Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Bluhm, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Kieback, Elisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Marino, Stephen F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Oden, Felix UNSPECIFIED UNSPECIFIED UNSPECIFIED Westermann, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Chmielewski, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Abken, Hinrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Uckert, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoepken, Uta E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rehm, Armin UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language MEMORY STEM-CELLS; ANTITUMOR RESPONSE; RECEPTOR AFFINITY; RESISTANCE; DOMAIN; BCMA; EXPRESSION; IBRUTINIB; SURVIVAL; DENSITY Multiple languages Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17838