A modular and controllable T cell therapy platform for acute myeloid leukemia
| العنوان: | A modular and controllable T cell therapy platform for acute myeloid leukemia |
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| المؤلفون: | Monika Herrmann, Nadja C. Fenn, Stefanie Lesch, Christian Klein, Adrian Gottschlich, S Stoiber, Sebastian Kobold, Bruno L. Cadilha, Christian Augsberger, Melanie Schwerdtfeger, Marion Subklewe, Bettina Brauchle, Saskia Schmitt, Stefan Endres, Lisa Rohrbacher, Felicitas Rataj, Abbass Darwich, M. Benmebarek, A Öner, Matthias Seifert, Karl-Peter Hopfner |
| المصدر: | Leukemia Leukemia 35, 2243–2257 (2021) |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, Myeloid, T cell, medicine.medical_treatment, T-Lymphocytes, CD33, Receptors, Antigen, T-Cell, Cancer immunotherapy, Mice, SCID, Biology, Immunotherapy, Adoptive, Article, Acute myeloid leukaemia, Mice, Targeted therapies, Antigen, Mice, Inbred NOD, hemic and lymphatic diseases, medicine, Tumor Cells, Cultured, Animals, Humans, Leukemia, Experimental, Myeloid leukemia, Hematology, Xenograft Model Antitumor Assays, Transplantation, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Oncology, Cancer research, Female, Stem cell |
| الوصف: | 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. Keypoints Modular platform enabling controlled targeting of AML by SAR-transduced T cells in combination with tandem scFv constructs. Efficient lysis of primary AML blasts in vitro and strong antitumoral effects and T cell persistence in xenograft models. |
| وصف الملف: | application/pdf |
| تدمد: | 0887-6924 |
| DOI: | 10.1038/s41375-020-01109-w |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::be6929486c679df507b1cabb18916a5f |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....be6929486c679df507b1cabb18916a5f |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 08876924 |
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| DOI: | 10.1038/s41375-020-01109-w |