Effect of a novel IL-2 cytokine immune agonist (NKTR-214) on proliferating CD8+T cells and PD-1 expression on immune cells in the tumor microenvironment in patients with prior checkpoint therapy.

Abstract

2545 Background: NKTR-214 is a CD122-biased agonist designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) to preferentially activate and expand effector CD8+ T and NK cells over T regulatory cells in the tumor microenvironment. Immune changes in the tumor microenvironment after NKTR-214 treatment was assessed in patients with locally advanced or metastatic solid tumors. Methods: NKTR-214 was administered IV in an outpatient setting q2w or q3w. Serial blood and tumor tissue samples were collected to measure immune activation using immunophenotyping including flow cytometry, immunohistochemistry (IHC), T cell clonality and gene expression analyses. Results: 26 patients (pts) have been treated with NKTR-214 at q3w, 4@0.003, 9@0.006, 6@0.009 and 1@0.012 mg/kg. Six pts received 0.006 mg/kg q2w. 58% of pts had prior immunotherapy. The most common Gr1-2 TRAEs were fatigue (73%) and pruritus (65%), and decreased appetite (46%). One pt experienced Gr3 syncope and hypotension at the highest dose tested and continued treatment at a lower dose. No drug-related AEs led to study discontinuation. No immune-related AEs or capillary leak syndrome were observed. 6 pts (23%) experienced tumor shrinkage from 10-30%. Three immunotherapy naïve pts receiving sequential anti-PD1 therapy, after ending treatment with NKTR-214, experienced significant tumor regression at first scan. In all pts evaluated, blood samples showed increases in newly proliferating (Ki67+) T and NK cells 8 days post dose. Flow cytometry and/or IHC revealed an up to 10-fold increase from baseline in tumor CD8+T and NK cells in the tumor microenvironment, with minimal changes to Tregs. PD-1 expression increased 2-fold in TILs. Gene expression analysis of tumor tissue showed increases in several immune checkpoint genes, cytotoxic markers (IFNg, PRF1, and GZMB), as well as a dynamic change in T cell clonality. Conclusions: Based on a favorable safety profile and strong correlative biomarker data, a phase 1/2 trial combining NKTR-214 and nivolumab is currently enrolling. Clinical trial information: NCT02869295.

A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors

“…2E), may have dampened the potential of these CD8 + PD-1 + T cells to convert patients into responders (31)(32)(33). Intriguingly, 1 month started anti-PD-1 treatment and experienced rapid tumor reductions at first scan on-treatment, resulting in partial responses (34). These anecdotal observations supported the hypothesis that NKTR-214 treatment may have conditioned the TME by expanding activated TILs, thereby potentially providing synergy with therapies that block inhibitory signals, such as those of the PD-1/PD-L1 axis.…”

Antitumor T-cell Homeostatic Activation Is Uncoupled from Homeostatic Inhibition by Checkpoint Blockade

“…Despite the importance of γ c cytokines for T-cell activation, their development as cancer therapies has been elusive. Recent improvements in γ c cytokine formulation and dosing [69] have yielded promising preliminary results, prompting combination trials with checkpoint blockade [69]. Our IT approach, similarly, provides transferred T-cells with increased access to (endogenous) γ c cytokines.…”

Cancer immunotherapy beyond immune checkpoint inhibitors

“…One patient had a 40% decrease in LDH, and another patient had an unconfirmed CR after only 6 weeks of treatment [ 128 ]. The latter trial revealed no dose-limiting toxicities, a tumor size reduction ranging from 10 to 30% in 6 out of 26 patients (23%), and an increase of T cells and NK cells within the tumor microenvironment in 100% of patients [ 129 ].…”