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进展平稳，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，用于进行治疗各种癌症的疫苗启动，基因修饰，基于细胞的疫苗。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沿着基础和临床研究科学家可以开始科学假设，创建测试假设所需的适当疗法，在临床前环境中进行原理验证实验，进行安全性和表征测试以支持1 ND应用，扩大和生产免疫治疗剂，协商所有必要的监管机构审查，进行临床试验，监测战略的临床和免疫效果，并根据基础研究实验室测试的临床试验结果产生新的假设。两种主要的疫苗在早期试验中已经产生了有效性的证据。这项研究将推动这些疫苗的发展，将它们与肺癌患者的肿瘤疫苗增强策略相结合。疫苗是（1）使用p53作为肿瘤抗原的基于树突细胞的疫苗，和（2）与肿瘤细胞混合的表达GM-CSF和CD 40配体的旁观者细胞系作为肿瘤抗原的来源。靶向肿瘤细胞免疫抑制作用的增强策略是：（1）ATRA，（2）1-甲基色氨酸（IDO抑制剂），和（3）淋巴细胞耗竭以消除T reg细胞并诱导稳态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。Moffitt癌症中心的临床数量很大（每年200，000次门诊访视），可以快速增加试验。继续保持稳定增长，因此计划今年招聘5名教师，然后在未来5年内每年招聘3名。这将为潜在的学员提供一个很好的来源，沿着血液学和肿瘤学以及外科肿瘤学奖学金培训计划。一个机构K12补助金到位，以支持这些人进行研究的保护时间，该机构最近被授予K30，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，并允许他投入更多精力进行临床研究和指导，这是必要的，因为免疫治疗计划在过去几年中急剧扩张。

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.