A Mouse Model to Assess Long Term Immunotherapy-related Adverse Effects in Children

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Cancer immunotherapy has emerged as the most potent and durable treatment for cancers in recent years. In some solid tumors and hematological malignancies, immunotherapy has become the standard of care, joining the ranks of conventional treatment such as surgery, chemotherapy, radiation and targeted therapy. Chimeric antigen receptor – T (CAR-T) therapy has made impressive progress in treatment of pediatric leukemia. It is highly anticipated that checkpoint inhibitor antibody immunotherapy, such anti-PD-1, anti-PD-L1, and anti-CTLA4, will be tested in pediatric cancers in clinical trials (some Phase 1 trials are ongoing) . However, the autoimmune adverse events (irAE) associated with the immunotherapy is quite severe, with greater than 50% of patients developing grade 3 and 4 organ toxicity in adult clinical trials. The report on a Phase 1 trial of anti-CTLA4 antibody (Ipilimumab) on pediatric cancer patients suggested similar rate of irAE as observed in adult, although the observation period is too short to identify issues unique for developmental defects unique for pediatric patients. Therefore, the major challenges in research effort for pediatric cancer immunotherapy are (1) establishing mouse models to recapitulate irAE, especially the long term irAE unique for pediatric patients; (2) using mouse models to study the irAE pathogenesis (3) searching new targets to reduce irAE without impeding anti-tumor efficacy. Damage related molecular patterns (DAMPs) play an important role in regulating tissue damages, antigen presenting cells activation and effector T cell functions. Our previous work demonstrated that CD24- Siglec signaling pathway suppresses inflammation triggered by DAMPs. We have established a mouse model that faithfully recapitulates the irAEs in major organs that have been reported in anti-CTLA 4 and anti- PD-1 immunotherapy clinical trials. Here we propose to characterize the long term irAE in mouse model, and to examine the role of DAMPs-binding protein CD24 and Siglecs in irAE pathogenesis.