Universität zu Köln

Bacher, Petra, Jochheim-Richter, Andrea, Mockel-Tenbrink, Nadine, Kniemeyer, Olaf ORCID: 0000-0002-9493-6402, Wingenfeld, Eva, Alex, Regina, Ortigao, Alice, Karpova, Darja, Lehrnbecher, Thomas, Ullmann, Andrew J., Hamprecht, Axel ORCID: 0000-0003-1449-5780, Cornely, Oliver, Brakhage, Axel A., Assenmacher, Mario, Bonig, Halvard ORCID: 0000-0003-0088-2675 and Scheffold, Alexander ORCID: 0000-0002-0626-343X (2015). Clinical-scale isolation of the total Aspergillus fumigatus-reactive T-helper cell repertoire for adoptive transfer. Cytotherapy, 17 (10). S. 1396 - 1406. OXFORD: ELSEVIER SCI LTD. ISSN 1477-2566

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Abstract

Background aims. Evidence of the criticality of the adaptive immune response for controlling invasive aspergillosis has been provided. This observation is supported by the fact that invasive aspergillosis, a grave complication of allogeneic stem cell transplantation, occurs long after myeloid reconstitution in patients with low T-cell engraftment and/or on immunosuppressants. Adoptive T-cell transfer might be beneficial, but idiosyncrasies of Aspergillus fumigatus and the anti-Aspergillus immune response render established selection technologies ineffective. Methods. We developed a Good Manufacturing Practice (GMP)-compliant protocol for preparation of A. fumigatus specific CD4+ cells by sequentially depleting regulatory and cytotoxic T cells, activating A. fumigatus-specific T-helper cells with GMP-grade A. fumigatus lysate, and immuno-magnetically isolating them via the transiently up-regulated activation marker, CD137. Results. In 13 full-scale runs, we demonstrate robustness and feasibility of the approach. From 2 x 10(9) peripheral blood mononuclear cells, we isolated 27 x 10(3)-318 x 10(3) Aspergillus-specific T-helper cells. Frequency among total T cells was increased, on average, by 200-fold. Specific studies indicate specificity and functionality: After non-specific in vitro expansion and re-stimulation with different antigens, we observed strong cytokine responses to A. fumigatus and some other fungi including Candida albicans, but none to unrelated antigens. Discussion. Our technology isolates naturally occurring Aspergillus-specific T-helper cells within 2 days of identifying the clinical indication. Rapid adoptive transfer of Aspergillus-specific T cells may be quite feasible; the clinical benefit remains to be demonstrated. A manufacturing license as an advanced-therapy medicinal product was received and a clinical trial in post-transplantation invasive aspergillosis patients approved. The product is dosed at 5 x 10E3/kg T cells (single intravenous injection), of which at least 10% must be A. fumigatus specific.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bacher, Petra UNSPECIFIED UNSPECIFIED UNSPECIFIED Jochheim-Richter, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Mockel-Tenbrink, Nadine UNSPECIFIED UNSPECIFIED UNSPECIFIED Kniemeyer, Olaf UNSPECIFIED orcid.org/0000-0002-9493-6402 UNSPECIFIED Wingenfeld, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Alex, Regina UNSPECIFIED UNSPECIFIED UNSPECIFIED Ortigao, Alice UNSPECIFIED UNSPECIFIED UNSPECIFIED Karpova, Darja UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehrnbecher, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Ullmann, Andrew J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hamprecht, Axel UNSPECIFIED orcid.org/0000-0003-1449-5780 UNSPECIFIED Cornely, Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Brakhage, Axel A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Assenmacher, Mario UNSPECIFIED UNSPECIFIED UNSPECIFIED Bonig, Halvard UNSPECIFIED orcid.org/0000-0003-0088-2675 UNSPECIFIED Scheffold, Alexander UNSPECIFIED orcid.org/0000-0002-0626-343X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-391969
DOI:	10.1016/j.jcyt.2015.05.011
Journal or Publication Title:	Cytotherapy
Volume:	17
Number:	10
Page Range:	S. 1396 - 1406
Date:	2015
Publisher:	ELSEVIER SCI LTD
Place of Publication:	OXFORD
ISSN:	1477-2566
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ADENOVIRUS INFECTION; IMMUNE-RESPONSES; ANTIGENS; CD4(+); CD8(+); GENERATION; EXPANSION; RECONSTITUTION; LYMPHOCYTES; EXPRESSION Multiple languages Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/39196