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- Open Access
Synergistic antitumor activity of the CD122-biased immunostimulatory cytokine NKTR-214 when combined with anti-PD-1 in murine tumor models
© Murali et al. 2015
- Published: 4 November 2015
- Treg Cell
- Tumor Growth Inhibition
- Murine Tumor Model
- Initial Tumor Volume
- Dose Initiation
NKTR-214 is an immunotherapeutic drug that exerts its biological activity by binding and activating the interleukin-2 (IL-2) receptor beta subunit (IL-2Rb), thereby causing expansion of memory effector T cells in the tumor. NKTR-214 consists of 4-6 releasable polyethylene glycol (PEG) chains conjugated to IL-2 at a defined region within the protein. In vivo, some of these PEG chains slowly release to generate active IL-2 conjugates. The location of these PEG chains on IL-2 interferes with its interaction on the IL-2 receptor alpha (IL-2Ra), responsible for activating undesirable Treg cells in tumor. In vivo, the receptor bias markedly increases the ratio of tumor killing CD8 T cells to Treg cells in tumors, while simultaneously leading to high and sustained tumor exposure. NKTR-214 showed marked single agent efficacy in aggressive murine tumors, and synergy with anti-CTLA-4, producing durable responses. Here, we examine the efficacy and mechanism of NKTR-214 combined with anti-PD-1 in murine tumor models.
Mice bearing subcutaneous CT26 colon, EMT6 mammary, or LLC Lewis Lung carcinoma tumors were treated with NKTR-214 i.v. every nine days (three administrations), murine anti-PD-1 twice-weekly for three weeks, or both in combination. Efficacy was determined based on tumor growth inhibition relative to vehicle (TGI), long-term tumor growth delay measured by time to reach 4x initial tumor volume (Tumor Volume Quadrupling Time, TVQT), and number of long term tumor-free animals.
In the CT26 model, single agent NKTR-214 led to greater TGI (66%) at day 11 than anti-PD-1 alone (37%). The combination proved synergistic with 9/10 animals tumor-free 100 days after dosing initiation. The EMT6 model proved more resistant to single-agent therapy, with NKTR-214 yielding 42% TGI at day 17. While TGI was not enhanced by addition of anti-PD-1, TVQT was increased to 29.6 days relative to single agent NKTR-214 (16.7) and vehicle (10.9), with 4/10 tumor free animals 73 days after dosing initiation. Finally, the LLC model proved sensitive to NKTR-214 single agent, with a 59% TGI at day 11 and 2/10 animals tumor free, while anti-PD-1 alone was not active. The combination of the two agents increased TVQT (20 days) compared to NKTR-214 alone (14), anti-PD1 alone (8) and vehicle (7), and increased tumor-free animals (4/10) relative to NKTR-214 (2/10) and anti-PD1 (1/10) alone.
NKTR-214 provides an antibody-like dosing regimen and complementary mechanism of action to checkpoint inhibition. The synergy observed in mouse models holds promise for durable responses in humans.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.