Abstract
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.
Correction Statement
This article has been corrected with minor changes. These changes do not impact the academic content of the article.
Acknowledgments
Rag2−/−γc−/− mice on BALB/c background were provided by CIEA (Kawasaki, Japan) and Taconic. The authors thank Laura Russell and the Department of Scientific Publications, The University of Texas MD Anderson Cancer Center, for reviewing the manuscript and providing constructive comments. Figures were produced using Servier Medical Art (https://smart.servier.com/).
Author contributions
S.T. designed the research, performed the experiments, analyzed the data and wrote the paper; G.M., P.G.A., S.A., M.C.R., F.B. performed the in vitro studies; R.Z., P.B., G.G., T.V.R. and S.M. performed the in vivo studies; M.M., F.N. and G.M. performed Nanostring experiments and reviewed the manuscript; C.I. analyzed Nanostring data and reviewed the manuscript; L.S. assisted in human studies; M.P. analyzed data; V.G., M.J.K., A.B., F.C.C., E.B. and P.G. interpreted data and assisted in writing the paper; and M.T.S.B. designed and supervised the project, performed the experiments, analyzed the data and wrote the paper.
Disclosure statement
E.B. is currently an employee of BMS/Celgene, but with no conflicting interest with the current manuscript. All the remaining authors declare no competing financial interests.