Advances in CAR-T and CAR-NK cell therapy in follicular lymphoma: a review

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma and is characterized by prolonged survival but recurrent relapses. The unmet need is greatest among patients with high-risk disease, including progression of disease within 24 months of first-line immunochemotherapy (POD24), double-refractory disease, histologic transformation, and exposure to multiple previous lines of therapy. In pivotal single-arm studies enrolling heavily pretreated patients, CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies produced overall response rates of 86-97% and complete response rates of 68-94%, with durable disease control in a substantial proportion of patients. However, autologous CAR-T therapy is limited by individualized manufacturing, the potential need for bridging therapy, intensive monitoring, unique toxicities, and restricted access outside specialized centers. This review summarizes the efficacy and safety of approved CAR-T products in relapsed/refractory FL, explains how differences in receptor architecture and costimulatory signaling may affect cellular kinetics and toxicity, and discusses emerging alternative targets, dual-target constructs, combination strategies, and CAR-natural killer (CAR-NK) cell platforms. CAR-NK cells represent a promising investigational off-the-shelf platform; however, current clinical evidence is derived predominantly from early-phase studies involving heterogeneous B-cell malignancies, with limited FL-specific data. Their efficacy, durability, safety, and scalability in FL therefore remain to be established in dedicated clinical studies.