The TLR9 agonist (GNKG168) induces a unique immune activation pattern in vivo in children with minimal residual disease positive acute leukemia: Results of the TACL T2009-008 phase I study

Abstract

Abstract Background: Preclinical studies show that TLR9 agonists can eradicate leukemia by induction of immune responses in vivo against AML and ALL. These studies demonstrated that TLR9 agonists induce an immediate NK response followed by adaptive T and B cells responses resulting in long term anti-leukemia immunity. Methods: The Therapeutic Advances in Childhood Leukemia and Lymphoma Phase I consortium performed a pilot study on 3 patients with MRD positive acute leukemia after an initial remission on conventional chemotherapy (TACL T2009-008) with the TLR 9 agonist (GNKG168). To guide future trial development, we evaluated the impact of GNKG168 by Nanostring on the expression 608 genes before and 8\u2009days after initiation of GNKG168 therapy. Results: Twenty-three out of 578 markers on the nanostring panel showed significant difference (p\u2009≤\u20090.05). We focused on 8 markers that had the greatest differences with p\u2009<\u20090.01. Two genes were increased, promyelocytic leukemia protein (PML) and H-RAS, and 6 were decreased, Single Ig and TIR Domain containing (SIGIRR, IL1R8), interleukin 1 receptor 1 (IL1RL1, ST2), C-C Motif chemokine receptor 8 (CCR8), interleukin 7\u2009R (IL7R), cluster of differentiation 8B (CD8B), and cluster of differentiation 3 (CD3D). Tumor inhibitory pathways were downregulated including the SIGIRR (IL1R8), important in IL-37 signaling and NK cell inhibition. TLR9 can induce IL-33, which is known to downregulate ST2 (IL1RL1) a receptor for IL-33. Conclusion: GNKG168 therapy is associated with immunologic changes in pediatric leukemia patients. Further work with a larger sample size is required to assess the impact of these changes on disease treatment and persistence of leukemia remission.