A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rßγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors.
Cancer Discov
; 9(6): 711-721, 2019 06.
Article
in En
| MEDLINE
| ID: mdl-30988166
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Polyethylene Glycols
/
Signal Transduction
/
Interleukin-2
/
Interleukin-2 Receptor alpha Subunit
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Neoplasms
Type of study:
Clinical_trials
/
Etiology_studies
Limits:
Humans
Language:
En
Journal:
Cancer Discov
Year:
2019
Document type:
Article