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1.
Pediatr Blood Cancer ; 65(11): e27313, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30015384

RESUMO

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) and synovial sarcoma are rare tumors with dismal outcomes requiring new therapeutic strategies. Immunotherapies have shown promise in several cancer types, but have not been evaluated in DSRCT and synovial sarcoma. Because the immune microenvironment can provide indications of the inflammatory nature of tumors, immunohistochemical staining is able to assess the tumor immune infiltrates in both tumor types. PROCEDURE: Using tissue microarrays of DSRCT and synovial sarcoma tumor samples, we detected tumoral HLA-A/B/C, beta-2-microglobulin(B2M), and PD-L1 expression, and quantified tumor-infiltrating lymphocytes expressing CD4, CD8, CD56, CD45RO, or FOXP3 by immunohistochemistry. We used staining intensity on a scale of 0-3 and percentage of tumor stained to determine HLA, B2M, and PD-L1 scores. We calculated the cytotoxic T lymphocyte (CTL) target score as HLA score × B2M score/100. RESULTS: In diagnostic samples, we found high HLA and CTL target scores and low PD-L1 expression with decreased scores in recurrence for both tumor types. We found an increase in CD56+ natural killer cells in DSRCT samples from diagnosis to recurrence. CONCLUSIONS: We found similar immunostimulatory profiles in DSRCT and synovial sarcoma. Our findings suggest that DSRCT and synovial sarcoma may be amenable to immunotherapies, albeit there was significant heterogeneity. Interestingly, HLA and CTL target scores decreased at recurrence, possibly reflecting immunoevasion. Our findings suggest both tumor types may be amendable to CTL-based therapies at diagnosis but less so at relapse. Our results support further investigation into the prognostic and predictive value of these findings in a larger dataset.


Assuntos
Tumor Desmoplásico de Pequenas Células Redondas/imunologia , Recidiva Local de Neoplasia/imunologia , Sarcoma Sinovial/imunologia , Neoplasias de Tecidos Moles/imunologia , Biomarcadores Tumorais/imunologia , Tumor Desmoplásico de Pequenas Células Redondas/patologia , Antígenos HLA/imunologia , Humanos , Imunofenotipagem , Imunoterapia , Linfócitos do Interstício Tumoral/imunologia , Recidiva Local de Neoplasia/patologia , Sarcoma Sinovial/patologia , Neoplasias de Tecidos Moles/patologia , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/imunologia
2.
J Clin Oncol ; 30(15): 1849-56, 2012 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-22508822

RESUMO

PURPOSE: Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT). PATIENTS AND METHODS: Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated. RESULTS: Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed. CONCLUSION: Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Tumor Desmoplásico de Pequenas Células Redondas/tratamento farmacológico , Receptor IGF Tipo 1/antagonistas & inibidores , Sarcoma de Ewing/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Neoplasias Ósseas/sangue , Neoplasias Ósseas/genética , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Tumor Desmoplásico de Pequenas Células Redondas/sangue , Tumor Desmoplásico de Pequenas Células Redondas/imunologia , Tumor Desmoplásico de Pequenas Células Redondas/mortalidade , Tumor Desmoplásico de Pequenas Células Redondas/secundário , Feminino , Humanos , Hibridização in Situ Fluorescente , Fator de Crescimento Insulin-Like I/metabolismo , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA/genética , Receptor IGF Tipo 1/imunologia , Sarcoma de Ewing/sangue , Sarcoma de Ewing/genética , Sarcoma de Ewing/imunologia , Sarcoma de Ewing/mortalidade , Sarcoma de Ewing/secundário , Análise de Sequência de RNA , Fatores de Tempo , Translocação Genética , Resultado do Tratamento , Adulto Jovem
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