Pathogenetic and prognostic studies for improved therapy of Merkel cell carcinoma

描述（由申请人提供）：默克尔细胞癌（MCC）是一种侵袭性，多瘤病毒相关的皮肤癌，据报道发病率在20年内翻了两倍，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）参与了大约80%的MCC肿瘤的发病机制。一些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，为开发这种经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标本和建立的多学科合作使得免疫观察快速转化为体内应用成为可能。使用前期K24的支持下,我们有了两个新的R01基金资助开展三个“资助”的目标是:1)确定目标MCPyV的血清学检查是否有临床实用程序,目标2)地图MCPyV-specific T细胞抗原表位和创建工具来隔离,描述和增强细胞免疫反应,和目标3)I / II期临床试验,评估相结合的多克隆特异性T细胞过继治疗随着HLA-upregulating佐剂在16世纪挑战集团的病人。目前尚未得到资助的另外三个目标也将得到本K24的支持：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)利用多机构和国家注册数据集制定下一个AJCC分期系统和MCC治疗指南；目标6)与癌症免疫治疗试验网络合作，在多中心临床试验中确定PD1治疗转移性默克尔细胞癌的疗效。自K24开始以来，Nghiem博士已经指导了49名不同学科的各级学员（其中41名直接参与了Nghiem博士的研究），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开始以来，参与Nghiem博士研究的41名学员中，16名学员目前担任教职，另外22名仍在临床或以患者为导向的研究培训中。在这41名学员中，有32人与Nghiem博士合作发表了至少一篇论文。目前，Nghiem博士在K24机制主要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/医学博士研究生。在本资助期内（2009年至今），已经发表了27篇原创研究，所有这些研究都与K24的目标有关，其中26篇是与一名或多名学员共同撰写的。目前，Nghiem博士65%的工作致力于由K24资助的指导和面向患者的研究，以及由K24资助的种子项目产生的两个与MCC相关的r05。如果没有K24的支持，他现在投入到临床和行政职责上的20%的精力将需要大幅增加。

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.