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:
CreatorsEmailORCIDORCID Put Code
Hombach, Andreas A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goergens, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chmielewski, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Murke, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kimpel, JanineUNSPECIFIEDorcid.org/0000-0002-5210-7905UNSPECIFIED
Giebel, BerndUNSPECIFIEDorcid.org/0000-0003-2446-948XUNSPECIFIED
Abken, HinrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
ADVANCED HODGKINS-LYMPHOMA; CD28 COSTIMULATION; SPACER DOMAIN; SOLUBLE CD30; ACTIVATION; EXPRESSION; LYMPHOCYTES; IMMUNOTHERAPY; PROTECTION; LINEAGESMultiple languages
Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26776

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