个例子。在过去的8年里，候选人已经建立了一个有效的基础设施，用于开展研究者发起的、基因修饰的、基于细胞的疫苗，用于治疗各种癌症。该项目最近被Moffitt高级领导层确定为癌症中心将支持的5个高优先级项目之一，候选人最近被任命为免疫学和免疫治疗项目的联合项目负责人。有了这个功能齐全的基础设施，经验丰富的工作人员以及基础和临床研究科学家可以从科学假设开始，创建测试假设所需的适当治疗方法，在临床前环境中进行原理验证实验，进行安全性和特性测试以支持nd应用，扩大和生产免疫治疗药物，谈判所有所需的监管机构审查，进行临床试验，监测该策略的临床和免疫效果，并根据在基础研究实验室测试的临床试验结果产生新的假设。有两种主要疫苗在早期试验中产生了有效的证据。拟议的研究将推动这些疫苗向前发展，将它们与肺癌患者的肿瘤疫苗增强策略相结合。这两种疫苗分别是：(1)以p53为肿瘤抗原的树突状细胞疫苗，以及(2)与肿瘤细胞混合的表达GM-CSF和CD40配体的旁观者细胞系作为肿瘤抗原来源。针对肿瘤细胞免疫抑制作用的增强策略有：(1)ATRA,(2) 1-甲基色氨酸（IDO抑制剂），(3)淋巴细胞清除T细胞，诱导稳态T细胞增殖。该候选人目前正在指导7名肿瘤学研究员和助理教授开发和开展涉及这些方法的10项临床试验。莫菲特癌症中心有很大的临床量（每年20万门诊访问量），这使得试验可以快速积累。我们还在稳步增长，所以我们计划今年招聘5名教员，在接下来的5年里每年招聘3名。这将提供一个极好的潜在学员来源，以及血液学和肿瘤学，以及外科肿瘤学奖学金培训项目。一项机构K12拨款到位，以支持这些个人进行研究的保护时间，该机构最近获得了K30拨款，以支持以患者为导向的临床研究培训。目前的拨款将允许候选人免除许多行政责任，并允许他投入更多的精力进行临床研究和指导，这是考虑到免疫治疗项目在过去几年中急剧扩张所必需的。

DESCRIPTION (provided by applicant): Given the plateau in progress made with conventional treatment modalities for many cancers, novel treatment modalities need to be developed. Immunotherapy is an example. Over the past 8 years the Candidate has built an effective infrastructure for conducting investigator-initiated, gene-modified, cell- based vaccines for the treatment of a variety of cancers. This program was recently identified by the Moffitt senior leadership as one of 5 high priority programs that the cancer center will be supporting, and the Candidate was recently named Co-Program Leader of the Immunology and Immunotherapy Program. With this fully functional infrastructure, experienced staff along with the basic and clinical research scientists can begin with a scientific hypothesis, create the appropriate therapeutics needed to test the hypothesis, perform proof-of-principle experiments in the preclinical setting, perform the safety and characterization testing in support of 1ND applications, scale up and manufacture the immunotherapeutics, negotiate all of the required regulatory agency review, conduct the clinical trial, monitor the clinical and immunologic effects of the strategy, and generate new hypotheses based on the results of the clinical trials that are tested in the basic research laboratories. Two main vaccines have produced evidence of efficacy in early phase trials. The research proposed will move these vaccines forward, combining them with tumor vaccine augmentation strategies in lung cancer patients. The vaccines are (1) a dendritic cell-based vaccine using p53 as the tumor antigen, and (2) a GM-CSF and CD40 ligand-expressing bystander cell line admixed with tumor cells as the source of tumor antigens. The augmentation strategies targeting the immunosuppressive effects of tumor cells are: (1) ATRA, (2) 1-methyl tryptophan (IDO inhibitor), and (3) lymphodepletion to eliminate T reg cells and induce homeostatic T cell proliferation. The candidate is currently mentoring 7 Oncology Fellows and Assistant Professors in developing and conducting 10 clinical trials involving these approaches. The Moffitt Cancer Center has a large clinical volume (200,000 clinic visits per year) which allows for rapid accrual to trials. There continues to be steady growth, and so there is a plan to recruit 5 faculty this year and then 3 per year over the next 5 years. This will provide an excellent source of potential mentees, along with the Hematology and Oncology, and Surgical Oncology Fellowship training programs. An institutional K12 grant is in place to support protected time for these individuals to perform research, and the institution was recently awarded a K30 to support patient oriented clinical research training. The current grant would allow the Candidate to be excused from numerous administrative responsibilities and allow him to commit more effort to conducting clinical research and mentoring, which is necessary given the dramatic expansion of the Immunotherapy Program over the past several years.