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.

Public Health Relevance

Merkel cell carcinoma (MCC) is an uncommon, virus-associated, often-lethal skin cancer that is strongly linked to immune function. Using support from the K24, a vibrant patient oriented research effort has been established in Seattle that has led to 27 origina research publications since 2009. Extensive mentee involvement (41 mentees have been directly involved in research since the start of the K24) has been a hallmark of these efforts and the program is poised to move into several exciting immune and mechanism- based clinical trials in this competing renewal proposal based on findings during the current K24 period.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
2K24CA139052-06
Application #
8699412
Study Section
Subcommittee B - Comprehensiveness (NCI)
Program Officer
Lim, Susan E
Project Start
2014-09-01
Project End
2019-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Iyer, Jayasri G; Parvathaneni, Kaushik; Bhatia, Shailender et al. (2016) Paraneoplastic syndromes (PNS) associated with Merkel cell carcinoma (MCC): A case series of 8 patients highlighting different clinical manifestations. J Am Acad Dermatol 75:541-7
Bhatia, Shailender; Storer, Barry E; Iyer, Jayasri G et al. (2016) Adjuvant Radiation Therapy and Chemotherapy in Merkel Cell Carcinoma: Survival Analyses of 6908 Cases From the National Cancer Data Base. J Natl Cancer Inst 108:
Goh, Gerald; Walradt, Trent; Markarov, Vladimir et al. (2016) Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. Oncotarget 7:3403-15
Nghiem, Paul T; Bhatia, Shailender; Lipson, Evan J et al. (2016) PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med 374:2542-52
Paulson, Kelly G; Lewis, Christopher W; Redman, Mary W et al. (2016) Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: A prospective validation study. Cancer :
Vandeven, Natalie A; Nghiem, Paul (2016) Merkel Cell Carcinoma: An Unusually Immunogenic Cancer Proves Ripe for Immune Therapy. J Oncol Pract 12:649-50
Church, Candice D; Nghiem, Paul (2015) How does the Merkel polyomavirus lead to a lethal cancer? Many answers, many questions, and a new mouse model. J Invest Dermatol 135:1221-4
Iyer, Jayasri G; Parvathaneni, Upendra; Gooley, Ted et al. (2015) Single-fraction radiation therapy in patients with metastatic Merkel cell carcinoma. Cancer Med 4:1161-70
Paulson, Kelly G; Iyer, Jayasri G; Simonson, William T et al. (2014) CD8+ lymphocyte intratumoral infiltration as a stage-independent predictor of Merkel cell carcinoma survival: a population-based study. Am J Clin Pathol 142:452-8
Paulson, Kelly G; Tegeder, Andrew; Willmes, Christoph et al. (2014) Downregulation of MHC-I expression is prevalent but reversible in Merkel cell carcinoma. Cancer Immunol Res 2:1071-9

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