Pathogenetic and prognostic studies for improved therapy of Merkel cell carcinoma

描述（由申请方提供）：默克尔细胞癌（MCC）是一种侵袭性多瘤病毒相关皮肤癌，报告的发病率在20年内翻了两番，5年疾病相关死亡率超过40%。尽管它对健康的影响越来越大，但很少有临床试验关注这种疾病。2008年发现的默克尔细胞多瘤病毒（MCPyV）参与了约80%的MCC肿瘤的发病机制。有几条证据表明免疫功能在MCC中的重要性。MCC的病毒依赖性，结合最近对其免疫逃避机制可逆性的重要见解，为开发这种通常致命的癌症的合理治疗提供了令人兴奋的机会。一套独特的强大的临床注释MCC标本和建立多学科合作，允许快速翻译的免疫观察体内应用。在前期K24的支持下，我们获得了两项新的R 01赠款，以实现三个“资助”目标：目的1）确定MCPyV的血清学测试是否具有临床实用性，目的2）绘制MCPyV特异性T细胞表位并创建分离、表征和增强细胞免疫应答的工具，以及目的3）在I/II期试验中，评估多克隆病毒特异性过继性T细胞治疗沿着与HLA上调佐剂在16名MCC患者中的组合。另外三个目标，目前没有资金，也将由这个K24支持：目的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，目的5）使用多机构和国家登记数据集开发下一个AJCC分期系统和MCC治疗指南，目的6）在与癌症免疫治疗试验网络合作的多中心临床试验中确定PD 1治疗在转移性默克尔细胞癌中的疗效。 自K24开始以来，Nghiem博士已经指导了49名学员（其中41人直接参与了Nghiem博士的研究），这些学员来自各个级别的不同学科，直到助理教授。41名学员中有40名（98%）参与了以患者为导向的研究。自K24开始以来，在Nghiem博士参与研究的41名学员中，有16名学员目前担任教职，另有22名仍在接受临床或以患者为导向的研究培训。在这41名学员中，有32人至少与Nghiem博士一起发表过一次论文。目前，Nghiem博士在K24机制的主要重点职业类别中指导15名研究学员：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/MD-PhD学生。在目前的资助期间（2009年至今），已发表了27项原创研究，所有这些研究都与K24的目标有关，其中26项是与一名或多名学员共同撰写的。目前，Nghiem博士65%的精力用于指导和以患者为导向的研究，这些研究由K24和两个MCC相关的R 01资助，这些R 01来自K24资助的种子项目。如果没有K24的支持，他现在致力于临床和行政职责的20%的努力将需要显著扩大。

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.