27P Efficacy and safety of CAR T cell therapy compared to standard of care in non-Hodgkin lymphoma

Background: Liver pathogenesis, including metabolic-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC), involves chronic inflammation and fibrosis.Despite the growing incidence, early intervention options for MASH-related HCC are limited.Signal transducer and activator of transcription 3 (STAT3), a key mediator in inflammation and tumorigenesis, presents a potential target to reduce disease progression and tumour development in the liver.Methods: Recognizing the need for precise interventions, we developed a selective STAT3-targeting RNA interfering oligo duplex as a gene therapy for STAT3-driven cancers.We employed a customized GalNAc conjugation for liver-specific delivery.Using a STAM mouse model, the Stat3-GalNAc agent was administered either before MASH formation or HCC development to evaluate the impact of STAT3 inhibition at different stages of MASH-HCC progression. Results:The novel siRNA duplex demonstrated specificity in inhibiting STAT3 activity without interfering with other STAT family members, with significant inhibition in clonogenicity in STAT3-driven cancer cell lines.In vivo observation suggests that administration of GalNAc-Stat3 conjugate in the STAM mouse model delayed the onset of hepatocarcinogenesis, while steatosis remained unchanged.Conclusions: Our research underscores the critical role of precise molecular targeting in cancer therapy and introduces a novel genetic therapeutic strategy to address the limitations of existing RNA-based technologies.By elucidating the impact of STAT3 on liver pathogenesis, we aim to advance the development of effective, personalized treatments to manage MASLD driven HCC.