Tu130 - Generation of Gut-Specific-Engineered Treg-like Cells (GI-CD4LVFOXP3) for Pediatric Crohn’s Disease Treatment

Babajide Ojo – Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford Medical School, Palo Alto, CA, United States – Stanford University; Akshaya Ramachandran – Department of Pediatrics,Division of Hematology-Oncology-Stem Cell Transplantation and Regenerative Medicine – Stanford University; Jenny Wu – Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford Medical School, Palo Alto, CA, United States – Stanford University; Tracy Tran – Department of Surgery, Division of Pediatric Surgery – Stanford University; Maria Roncarolo, MD – Professor, Department of Pediatrics,Division of Hematology-Oncology-Stem Cell Transplantation and Regenerative Medicine, Stanford University; James Dunn, MD – Professor, Department of Bioengineering, Stanford University; Michael Rosen, MD – Professor, Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford Medical School, Palo Alto, CA, United States, Stanford University; Rosa Bacchetta, MD – Department of Pediatrics,Division of Hematology-Oncology-Stem Cell Transplantation and Regenerative Medicine – Stanford University

Abstract Text: Crohn’s disease (CD) is a predominant form of inflammatory bowel disease characterized by chronic inflammation in the gut that affects millions of people worldwide. The CD is more prevalent in the pediatric population and less likely to respond to conventional therapies. Further, gut damage induced by uncontrolled inflammation often requires surgery and hospitalization and is a source of poor quality of life and suffering for many children as well as their families. To provide alternative treatments, we are developing gut-specific-engineered Treg-like cells (GI-CD4LVFOXP3), a patient-specific “living drug” that could control excess inflammation in the gut and support gut repair. Immunophenotyping of peripheral blood from CD patients showed the signature of inflammation and an increase in effector-T cells expressing gut-homing receptor 47+ integrins. We are generating GI-CD4LVFOXP3 Tregs from CD4+-T cells expressing gut-homing receptor 47+ integrins isolated from peripheral blood to promote gut homing and transient expression of ST2 to enhance the responsiveness to danger signal IL-33. GI-CD4LVFOXP3 showed expression of Tregs markers and gut repair molecule amphiregulin and IL-22. Enteroids derived from CD patients but not from HD controls showed alteration in polarity, differentiation capacity, and transepithelial resistance. We aim to obtain data supporting the therapeutic efficacy of GI-CD4LVFOXP3 using autologous gut organoids, as preliminary evidence that GI-CD4LVFOXP3 will be a potent therapeutics for CD and co-culture of GI-CD4LVFOXP3 and enteroids will demonstrate the efficacy of these cells in reversing epithelial gut damage.