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Benmebarek, M.R.* ; Cadilha, B.L.* ; Herrmann, M.* ; Lesch, S.* ; Schmitt, S.* ; Stoiber, S.* ; Darwich, A.* ; Augsberger, C.* ; Brauchle, B.* ; Rohrbacher, L.* ; Oner, A.* ; Seifert, M.* ; Schwerdtfeger, M.* ; Gottschlich, A.* ; Rataj, F.* ; Fenn, N.C.* ; Klein, C.* ; Subklewe, M.* ; Endres, S. ; Hopfner, K.P.* ; Kobold, S.

A modular and controllable T cell therapy platform for acute myeloid leukemia.

Leukemia 35, 2243–2257 (2021)
Publ. Version/Full Text DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Targeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Chimeric Antigen Receptors; Hematopoietic Stem-cells; Engaging Antibody; Binding-affinity; Aml; Immunotherapy; Cd33; Blinatumomab; Activation; Expression
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Journal Leukemia
Quellenangaben Volume: 35, Issue: , Pages: 2243–2257 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)
Grants Jose-Carreras Foundation
MarieSklodowska-Curie Program Training Network for Optimizing Adoptive T Cell Therapy of Cancer - H2020 Program of the European Union
Hector foundation
International Doctoral Program i-Target: Immunotargeting of Cancer - Elite Network of Bavaria
Melanoma Research Alliance
Else Kroner-FreseniusStiftung
German Cancer Aid
Ernst-Jung-Stiftung
LMU Munich's Institutional Strategy LMUexcellent
Bundesministerium fur Bildung und Forschung Project Oncoattract
European Research Council
German Research Foundation (DFG)
Fritz-Bender Foundation
Marie-Sklodowska-Curie Program Training Network for the Immunotherapy of Cancer - H2020 Program of the European Union