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Lenalidomide enhances CD23.CAR T cell therapy in chronic lymphocytic leukemia

2022; Taylor & Francis; Volume: 63; Issue: 7 Linguagem: Inglês

10.1080/10428194.2022.2043299

1042-8194

Sarah Tettamanti, Maria Caterina Rotiroti, Greta Maria Paola Giordano Attianese, Silvia Arcangeli, Ronghua Zhang, Priyanka Banerjee, Giovanni Galletti, Sheighlah McManus, Massimiliano Mazza, Fabio Nicolini, Giovanni Martinelli, Cristina Ivan, Tania Véliz Rodríguez, Federica Barbaglio, Lydia Scarfò, Maurilio Ponzoni, William G. Wierda, Varsha Gandhi, Michael J. Keating, Andrea Biondi, Federico Caligaris‐Cappio, Ettore Biagi, Paolo Ghia, Maria Teresa Sabrina Bertilaccio,

Chronic Lymphocytic Leukemia Research

Chimeric antigen receptors (CAR)-modified T cells are an emerging therapeutic tool for chronic lymphocytic leukemia (CLL). However, in patients with CLL, well-known T-cell defects and the inhibitory properties of the tumor microenvironment (TME) hinder the efficacy of CAR T cells. We explored a novel approach combining CARs with lenalidomide, an immunomodulatory drug that tempers the immunosuppressive activity of the CLL TME. T cells from patients with CLL were engineered to express a CAR specific for CD23, a promising target antigen. Lenalidomide maintained the in vitro effector functions of CD23.CAR+ T cells effector functions in terms of antigen-specific cytotoxicity, cytokine release and proliferation. Overall, lenalidomide preserved functional CAR T-CLL cell immune synapses. In a Rag2−/−γc−/−-based xenograft model of CLL, we demonstrated that, when combined with low-dose lenalidomide, CD23.CAR+ T cells efficiently migrated to leukemic sites and delayed disease progression when compared to CD23.CAR+ T cells given with rhIL-2. These observations underline the therapeutic potential of this novel CAR-based combination strategy in CLL.