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CAR T cells with enhanced sensitivity to B cell maturation antigen for the targeting of B cell non-Hodgkin's lymphoma and multiple myeloma

Item Type:Article
Title:CAR T cells with enhanced sensitivity to B cell maturation antigen for the targeting of B cell non-Hodgkin's lymphoma and multiple myeloma
Creators Name:Bluhm, J. and Kieback, E. and Marino, S.F. and Oden, F. and Westermann, J. and Chmielewski, M. and Abken, H. and Uckert, W. and Höpken, U.E. and Rehm, A.
Abstract:Autologous T cells genetically modified with a chimeric antigen receptor (CAR) redirected at CD19 have potent activity in the treatment of B cell leukemia and B cell non-Hodgkin's lymphoma (B-NHL). Immunotherapies to treat multiple myeloma (MM) targeted the B cell maturation antigen (BCMA), which is expressed in most cases of MM. We developed a humanized CAR with specificity for BCMA based on our previously generated anti-BCMA monoclonal antibody. The targeting single-chain variable fragment (scFv) domain exhibited a binding affinity in the low nanomolar range, conferring T cells with high functional avidity. Redirecting T cells by this CAR allowed us to explore BCMA as an alternative target for mature B-NHLs. We validated BCMA expression in diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia. BCMA CAR T cells triggered target cell lysis with an activation threshold in the range of 100 BCMA molecules, which allowed for an efficient eradication of B-NHL cells in vitro and in vivo. Our data corroborate BCMA is a suitable target in B cell tumors beyond MM, providing a novel therapeutic option for patients where BCMA is expressed at low abundance or where anti-CD19 immunotherapies have failed due to antigen loss.
Keywords:Multiple Myeloma, B Cell Non-Hodgkin's Lymphoma, B Cell Maturation Antigen, Chimeric Antigen Receptor T Cells, Adoptive T Cell Therapy, Animals, Mice
Source:Molecular Therapy
ISSN:1525-0016
Publisher:Elsevier / Cell Press (U.S.A.)
Volume:26
Number:8
Page Range:1906-1920
Date:1 August 2018
Official Publication:https://doi.org/10.1016/j.ymthe.2018.06.012
PubMed:View item in PubMed

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