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）：考虑到许多癌症的常规治疗方式正在进行的高原，需要开发新的治疗方式。免疫疗法就是一个例子。在过去的八年中，候选人建立了一种有效的基础设施，用于进行研究者发起的基因改性，基于细胞的基于细胞的疫苗，以治疗各种癌症。莫菲特高级领导层最近将该计划确定为癌症中心将支持的5个高优先计划之一，候选人最近被任命为免疫学和免疫疗法计划的共同计划。借助这种功能齐全的基础设施，经验丰富的员工以及基本和临床研究的科学家可以从科学假设开始，创建在临床前设置中进行测试，进行原则证明实验所需的适当治疗剂，执行安全和表征测试，以对1ND应用程序进行支持，并进行临床，并制造了对免疫临床的监测，并在所有临床上进行了监视，并对所有临床进行了调查，对所有的临床进行了调查，对所有的临床进行了调查。该策略的免疫学影响，并根据基础研究实验室中测试的临床试验的结果产生新的假设。两种主要疫苗在早期试验中产生了功效的证据。提出的研究将向前进，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状细胞的疫苗，以及（2）GM-CSF和CD40表达配体的旁观者细胞系与肿瘤细胞混合为肿瘤抗原的来源。针对肿瘤细胞免疫抑制作用的增强策略是：（1）ATRA，（2）1-甲基色氨酸（IDO抑制剂）和（3）淋巴结凝集以消除T REN REN REN REN RENEN并诱导稳态T细胞增殖。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进行10项涉及这些方法的临床试验。莫菲特癌症中心的临床量很大（每年20万次诊所就诊），可以快速应对试验。持续增长稳定，因此有一个计划在今年招募5位教职员工，然后在未来5年内每年3名。这将为潜在的受训者以及血液学和肿瘤学以及外科肿瘤学奖学金培训计划提供极好的来源。建立了机构K12赠款，以支持这些人进行研究的保护时间，并且该机构最近获得了K30授予以患者为导向的临床研究培训。当前的赠款将使候选人从众多的行政职责中原谅，并允许他为进行临床研究和指导而付出更多的努力，考虑到过去几年的免疫疗法计划的急剧扩展，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