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A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rßγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors.
Bentebibel, Salah-Eddine; Hurwitz, Michael E; Bernatchez, Chantale; Haymaker, Cara; Hudgens, Courtney W; Kluger, Harriet M; Tetzlaff, Michael T; Tagliaferri, Mary A; Zalevsky, Jonathan; Hoch, Ute; Fanton, Christie; Aung, Sandra; Hwu, Patrick; Curti, Brendan D; Tannir, Nizar M; Sznol, Mario; Diab, Adi.
Afiliación
  • Bentebibel SE; The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Hurwitz ME; Yale School of Medicine, New Haven, Connecticut.
  • Bernatchez C; The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Haymaker C; The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Hudgens CW; The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Kluger HM; Yale School of Medicine, New Haven, Connecticut.
  • Tetzlaff MT; The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Tagliaferri MA; Nektar Therapeutics, San Francisco, California.
  • Zalevsky J; Nektar Therapeutics, San Francisco, California.
  • Hoch U; Nektar Therapeutics, San Francisco, California.
  • Fanton C; Nektar Therapeutics, San Francisco, California.
  • Aung S; Nektar Therapeutics, San Francisco, California.
  • Hwu P; The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Curti BD; Providence Cancer Institute and Earle A. Chiles Research Institute, Portland, Oregon.
  • Tannir NM; The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Sznol M; Yale School of Medicine, New Haven, Connecticut.
  • Diab A; The University of Texas MD Anderson Cancer Center, Houston, Texas. adiab@mdanderson.org.
Cancer Discov ; 9(6): 711-721, 2019 06.
Article en En | MEDLINE | ID: mdl-30988166
NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor ßγ to drive increased proliferation and activation of CD8+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks. SIGNIFICANCE: We believe that IL2- and IL2 pathway-targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors.See related commentary by Sullivan, p. 694.This article is highlighted in the In This Issue feature, p. 681.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Polietilenglicoles / Transducción de Señal / Interleucina-2 / Subunidad alfa del Receptor de Interleucina-2 / Neoplasias Tipo de estudio: Clinical_trials / Etiology_studies Límite: Humans Idioma: En Revista: Cancer Discov Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Polietilenglicoles / Transducción de Señal / Interleucina-2 / Subunidad alfa del Receptor de Interleucina-2 / Neoplasias Tipo de estudio: Clinical_trials / Etiology_studies Límite: Humans Idioma: En Revista: Cancer Discov Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos