TY - JOUR
T1 - A first-in-human study and biomarker analysis of NKTR-214, a novel IL2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors
AU - Bentebibel, Salah Eddine
AU - Hurwitz, Michael E.
AU - Bernatchez, Chantale
AU - Haymaker, Cara
AU - Hudgens, Courtney W.
AU - Kluger, Harriet M.
AU - Tetzlaff, Michael T.
AU - Tagliaferri, Mary A.
AU - Zalevsky, Jonathan
AU - Hoch, Ute
AU - Fanton, Christie
AU - Aung, Sandra
AU - Hwu, Patrick
AU - Curti, Brendan D.
AU - Tannir, Nizar M.
AU - Sznol, Mario
AU - Diab, Adi
N1 - Funding Information:
This project was supported in part by the Translational Molecular Pathology-Immunoprofiling lab (TMP-IL) at the Department Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center. Funding for this study was provided by Nektar Therapeutics. We thank the patients, their caregivers and families, and the investigators who participated in this study. We also thank Phillips Gilmore Oncology Communications for providing editorial support, funded by Nektar Therapeutics.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/6
Y1 - 2019/6
N2 - NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor βγ to drive increased pro-liferation 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 tolerabil-ity, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors.
AB - NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor βγ to drive increased pro-liferation 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 tolerabil-ity, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=85067213112&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067213112&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-18-1495
DO - 10.1158/2159-8290.CD-18-1495
M3 - Article
C2 - 30988166
AN - SCOPUS:85067213112
SN - 2159-8274
VL - 9
SP - 711
EP - 721
JO - Cancer discovery
JF - Cancer discovery
IS - 6
ER -