Preclinical Efficacy of Decoy-Resistant IL-18 in Hematological Malignancies

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 IL-18 signaling. Accordingly, Decoy-Resistant IL-18 (DR-18), an engineered IL-18 cytokine capable of interacting with the IL-18 receptor but resistant to IL-18BP inhibition, has demonstrated enhanced therapeutic potential in mouse solid tumor models, both as a single agent and in combination with anti-PD-1 [Zhou T, et al. Nature. 2020;583(7817):609-614.], and in leukemia following allogeneic bone marrow transplantation (alloBMT) [Minnie SA et al. Sci Immunol. 2022;7(76):eabo3420]. Here we evaluated murine DR-18 in a diverse set of mouse hematological tumor models, including in combination with conventional chemotoxic and immunotherapeutic agents. mDR-18's effect on survival was assessed and the immune cells required for mDR-18 activity were identified by depletion studies.

Results: Treatment with mDR-18 elicited strong efficacy as a single agent and showed combination activity across diverse syngeneic mouse models of hematological tumors. mDR-18 demonstrated robust single agent activity in tumor growth inhibition for subcutaneously implanted A20 B-cell lymphoma (95%), C1498 Acute myeloid leukemia (85%), and MPC-11 Plasma cell myeloma (50%). Combination treatment of mDR-18 with Aza+Vento chemotherapy increased treatment efficacy in C1498 (95%). mDR18 also showed increased survival as a single agent that was enhanced in combination with Aza+Vento. To ascertain the immune cells required for this activity of mDR-18, animals with C1498 tumors were treated with mDR-18 while depleting either CD4+, CD8+, NK1.1+, or both CD4+ & CD8+ cells from the mice. The activity of mDR-18 was abrogated in CD8+ and CD4+/CD8+ cell depleted animals. Examining the role of mDR-18 in combination with Blinatumomab, a CD3-CD19 bi-specific T-Cell engager, demonstrated greater tumor growth inhibition and a more durable response than monotherapy with either agent.

Conclusion: These studies extend the efficacy of DR-18 therapy in hematologic malignancies and demonstrate the potential benefit of combining DR-18 with additional agents beyond anti-PD-1, including chemotherapy and T cell engagers. These findings strengthen the rationale for expanding the use of the Phase I human DR-18 cytokine (ST-067, NCT04787042 & NCT06492707) in combination therapies for patients with hematological tumors.

Lindquist:Simcha Therapeutics: Current Employment, Current equity holder in private company. Liu:Simcha Therapeutics: Current Employment, Current equity holder in private company. Ring:Simcha Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Uppal:Simcha Therapeutics: Current Employment, Current equity holder in private company.