Prognostic value of antibodies to Merkel cell polyomavirus T antigens and VP1 protein in patients with Merkel cell carcinoma

Samimi, Mahtab; Molet, Lucie; Fleury, Maxime; Laude, Hélène; Carlotti, A.; Gardair, Charlotte; Baudin, Martine; Gouguet, L.; Maubec, Ève; Avenel-Audran, M.; Estève, É.; Wierzbicka-Hainaut, E.; Bénéton, N.; Aubin, F.; Rozenberg, Flore; Dupin, Nicolas; Avril, Marie-Françoise; Lorette, G.; Guyétant, Serge; Coursaget, Pierre; Touzé, Antoine

doi:10.1111/bjd.14313

Cited by 59 publications

(53 citation statements)

References 37 publications

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“…27), were detected by ELISA using MCPyV virus-like particles (VLP) and the recombinant LT/ST. VLPs and LT/ST were generated and purified as previously described (27,28). Detection of VP1 and LT/ST antibodies by indirect ELISA was performed as previously described (27,28).…”

Section: Detection Of Serum Igg Antibodies Against Mcpyv Vp1 Protein mentioning

confidence: 99%

Merkel Cell Carcinomas Arising in Autoimmune Disease Affected Patients Treated with Biologic Drugs, Including Anti-TNF

Rotondo

Bononi

Puozzo

et al. 2017

Clinical Cancer Research

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Purpose: The purpose of this investigation was to characterize Merkel cell carcinomas (MCC) arisen in patients affected by autoimmune diseases and treated with biologic drugs.Experimental Design: Serum samples from patients with MCC were analyzed for the presence and titer of antibodies against antigens of the oncogenic Merkel cell polyomavirus (MCPyV). IgG antibodies against the viral oncoproteins large T (LT) and small T (ST) antigens and the viral capsid protein-1 were analyzed by indirect ELISA. Viral antigens were recombinant LT/ST and viruslike particles (VLP), respectively. MCPyV DNA sequences were studied using PCR methods in MCC tissues and in peripheral blood mononuclear cells (PBMC). Immunohistochemical (IHC) analyses were carried out in MCC tissues to reveal MCPyV LT oncoprotein.Results: MCPyV DNA sequences identified in MCC tissues showed 100% homology with the European MKL-1 strain.PBMCs from patients tested MCPyV-negative. Viral DNA loads in the three MCC tissues were in the 0.1 to 30 copy/cell range. IgG antibodies against LT/ST were detected in patients 1 and 3, whereas patient 2 did not react to the MCPyV LT/ST antigen. Sera from the three patients with MCC contained IgG antibodies against MCPyV VP1. MCC tissues tested MCPyV LT-antigenpositive in IHC assays, with strong LT expression with diffuse nuclear localization. Normal tissues tested MCPyV LT-negative when employed as control.Conclusions: We investigated three new MCCs in patients affected by rheumatologic diseases treated with biologic drugs, including TNF. A possible cause-effect relationship between pharmacologic immunosuppressive treatment and MCC onset is suggested. Indeed, MCC is associated with MCPyV LT oncoprotein activity.

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Section: Detection Of Serum Igg Antibodies Against Mcpyv Vp1 Protein mentioning

confidence: 99%

Merkel Cell Carcinomas Arising in Autoimmune Disease Affected Patients Treated with Biologic Drugs, Including Anti-TNF

Rotondo

Bononi

Puozzo

et al. 2017

Clinical Cancer Research

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“…Antibodies against VP1 are prevalent in the general population, whereas antibodies against T antigens (TAgs) are more specific to patients with MCC [29]. Interestingly, high levels of VP1 antibodies at the time of MCC diagnosis may portend a better prognosis [30, 31]. In the patients that have them, antibodies against TAgs appear to reflect disease burden, falling after treatment and rising with known or occult recurrent disease [29, 30].…”

Section: Diagnosis and Work-upmentioning

confidence: 99%

Merkel Cell Carcinoma Therapeutic Update

Cassler

Merrill

Bichakjian

et al. 2016

Curr. Treat. Options in Oncol.

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Opinion statement Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

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“…8 High titers of anti-capsid antibodies at presentation have been reported to be a favorable prognostic factor. 20, 21 However, these antibodies (which mark previous exposure) are also detectable in >60% of healthy adults. 8, 10 Furthermore, titers of antibodies to the MCPyV capsid protein do not vary with MCC tumor burden 21, 22 and thus could not serve as a biomarker for recurrence.…”

Section: Introductionmentioning

confidence: 99%

“…22 Similarly, others have shown that patients with blood draws at the time of recurrence are more likely to have detectable antibodies than those with draws at the time of remission, although longitudinal patient-specific data was not presented. 21 …”

Section: Introductionmentioning

confidence: 99%

Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: A prospective validation study

Paulson

Lewis

Redman

et al. 2016

Cancer

143

127

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Background Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of >40%. Of the 2000 MCC cases/year in the USA, most are caused by the Merkel cell polyomavirus (MCPyV). Antibodies to MCPyV-oncoprotein (T-antigens) have been correlated with MCC tumor burden. We prospectively validated the clinical utility of MCPyV oncoprotein antibody titers for MCC prognostication and surveillance. Methods MCPyV-oncoprotein antibody detection was optimized in a clinical laboratory. A cohort of 219 patients with newly-diagnosed MCC were followed prospectively (median follow-up 1.9 years). Among seropositive patients, antibody titer and disease status were serially tracked. Results Antibodies to MCPyV-oncoproteins were rare among healthy individuals (1%) but present in most MCC patients (114 of 219, 52%, p<0.01). Seropositivity at diagnosis independently predicted decreased recurrence risk (HR=0.58; p=0.04) in multivariate analyses adjusted for age, sex, stage, and immunosuppression. Following initial treatment, seropositive patients whose disease did not recur had rapidly falling titers that became negative by a median of 8.4 months. Among seropositive patients who underwent serial evaluation (71 patients; 282 timepoints), an increasing oncoprotein titer had a positive predictive value of 66% for clinically evident recurrence while a decreasing titer had a negative predictive value of 97%. Conclusions Determination of oncoprotein antibody titer assists in the clinical management of newly diagnosed MCC patients by stratifying them into a higher risk seronegative cohort in whom radiologic imaging may play a more prominent role, and into a lower-risk seropositive cohort whose disease status can be tracked in part via oncoprotein antibody titer.

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Prognostic value of antibodies to Merkel cell polyomavirus T antigens and VP1 protein in patients with Merkel cell carcinoma

Abstract: VP1 antibodies constitute a prognostic marker at baseline, whereas T-antigen antibodies constitute a marker of disease recurrence or progression if detected > 12 months after diagnosis.

Cited by 59 publications

References 37 publications

Merkel Cell Carcinomas Arising in Autoimmune Disease Affected Patients Treated with Biologic Drugs, Including Anti-TNF

Merkel Cell Carcinomas Arising in Autoimmune Disease Affected Patients Treated with Biologic Drugs, Including Anti-TNF

Merkel Cell Carcinoma Therapeutic Update

Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: A prospective validation study

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