CD22-CAR T cell multiomic features linked to patient outcomes in CD19-CAR resistant large B cell lymphoma

More than half of patients with relapsed/refractory large B-cell lymphoma experience disease progression after CD19-directed chimeric antigen receptor (CAR19) T-cell therapy. We investigated CAR22 therapy in 38 patients with CAR19-refractory disease, achieving 68% overall response rate (ORR) and 53% complete response rate (CR)(NCT04088890). Long-term follow-up (median 43.5 months), revealed sustained clinical benefit among complete responders, who achieved a median progression-free survival of 52 months and a 75% estimated 3-year overall survival rate. Using multi-omics analyses, we identified that intrinsic T-cell stemness characteristics present at apheresis associated with therapeutic success. Responding patients exhibited elevated TCF7 and LEF1 transcription factor activity and enhanced chromatin accessibility at TCF/LEF binding motifs. CAR T-cell products from CR patients demonstrated higher T-cell receptor diversity. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) was associated with interferon-stimulated gene expression and STAT2 activity. These findings challenge the paradigm that T cells are irreversibly compromised after CAR therapy failure and provide mechanistic insights for optimizing sequential CAR therapies.