{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T15:50:32Z","timestamp":1793893832872,"version":"4.8.0"},"reference-count":45,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,2,14]],"date-time":"2019-02-14T00:00:00Z","timestamp":1550102400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006436","name":"Celgene","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006436","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Chemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma (<jats:styled-content style=\"fixed-case\">FL<\/jats:styled-content>) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R<jats:sup>2<\/jats:sup>) has shown clinical synergy in front\u2010line and relapsed\/refractory <jats:styled-content style=\"fixed-case\">FL<\/jats:styled-content>. Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer (<jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content>) cells <jats:italic>ex\u00a0vivo<\/jats:italic> from <jats:styled-content style=\"fixed-case\">FL<\/jats:styled-content> patients by enhancing proliferative capacity and T\u2010helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody\u2010dependent cellular cytotoxicity in sensitive and chemo\u2010resistant <jats:styled-content style=\"fixed-case\">FL<\/jats:styled-content> cells, via a cereblon\u2010dependent mechanism. While single\u2010agent lenalidomide and rituximab increased formation of lytic <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content> cell immunological synapses with primary <jats:styled-content style=\"fixed-case\">FL<\/jats:styled-content> tumour cells, the combination was superior and correlated with enhanced cytotoxicity. Immunophenotyping of <jats:styled-content style=\"fixed-case\">FL<\/jats:styled-content> patient samples from a phase 3 trial revealed that R<jats:sup>2<\/jats:sup> treatment increased circulating T\u2010 and <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content>\u2010cell counts, while R\u2010chemotherapy was associated with reduced cell numbers. Finally, using an <jats:italic>in\u00a0vitro<\/jats:italic> 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<jats:sup>2<\/jats:sup> <jats:italic>versus<\/jats:italic> R\u2010chemotherapy. Taken together, we believe these data support a paradigm shift in the treatment of <jats:styled-content style=\"fixed-case\">FL<\/jats:styled-content> \u2013 moving from combination immunochemotherapy to chemotherapy\u2010free immunotherapy.<\/jats:p>","DOI":"10.1111\/bjh.15797","type":"journal-article","created":{"date-parts":[[2019,2,15]],"date-time":"2019-02-15T01:35:22Z","timestamp":1550194522000},"page":"240-253","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Combination lenalidomide\u2010rituximab immunotherapy activates anti\u2010tumour immunity and induces tumour cell death by complementary mechanisms of action in follicular lymphoma"],"prefix":"10.1111","volume":"185","author":[{"given":"Hsiling","family":"Chiu","sequence":"first","affiliation":[{"name":"Celgene Corporation Summit NJ 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