Bluhm, Julia, Kieback, Elisa, Marino, Stephen F., Oden, Felix, Westermann, Joerg, Chmielewski, Markus, Abken, Hinrich, Uckert, Wolfgang, Hoepken, Uta E. and Rehm, Armin (2018). CAR T Cells with Enhanced Sensitivity to B Cell Maturation Antigen for the Targeting of B Cell Non-Hodgkin's Lymphoma and Multiple Myeloma. Mol. Ther., 26 (8). S. 1906 - 1921. CAMBRIDGE: CELL PRESS. ISSN 1525-0024

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bluhm, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kieback, ElisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marino, Stephen F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oden, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Westermann, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chmielewski, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abken, HinrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uckert, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoepken, Uta E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rehm, ArminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-178380
DOI: 10.1016/j.ymthe.2018.06.012
Journal or Publication Title: Mol. Ther.
Volume: 26
Number: 8
Page Range: S. 1906 - 1921
Date: 2018
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1525-0024
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MEMORY STEM-CELLS; ANTITUMOR RESPONSE; RECEPTOR AFFINITY; RESISTANCE; DOMAIN; BCMA; EXPRESSION; IBRUTINIB; SURVIVAL; DENSITYMultiple languages
Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17838

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