Abstract 1598: Single agent NKTR-214, a biased IL2 pathway agonist, increases immune cell infiltrates in brain tumors and prolongs survival in rodent (rattus) glioblastoma (GBM)
Authors: Recht Lawrence , Nagpal Seema , Jang Taichang , Merchant Milton , Choi Irene , Hoch Ute , Charych Deborah 
Published: July 2017

Abstract
Background: Immunotherapy is an attractive option for brain tumor therapy if a robust infiltrative T cell response can be elicited in the tumor. NKTR-214 is a CD122-biased cytokine agonist conjugated with multiple releasable chains of polyethylene glycol and designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβγ) to preferentially activate and expand effector CD8+ T and NK cells over Tregs. To assess the potential activity of single agent NKTR-214 in GBM, we used an orthotopic rat glioblastoma survival model.
Methods:NKTR-214 was administered at 0.1 or 0.3 mg/kg q2w iv to Sprague-Dawley rats starting 2 or 7 days (D2, D7) post (p)-implantation of 106 C6 glioma cells into the right striatum. The model requires euthanasia by ~D14 due to tumor burden. Brain tumors were characterized by magnetic resonance (MR) and immunohistochemistry (IHC) for infiltration of CD4+ and CD8+ T cells and for retention of PEG polymer in brain tumor.
Results: Compared to rats receiving vehicle (n = 15), survival was significantly prolonged after NKTR-214 treatment (n = 43, mean 17.2 vs. 10.0 days (P &lt; 0.001) with 15% of rats across all groups alive and tumor-free at Day 50 when the study was terminated. Both doses were equally effective and well tolerated. Surprisingly, treated rats bearing large MR-detectable D7 tumors survived significantly longer compared to rats bearing microscopic D2 tumors (6/21 or ~30% versus 0/21 or 0% respectively at D50, mean 23.1 vs. 12 days, P &lt; 0.004). Concordantly, CD8+ T cells in D7 tumors were significantly increased after NKTR-214 therapy compared to vehicle and D2 tumors, while CD4+ remained low with no significant difference between groups. PEG polymer was detected in the tumor at least 72 hours p-injection.
Conclusions: NKTR-214 is well tolerated, prolongs survival and induces immunological activity in the brain when administered to rats harboring orthotopic GBM. While there was no significant dose dependence, a marked increase in survival was observed when larger D7 tumors were treated with NKTR-214 compared to microscopic D2 tumors, associated with increased intratumoral CD8+ T cells. Levels of CD4+ were unchanged, consistent with the mechanism of CD-122 biased activation of the IL2 pathway. While requiring further study, it is intriguing that the increased sensitivity of larger tumors also corresponds to onset of angiogenesis and rapid tumor growth in this model. NKTR-214 is currently being evaluated in an outpatient Phase 1 / 2 clinical trial for the treatment of solid tumors. The results presented suggest a potential role for NKTR-214 in the treatment of patients afflicted with GBM.
Citation Format: Lawrence Recht, Seema Nagpal, Taichang Jang, Milton Merchant, Irene Choi, Ute Hoch, Deborah Charych. Single agent NKTR-214, a biased IL2 pathway agonist, increases immune cell infiltrates in brain tumors and prolongs survival in rodent (rattus) glioblastoma (GBM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1598. doi:10.1158/1538-7445.AM2017-1598