RESUMEN
BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive, high-grade, cutaneous neuroendocrine tumour (NET). Agents blocking programmed death 1/programmed death ligand 1 have efficacy in metastatic MCC (mMCC), but half of patients do not derive durable benefit. Somatostatin analogues (SSAs) are commonly used to treat low- and moderate-grade NETs that express somatostatin receptors (SSTRs). OBJECTIVES: To assess SSTR expression and the efficacy of SSAs in mMCC, a high-grade NET. Methods In this retrospective study of 40 patients with mMCC, SSTR expression was assessed radiologically by somatostatin receptor scintigraphy (SRS; n = 39) and/or immunohistochemically when feasible (n = 9). Nineteen patients (18 had SRS uptake in MCC tumours) were treated with SSA. Disease control was defined as progression-free survival (PFS) of ≥ 120 days after initiation of SSA. RESULTS: Thirty-three of 39 patients (85%) had some degree (low 52%, moderate 23%, high 10%) of SRS uptake. Of 19 patients treated with SSA, seven had a response-evaluable target lesion; three of these seven patients (43%) experienced disease control, with a median PFS of 237 days (range 152-358). Twelve of 19 patients did not have a response-evaluable lesion due to antecedent radiation; five of these 12 (42%) experienced disease control (median PFS of 429 days, range 143-1757). The degree of SSTR expression (determined by SRS and/or immunohistochemistry) did not correlate significantly with the efficacy endpoints. CONCLUSIONS: In contrast to other high-grade NETs, mMCC tumours appear frequently to express SSTRs. SSAs can lead to clinically meaningful disease control with minimal side-effects. Targeting of SSTRs using SSA or other novel approaches should be explored further for mMCC.
Asunto(s)
Carcinoma de Células de Merkel , Neoplasias Cutáneas , Carcinoma de Células de Merkel/tratamiento farmacológico , Humanos , Receptores de Somatostatina , Estudios Retrospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Somatostatina/uso terapéuticoRESUMEN
Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.
Asunto(s)
Carcinoma de Células de Merkel/terapia , Genes MHC Clase I/genética , Inmunoterapia Adoptiva/métodos , Recurrencia Local de Neoplasia/genética , Infecciones por Polyomavirus/terapia , Neoplasias Cutáneas/terapia , Escape del Tumor/genética , Infecciones Tumorales por Virus/terapia , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/trasplante , Carcinoma de Células de Merkel/genética , Carcinoma de Células de Merkel/inmunología , Carcinoma de Células de Merkel/virología , Receptores Coestimuladores e Inhibidores de Linfocitos T/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica , Genes MHC Clase I/inmunología , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/trasplante , Masculino , Poliomavirus de Células de Merkel/inmunología , Poliomavirus de Células de Merkel/aislamiento & purificación , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Infecciones por Polyomavirus/genética , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/virología , Neoplasias Testiculares/inmunología , Neoplasias Testiculares/secundario , Neoplasias Testiculares/virología , Transcripción Genética/inmunología , Trasplante Autólogo/métodos , Infecciones Tumorales por Virus/genética , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virologíaRESUMEN
Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer with a higher propensity for recurrence and metastasis than melanoma or squamous cell carcinoma. Despite aggressive behavior and the tripling of its reported incidence in the past 20 years, there is extensive confusion about how MCC should be managed. Here we address two issues that have impeded optimal MCC management: lack of a consensus staging system and lack of unique diagnostic codes for MCC. Five conflicting systems currently used to stage MCC will be replaced by one system in 2010 that will diminish confusion about prognosis and management among physicians and patients. The diagnostic bundling of MCC with numerous less aggressive skin cancers leads to care refusals by insurance and an inability to track MCC care costs. Worldwide adoption in 2009 of specific diagnostic codes for MCC will also improve understanding and management of this often-lethal skin cancer.