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Summary  Chemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma ( FL ) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R 2 ) has shown clinical synergy in front‐line and relapsed/refractory  FL . Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer ( NK ) cells  ex vivo  from  FL  patients by enhancing proliferative capacity and T‐helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody‐dependent cellular cytotoxicity in sensitive and chemo‐resistant  FL  cells, via a cereblon‐dependent mechanism. While single‐agent lenalidomide and rituximab increased formation of lytic  NK  cell immunological synapses with primary  FL  tumour cells, the combination was superior and correlated with enhanced cytotoxicity. Immunophenotyping of  FL  patient samples from a phase 3 trial revealed that R 2  treatment increased circulating T‐ and  NK ‐cell counts, while R‐chemotherapy was associated with reduced cell numbers. Finally, using an  in vitro  model of myeloid differentiation, we demonstrated that lenalidomide caused a reversible arrest in neutrophil maturation that was distinct from a cytotoxic chemotherapeutic agent, which may help explain the lower rates of neutropenia observed with R 2   versus  R‐chemotherapy. Taken together, we believe these data support a paradigm shift in the treatment of  FL  – moving from combination immunochemotherapy to chemotherapy‐free immunotherapy.

british journal of haematology

Combination lenalidomide‐rituximab immunotherapy activates anti‐tumour immunity and induces tumour cell death by complementary mechanisms of action in follicular lymphoma