IMMU-19. PRECLINICAL THERAPEUTIC ACTIVITY AND PET IMAGING OF STING AGONIST 8803 IN GLIOBLASTOMA

作者：Hinda Najem, Spencer T. Lea, Shashwat Tripathi, Lisa Hurley, Chao-Hsien Chen, Moloud Sooreshjani, Michelle Bowie, Genevieve Hartley, Sebastián Pacheco, Crismita Dmello, Catalina Lee-Chang, Daniele Procissi, Rimas V. Lukas, Maciej S. Lesniak, David M. Ashley, Michael A. Curran, Irina V. Balyasnikova, Amy B. Heimberger · 发表于：Neuro-Oncology · 年份：2024 · DOI：10.1093/neuonc/noae165.0612 · 被引用次数：2 · 研究领域：Cancer Research and Treatments

Abstract STING (stimulator of interferon genes) activation triggers interferon (IFN) release within the tumor microenvironment from myeloid cells and other cell types, inducing proinflammatory anti-tumor immune responses. The small molecule STING agonist, 8803, elicits long-term survival in 56% (QPP4; p=0.0003) to 100% (QPP8; p<0.0001) of mice with orthotopically implanted immune checkpoint-resistant glioblastoma models after 2-3 doses. In humanized mice, in which glioblastoma-cell STING is epigenetically silenced, 8803 therapeutic activity is maintained. The combination therapy of 8803 with anti-PD-1 relatively further enhances survival in immune checkpoint-resistant models. Ex vivo flow cytometry and proteomic sequential multiplex profiling during the therapeutic window demonstrate global immunological reprogramming, specific tumor-antigen immune responses, increased tumor immune effector trafficking, and release of IFN. It has been shown that IFN signaling augments intracellular nucleotide metabolism and increases [18F]-FLT uptake in pancreatic cancer. We evaluated the longitudinal [18F]-FLT uptake in CT-2A-bearing mice using MRI/PET/CT at days 0, 2, and 4 after intratumoral 8803 delivery. Brain images were acquired before and after [18F]-FLT tracer and 8803 administrations. The CT was used for PET attenuation/correction, and the MRI was used for tumor segmentation. Regional analysis of PET-derived [18F]-FLT SUV maps used advanced image processing approaches as a fu...