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Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance.
Roh, Whijae; Chen, Pei-Ling; Reuben, Alexandre; Spencer, Christine N; Prieto, Peter A; Miller, John P; Gopalakrishnan, Vancheswaran; Wang, Feng; Cooper, Zachary A; Reddy, Sangeetha M; Gumbs, Curtis; Little, Latasha; Chang, Qing; Chen, Wei-Shen; Wani, Khalida; De Macedo, Mariana Petaccia; Chen, Eveline; Austin-Breneman, Jacob L; Jiang, Hong; Roszik, Jason; Tetzlaff, Michael T; Davies, Michael A; Gershenwald, Jeffrey E; Tawbi, Hussein; Lazar, Alexander J; Hwu, Patrick; Hwu, Wen-Jen; Diab, Adi; Glitza, Isabella C; Patel, Sapna P; Woodman, Scott E; Amaria, Rodabe N; Prieto, Victor G; Hu, Jianhua; Sharma, Padmanee; Allison, James P; Chin, Lynda; Zhang, Jianhua; Wargo, Jennifer A; Futreal, P Andrew.
Afiliação
  • Roh W; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Chen PL; Cancer Biology Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
  • Reuben A; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Spencer CN; Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Prieto PA; Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Miller JP; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Gopalakrishnan V; Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Wang F; Oncology Research for Biologics and Immunotherapy Translation, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Cooper ZA; Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Reddy SM; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Gumbs C; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Little L; Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Chang Q; Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Chen WS; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Wani K; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • De Macedo MP; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Chen E; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Austin-Breneman JL; Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Jiang H; Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Roszik J; Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Tetzlaff MT; Pathology Department, A.C.Camargo Cancer Center, São Paulo, SP-01509-010, Brazil.
  • Davies MA; Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Gershenwald JE; Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Tawbi H; Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Lazar AJ; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Hwu P; Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Hwu WJ; Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Diab A; Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Glitza IC; Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Patel SP; Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Woodman SE; Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Amaria RN; Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Prieto VG; Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Hu J; Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Sharma P; Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Allison JP; Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Chin L; Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Zhang J; Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Wargo JA; Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Futreal PA; Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sci Transl Med ; 9(379)2017 03 01.
Article em En | MEDLINE | ID: mdl-28251903
ABSTRACT
Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T cell receptor sequencing and whole-exome sequencing within the same cohort and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of CNAs identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was nonredundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Resistencia a Medicamentos Antineoplásicos / Antígeno CTLA-4 / Receptor de Morte Celular Programada 1 / Neoplasias Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Resistencia a Medicamentos Antineoplásicos / Antígeno CTLA-4 / Receptor de Morte Celular Programada 1 / Neoplasias Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article