First-in-human evaluation of a no-alpha interleukin-2 mutein: safety and preliminary pharmacodynamic and clinical effect

Abstract

Introduction: Interleukin 2 (IL-2) is essential for immune system activation. To reduce toxicity and prevent the activation of regulatory T cells (T-regs), a novel IL-2 variant containing 4-point mutations that prevent its interaction with the alpha chain of the receptor was designed. In preclinical studies, the no-alpha mutein preferentially stimulate CD8-T cells and natural killer (NK) cells compared to Tregs. Mutein also showed greater antitumor capacity than the native molecule in several tumor models.

Methods: Patients with advanced solid tumors were included in a single-arm dose-escalation Phase I trial. The objectives of this study were to evaluate the safety and identify the recommended phase 2 dose. The effects on the most important immune subpopulations and preliminary objective response were also assessed. The protocol was listed in the National Registry for Clinical Trials (https://rpcec.sld.cu/ensayos/RPCEC00000234-En).

Results and discussion: In this phase I trial, 13 patients with advanced cancer were treated with five dose levels of IL-2 mutein, from 300 to 2400 IU/kg. The treatment was safe, and the maximum tolerated dose was not reached. Dose escalation did not continue, as a greater clinical and pharmacodynamic effect was observed at intermediate doses. One patient developed a possibly related serious event consisting on ventricular dysfunction and pneumonitis. No toxic deaths or vascular leak syndromes were detected, and the most frequent toxicities were chills, fever, and tachycardia. After treatment, most patients experienced an expansion of the total lymphocyte counts and the CD8-T cells and NK cells.

Clinical trial registration: https://rpcec.sld.cu/ensayos/RPCEC00000234-En, identifier RPCEC00000234.

Keywords: cancer immunotherapy; first-in-human; interleukin-2; mutein; phase I.

Figure 1

Consort diagram showing inclusion, treatment allocation per dose level and retention throughout the study.

Figure 2

(A) Peripheral blood lymphocyte expansion after the treatment with no-alpha IL-2 mutein after cycle 1 (C1), cycle 2 (C2) or 1-month post-therapy (1M PT). (B) Maximum fold expansion per patient.

Figure 3

Gating strategy to analyze proliferation levels of NK, CD8 T cells and T-regs subsets. Proliferation levels and frequency of relevant lymphocyte populations (CD8 lymphocytes, NK and regulatory T cells) before and after treatment. Asterisks represent statistical significance where *** indicates greater significance.

Figure 4

Water-fall plots showing the individual response according RECIST 1.1, after completing the mutein course (A) as well as the best overall response achieved during the 12 months follow-up (B). (C) Swimmer plot describing the individual patient outcome including best response and survival. Patients 5 and 7 are alive at the moment of data cutoff (black arrows).