Abstract 4073: Decoy-resistant IL-18 enhances checkpoint inhibitor combinations beyond anti-PD-1 <i>in vitro</i> and <i>in vivo</i>
Authors: Jeffrey N. Lindquist, Kai Qin, Aaron M. Ring, Hirdesh Uppal
Journal: Cancer Research (2024)

Abstract Background: Interleukin-18 (IL18) is a proinflammatory cytokine that modulates both innate and adaptive immune responses. Historically, wild-type recombinant IL-18 has shown limited anti-tumor efficacy in preclinical models and clinical trials, likely due to upregulation of IL-18 binding protein (IL-18BP), a negative regulator of the IL-18 signaling axis. Accordingly, an engineered IL-18 cytokine capable of interacting with the IL-18 receptor, but resistant to IL-18BP interactions (i.e., “Decoy-Resistant IL-18”, DR-18), has demonstrated enhanced therapeutic potential in mouse tumor models, both as a single agent and in combination with anti-PD-1 [1, 2]. Here we evaluated murine DR-18 in combination with additional checkpoint inhibitors beyond anti-PD-1 in a set of mouse tumor models, and tested human DR-18 activity in vitro/ex vivo for activation of human immune cells and anti-tumor activity. Results: Treatment with mDR-18 elicited strong efficacy as a single agent and combination activity with immune checkpoint inhibitors (ICIs) across diverse syngeneic mouse models of solid tumors. As a single agent, mDR-18 demonstrated robust single agent activity in tumor growth inhibition for MC38 (&amp;gt;80%), CT26 (&amp;gt;60%) and B16-F10 (&amp;gt;55%). Combination treatment of mDR-18 with anti-PD-1, anti-CTLA-4, or anti-LAG-3 increased the efficacy for the MC38 (&amp;gt;85-95%), CT26 models (&amp;gt;80-85%), while the B16-F10 (&amp;gt;60%) showed smaller efficacy enhancement with the combinations. In vitro assays revealed human DR-18 (ST-067) activated immune cells and enhanced A549 tumor cell killing over 72hrs. Furthermore, ex vivo studies of 3D patient-derived tumor spheroids demonstrated that ST-067 impaired growth and increased immune cell infiltration, highlighting the potential of hDR-18 to enhance immune activity within the human tumor microenvironment. Conclusion: These studies expand the breadth of IL-18/checkpoint synergism beyond anti-PD-1 and confirm enhanced human immune response in vitro with the clinical candidate ST-067. Taken together, these findings strengthen the rationale for clinical combination of ST-067 with ICI agents in patients with solid tumors. 1.Zhou T, Damsky W, Weizman OE, et al. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature. 2020;583(7817):609-614. doi:10.1038/s41586-020-2422-62.Minnie SA, Waltner OG, Ensbey KS, et al. Depletion of exhausted alloreactive T cells enables targeting of stem-like memory T cells to generate tumor-specific immunity. Sci Immunol. 2022;7(76):eabo3420. doi:10.1126/sciimmunol.abo3420 Citation Format: Jeffrey N. Lindquist, Kai Qin, Aaron M. Ring, Hirdesh Uppal. Decoy-resistant IL-18 enhances checkpoint inhibitor combinations beyond anti-PD-1 in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4073.