Pathogenetic and prognostic studies for improved therapy of Merkel cell carcinoma

默克尔细胞癌改进治疗的发病机制和预后研究

基本信息

批准号：
8699412
负责人：
PAUL NGHIEM
金额：
$ 17.6万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8699412
关键词：
Adjuvant American Joint Committee on Cancer Antibodies Antigens Antiviral Agents Biological Assay Biological Markers CD8B1 gene Categories Clinical Clinical Trials Collaborations Data Set Dependence Discipline Disease Doctor of Philosophy Faculty Funding Grant Growth Guidelines Health Immune Immune Targeting Immune response Immunologics Immunosuppression Immunotherapy Incidence Infiltration Link Malignant Neoplasms Maps Medicine Mentors Merkel Cells Merkel cell carcinoma Midcareer Investigator Award in Patient-Oriented Research Multi-Institutional Clinical Trial Neoplasm Metastasis Nursing Faculty Oncogene Proteins Paper Pathogenesis Patients Peptide/MHC Complex Phase I/II Trial Polyomavirus Polyomavirus Transforming Antigens Positioning Attribute Prevalence Proteins Publications Publishing Registries Reporting Research Research Training Risk Role Safety Satellite Viruses Secure Seeds Serologic tests Serological Skin Cancer Specimen Staging System Students T cell response T cell therapy T-Lymphocyte T-Lymphocyte Epitopes Therapeutic Time Training Translations Tumor Antigens Viral Viral Tumor Antigens Virus base cancer immunotherapy career cell mediated immune response exhaust immune function immunogenic improved in vivo insight mortality outcome forecast patient oriented research professor prognostic programs public health relevance research study response tool tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-associated skin cancer with reported incidence that has quadrupled in 20 years and 5-year disease-associated mortality of over 40%. Despite its growing health impact, very few clinical trials have focused on this disease. The Merkel cell polyomavirus (MCPyV), discovered in 2008, is involved in the pathogenesis of approximately 80% of MCC tumors. Several lines of evidence suggest the importance of immune function in MCC. The viral dependence of MCC, combined with important recent insights into the reversibility of its immune evasion mechanisms, present exciting opportunities to develop rational therapy for this often-lethal cancer. A uniquely strong set of clinically annotated MCC specimens and established multi-disciplinary collaborations have allowed rapid translation of immune observations to in vivo application. Using support from the K24 in the prior period, we have secured two new R01 grants to carry out three "funded" Aims: Aim 1) Determine whether a serologic test for MCPyV has clinical utility, Aim 2) Map MCPyV-specific T-cell epitopes and create tools to isolate, characterize and augment the cellular immune response, and Aim 3) In a phase I/II trial, evaluate the combination of polyclonal virus-specific adoptive T cell therapy along with HLA-upregulating adjuvants in 16 MCC patients. Three additional Aims, currently un-funded, would also be supported by this K24: Aim 4) Determine the prevalence, prognostic and therapeutic significance of Merkel polyomavirus-negative MCC tumors, Aim 5) Develop the next AJCC staging system and therapeutic guidelines for MCC using multiinstitutional and national registry datasets, Aim 6) Determine the efficacy of PD1 therapy in metastatic Merkel cell carcinoma in a multi-center clinical trial in collaboration with the Cancer Immunotherapy Trials Network. Since the start of the K24, Dr. Nghiem has mentored 49 trainees (41 of whom were directly involved in research with Dr. Nghiem) in diverse disciplines at all levels up to Assistant Professor. 40 of 41 mentees (98%) were involved in patient-oriented research. Of the 41 trainees involved in research with Dr. Nghiem since the start of the K24, 16 mentees currently hold faculty positions, and an additional 22 remain in clinical or patient- oriented research training. 32 of these 41 mentees have at least one publication with Dr. Nghiem. Currently, Dr. Nghiem mentors 15 research trainees in the career categories that are the major focus of the K24 mechanism: 3 junior clinical faculty, 3 fellows, 4 clinical residents, and 5 graduate/MD-PhD students. During the current funding period (2009 - present), 27 original research studies have been published, all of which relate to the aims of the K24 and 26 of which are co-authored with one or more mentees. Currently, 65% of Dr. Nghiem's effort is devoted to mentoring and patient-oriented research funded by the K24 and by two MCC- related R01s that arose from seed projects funded by the K24. The 20% effort he now devotes to clinical and administrative responsibilities would need to expand significantly if not for support from the K24.

描述（由申请人提供）：默克尔细胞癌 (MCC) 是一种侵袭性多瘤病毒相关皮肤癌，据报道发病率在 20 年内翻了两番，5 年疾病相关死亡率超过 40%。尽管其对健康的影响越来越大，但很少有临床试验关注这种疾病。默克尔细胞多瘤病毒 (MCPyV) 于 2008 年发现，参与约 80% MCC 肿瘤的发病机制。多项证据表明免疫功能在 MCC 中的重要性。 MCC 的病毒依赖性，加上最近对其免疫逃避机制可逆性的重要见解，为开发针对这种常常致命的癌症的合理疗法提供了令人兴奋的机会。一组独特且强大的临床注释 MCC 标本和建立的多学科合作使免疫观察能够快速转化为体内应用。利用前期 K24 的支持，我们获得了两项新的 R01 拨款，以实现三个“资助”目标：目标 1) 确定 MCPyV 血清学测试是否具有临床实用性，目标 2) 绘制 MCPyV 特异性 T 细胞图谱表位并创建工具来分离、表征和增强细胞免疫反应，目标 3) 在 I/II 期试验中，评估多克隆病毒特异性过继性 T 细胞疗法与在 16 名 MCC 患者中使用 HLA 上调佐剂。该 K24 还将支持目前尚未资助的另外三个目标：目标 4) 确定默克尔多瘤病毒阴性 MCC 肿瘤的患病率、预后和治疗意义，目标 5) 开发下一个 AJCC 分期系统和 MCC 治疗指南使用多机构和国家注册数据集，目标 6) 在与癌症免疫治疗试验合作的多中心临床试验中确定 PD1 疗法对转移性默克尔细胞癌的疗效网络。自 K24 启动以来，Nghiem 博士已指导了 49 名学员（其中 41 名直接参与 Nghiem 博士的研究），涉及各个级别的不同学科，直至助理教授。 41 名学员中有 40 名 (98%) 参与了以患者为导向的研究。自 K24 启动以来，共有 41 名学员参与 Nghiem 博士的研究，其中 16 名学员目前担任教职，另外 22 名学员仍在接受临床或以患者为导向的研究培训。这 41 名学员中，有 32 人至少发表过一篇与 Nghiem 博士合作的出版物。目前，Nghiem 博士在 K24 机制重点关注的职业类别中指导 15 名研究实习生：3 名初级临床教师、3 名研究员、4 名临床住院医师和 5 名研究生/医学博士生。在当前资助期间（2009 年至今），已发表了 27 项原创研究，所有这些研究都与 K24 的目标相关，其中 26 项是与一名或多名学员共同撰写的。目前，Nghiem 博士 65% 的精力致力于指导和以患者为导向的研究，这些研究由 K24 和由 K24 资助的种子项目产生的两个 MCC 相关 R01 资助。如果没有 K24 的支持，他现在投入的 20% 的精力将用于临床和行政职责，这需要大幅增加。