Development of Immunotherapeutic Strategies in the Treatment of Lung Cancer

肺癌免疫治疗策略的发展

• 批准号: 8311051
• 负责人: SCOTT J. ANTONIA
• 金额: $ 17.12万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311051
• 关键词: Antigens; Autologous Tumor Cell; Award; Basic Science; CD40 Ligand; Cancer Center; Cancer Patient; Cancer Vaccines; Cell Line; Cells; Clinic Visits; Clinical; Clinical Research; Clinical Trials; Commit; Conduct Clinical Trials; Dendritic Cells; Development; Disease; Faculty; Fellowship; Gene-Modified; Genes; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Hematology; Immune response; Immunologics; Immunology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Individual; Induction of Apoptosis; Injection of therapeutic agent; Institution; Laboratories; Leadership; Malignant Neoplasms; Malignant neoplasm of lung; Mantle Cell Lymphoma; Mediation; Mentors; Modality; Monitor; Names; Normal Cell; Phase; Recruitment Activity; Research; Research Infrastructure; Research Personnel; Research Support; Research Training; SECTM1 gene; Safety; Scientist; Source; Surgical Oncology; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Time; Training Programs; Tretinoin; Tumor Antigens; Vaccines; base; conventional therapy; design; experience; high risk; inhibitor/antagonist; manufacturing scale-up; melanoma; methyl tryptophan; neoplastic cell; novel; oncology; patient oriented; pre-clinical; professor; programs; research study; response; sarcoma; soft tissue; tumor; tumor growth

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.

描述（由申请人提供）：鉴于许多癌症的常规治疗方式所取得的进展处于平台期，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，候选者已经建立了有效的基础设施，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。该项目最近被莫菲特高层领导确定为癌症中心将支持的 5 个高度优先项目之一，该候选人最近被任命为免疫学和免疫治疗项目联合项目负责人。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疗法，在临床前环境中进行原理验证实验，执行安全性和表征支持 1ND 应用的测试，扩大和生产免疫疗法，协商所有必需的监管机构审查，进行临床试验，监测策略的临床和免疫学效果，并根据临床试验的结果产生新的假设在基础研究实验室进行测试。两种主要疫苗已在早期试验中提供了有效性证据。拟议的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。这些疫苗是（1）使用p53作为肿瘤抗原的基于树突状细胞的疫苗，以及（2）与肿瘤细胞混合的表达GM-CSF和CD40配体的旁观细胞系作为肿瘤抗原的来源。针对肿瘤细胞免疫抑制作用的增强策略包括：(1) ATRA、(2) 1-甲基色氨酸（IDO 抑制剂）和 (3) 淋巴清除以消除 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。莫菲特癌症中心拥有庞大的临床量（每年 200,000 次就诊），可以快速积累试验。继续稳定增长，因此计划今年招聘 5 名教职人员，并在未来 5 年内每年招聘 3 名。这将提供潜在受训者的绝佳来源，以及血液学和肿瘤学以及外科肿瘤学奖学金培训计划。机构 K12 拨款已到位，以支持这些个人进行研究的受保护时间，并且该机构最近获得了 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众多行政职责，并允许他投入更多精力进行临床研究和指导，考虑到过去几年免疫治疗计划的急剧扩张，这是必要的。

项目成果

Soft tissue sarcoma clinical practice guidelines in oncology.

肿瘤学软组织肉瘤临床实践指南。

• 发表时间: 2005
• 期刊: Journal of the National Comprehensive Cancer Network : JNCCN
• 作者: Demetri,GeorgeD;Baker,LaurenceH;Beech,Derrick;Benjamin,Robert;Casper,EphraimS;Conrad3rd,ErnestU;DeLaney,ThomasF;Ettinger,DavidS;Heslin,MartinJ;Hutchinson,RayJ;Kiel,Krystyna;Kraybill,WilliamG;Letson,GDouglas;Neff,James
• 通讯作者: Neff,James

Phase II study of sunitinib malate, a multitargeted tyrosine kinase inhibitor in patients with relapsed or refractory soft tissue sarcomas. Focus on three prevalent histologies: leiomyosarcoma, liposarcoma and malignant fibrous histiocytoma.

• DOI: 10.1002/ijc.25843
• 发表时间: 2011-10-15
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Mahmood, S. Tariq;Agresta, Samuel;Vigil, Carlos E.;Zhao, Xiuhua;Han, Gang;D'Amato, Gina;Calitri, Ciara E.;Dean, Michelle;Garrett, Christopher;Schell, Michael J.;Antonia, Scott;Chiappori, Alberto
• 通讯作者: Chiappori, Alberto

Paclitaxel and TRAIL synergize to kill paclitaxel-resistant small cell lung cancer cells through a caspase-independent mechanism mediated through AIF.

• 发表时间: 2011-10
• 期刊: Anticancer research
• 影响因子: 2
• 作者: T. Hunter;Neil J. Manimala;K. Luddy;Tracy Catlin;S. Antonia