Universität zu Köln

Hombach, Andreas A., Goergens, Andre, Chmielewski, Markus, Murke, Florian, Kimpel, Janine ORCID: 0000-0002-5210-7905, Giebel, Bernd ORCID: 0000-0003-2446-948X and Abken, Hinrich (2016). Superior Therapeutic Index in Lymphoma Therapy: CD30(+) CD34(+) Hematopoietic Stem Cells Resist a Chimeric Antigen Receptor T-cell Attack. Mol. Ther., 24 (8). S. 1423 - 1435. CAMBRIDGE: CELL PRESS. ISSN 1525-0024

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Abstract

Recent clinical trials with chimeric antigen receptor (CAR) redirected T cells targeting CD19 revealed particular efficacy in the treatment of leukemia/lymphoma, however, were accompanied by a lasting depletion of healthy B cells. We here explored CD30 as an alternative target, which is validated in lymphoma therapy and expressed by a broad variety of Hodgkin's and non-Hodgkin's lymphomas. As a safty concern, however, CD30 is also expressed by lymphocytes and hematopoietic stem and progenitor cells (HSPCs) during activation. We revealed that HRS3scFv-derived CAR T cells are superior since they were not blocked by soluble CD30 and did not attack CD30(+) HSPCs while eliminating CD30(+) lymphoma cells. Consequently, normal hemato-and lymphopoiesis was not affected in the long-term in the humanized mouse; the number of blood B and T cells remained unchanged. We provide evidence that the CD30(+) HSPCs are protected against a CAR T-cell attack by substantially lower CD30 levels than lymphoma cells and higher levels of the granzyme B inactivating SP6/PI9 serine protease, which furthermore increased upon activation. Taken together, adoptive cell therapy with anti-CD30 CAR T cells displays a superior therapeutic index in the treatment of CD30(+) malignancies leaving healthy activated lymphocytes and HSPCs unaffected.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hombach, Andreas A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Goergens, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Chmielewski, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Murke, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Kimpel, Janine UNSPECIFIED orcid.org/0000-0002-5210-7905 UNSPECIFIED Giebel, Bernd UNSPECIFIED orcid.org/0000-0003-2446-948X UNSPECIFIED Abken, Hinrich UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-267769
DOI:	10.1038/mt.2016.82
Journal or Publication Title:	Mol. Ther.
Volume:	24
Number:	8
Page Range:	S. 1423 - 1435
Date:	2016
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1525-0024
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ADVANCED HODGKINS-LYMPHOMA; CD28 COSTIMULATION; SPACER DOMAIN; SOLUBLE CD30; ACTIVATION; EXPRESSION; LYMPHOCYTES; IMMUNOTHERAPY; PROTECTION; LINEAGES Multiple languages Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26776