CD70 Overexpression at Diagnosis Predicts Relapse and supports dual CD19-CD70 CAR-T Therapy in Follicular Lymphoma

Although first-line immunotherapy achieves remission in most patients with follicular lymphoma (FL), improved biomarkers and therapeutic strategies are required to identify and manage those who relapse. We investigated the immune microenvironment at diagnosis in uniformly treated FL patients with extended follow-up (>11 years), comparing relapsed and relapse-free cases. Transcriptomic profiling revealed enrichment of inflammatory response pathways in relapsed patients, including cytokine overexpression and upregulation of CD70, a molecule implicated in immune activation and inflammation. Multiplex immunofluorescence confirmed CD70 overexpression at diagnosis in tumor cells as well as in CD8⁺ and CD4⁺ T follicular helper (TFH) cells, correlating with inferior progression-free survival. Functional studies demonstrated that CD70⁺ tumor cells were more proliferative and induced CD70 expression in T cells, suggesting a feed-forward loop sustaining immune activation. To target these cells and enhance current CAR-T approaches, we engineered dual CD19-CD70 chimeric antigen receptor (CAR) T cells by co-transducing the CD19-CAR-T ARI-0001 with a CD27-based anti-CD70 CAR. Dual CAR-T cells exhibited enhanced in vitro cytotoxicity against patient-derived spheroids of FL, diffuse large B-cell lymphoma, and mantle cell lymphoma. In FL xenograft models, dual CAR-T treatment achieved superior disease control compared to monotargeted CAR-T cells, inducing complete tumor clearance in spleen and bone marrow. Collectively, these findings provide strong preclinical rationale for the clinical development of CD19-CD70 dual CAR-T therapy to improve outcomes in high-risk FL and potentially other B-cell non-Hodgkin lymphomas.