title: Regression of metastatic Merkel cell carcinoma following transfer of polyomavirus-specific T cells and therapies capable of re-inducing HLA class-I.
abstract: Merkel cell carcinoma (MCC) is an aggressive skin cancer that typically requires the persistent expression of Merkel cell polyomavirus (MCPyV) oncoproteins that can serve as ideal immunotherapeutic targets. Several immune evasion mechanisms are active in MCC including down-regulation of HLA class-I expression on tumor cells and dysfunctional endogenous MCPyV-specific CD8 T cell responses. To overcome these obstacles, we combined local and systemic immune therapies in a 67-year-old man, who developed metastatic MCPyV-expressing MCC. Intralesional IFNβ-1b or targeted single-dose radiation was administered as a pre-conditioning strategy to reverse the down-regulation of HLA-I expression noted in his tumors and to facilitate the subsequent recognition of tumor cells by T cells. This was followed by the adoptive transfer of ex vivo expanded polyclonal, polyomavirus-specific T cells as a source of reactive antitumor immunity. The combined regimen was well-tolerated and led to persistent up-regulation of HLA-I expression in the tumor and a durable complete response in two of three metastatic lesions. Relative to historical controls, the patient experienced a prolonged period without development of additional distant metastases (535 days compared to historic median of 200 days, 95% confidence interval = 154-260 days). The transferred CD8(+) T cells preferentially accumulated in the tumor tissue, remained detectable and functional for >200 days, persisted with an effector phenotype, and exhibited evidence of recent in vivo activation and proliferation. The combination of local and systemic immune stimulatory therapies was well-tolerated and may be a promising approach to overcome immune evasion in virus-driven cancers.
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA.
authors.forename: Aude G
authors.initials: AG
authors.lastname: Chapuis
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA ; Department of Medicine (Dermatology), University of Washington, Seattle, WA, USA.
authors.forename: Olga K
authors.initials: OK
authors.lastname: Afanasiev
authors.affiliation: Department of Medicine (Dermatology), University of Washington, Seattle, WA, USA.
authors.forename: Jayasri G
authors.initials: JG
authors.lastname: Iyer
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA ; Department of Medicine (Dermatology), University of Washington, Seattle, WA, USA.
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Paulson
authors.affiliation: Division of Radiation Oncology, UWMC, Seattle, WA, USA.
authors.forename: Upendra
authors.initials: U
authors.lastname: Parvathaneni
authors.affiliation: Division of Gastroenterology, UWMC, Seattle, WA, USA.
authors.forename: Joo Ha
authors.initials: JH
authors.lastname: Hwang
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA.
authors.forename: Ivy
authors.initials: I
authors.lastname: Lai
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA.
authors.forename: Ilana M
authors.initials: IM
authors.lastname: Roberts
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Sloan
authors.affiliation: Department of Medicine (Medical Oncology), University of Washington, Seattle, WA, USA.
authors.forename: Shailender
authors.initials: S
authors.lastname: Bhatia
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA.
authors.forename: Kendall C
authors.initials: KC
authors.lastname: Shibuya
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Gooley
authors.affiliation: Adaptive Biotechnologies, Seattle, WA, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Desmarais
authors.affiliation: Department of Medicine (Dermatology), University of Washington, Seattle, WA, USA ; Department of Laboratory Medicine, University of Washington, Seattle, WA, USA ; Department of Global Health, University of Washington, Seattle, WA, USA ; Vaccine and Infectious Disease Division, FHCRC, Seattle, WA, USA ; Benaroya Research Institute, Seattle, WA, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Koelle
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, USA.
authors.forename: Cassian
authors.initials: C
authors.lastname: Yee
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA ; Department of Medicine (Dermatology), University of Washington, Seattle, WA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Nghiem
mesh_terms: D000368:Aged; D000952:Antigens, Polyomavirus Transforming / Q000276:immunology / Q000378:metabolism; D015266:Carcinoma, Merkel Cell / Q000175:diagnosis / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D015536:Down-Regulation; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive; D008297:Male; D059965:Merkel cell polyomavirus / Q000276:immunology; D009362:Neoplasm Metastasis; D012878:Skin Neoplasms / Q000175:diagnosis / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000952:Antigens, Polyomavirus Transforming; D015395:Histocompatibility Antigens Class I