Altered T-lymphocyte biology following high-dose melphalan and autologous stem cell transplantation with implications for adoptive T-cell therapy
- In relapsed and refractory multiple myeloma (MM), adoptive cell therapies (ACT) including CAR-T-cells are under clinical investigation. However, relapse due to T-cell exhaustion or limited persistence is an obstacle. Before ACT are considered in MM, high-dose (HD) melphalan followed by autologous stem-cell transplantation (autoSCT) has been administered in most clinical situations. Yet, the impact of HD chemotherapy on T-cells in MM with respect to ACT is unclear. In this study, T-lymphocytes’ phenotypes, expansion properties, lentiviral transduction efficacy, and gene expression were examined with special respect to patients following HD melphalan. Significant impairment of T-cells’ expansion and transduction rates could be demonstrated. Expansion was diminished due to inherent disadvantages of the predominant T-cell phenotype but restored over time. The quantitative fraction of CD27−/CD28− T-cells before expansion was predictive of T-cell yield. Following autoSCT, the transduction efficacy was reduced by disturbed lentiviral genome integration. Moreover, an unfavorable T-cell phenotype after expansion was demonstrated. In initial analyses of CD107a degranulation impaired T-cell cytotoxicity was detected in one patient following melphalan and autoSCT. The findings of our study have potential implications regarding the time point of leukapheresis for CAR-T-cell manufacturing. Our results point to a preferred interval of more than 3 months until patients should undergo cell separation for CAR-T therapy in the specific situation post-HD melphalan/autoSCT. Monitoring of CD27−/CD28− T-cells, has the potential to influence clinical decision making before apheresis in MM.
Author: | Thomas MikaORCiDGND, Swetlana Ladigan-BaduraORCiDGND, Abdelouahid MaghnoujGND, Bakr MustafaGND, Susanne Klein-ScoryORCiDGND, Alexander BaraniskinGND, Sascha DöhringGND, Ilka FuchsGND, Stephan EhlGND, Stephan HahnORCiDGND, Roland SchroersORCiDGND |
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URN: | urn:nbn:de:hbz:294-78910 |
DOI: | https://doi.org/10.3389/fonc.2020.568056 |
Parent Title (English): | Frontiers in oncology |
Publisher: | Frontiers Media |
Place of publication: | Lausanne |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2021/02/18 |
Date of first Publication: | 2020/12/11 |
Publishing Institution: | Ruhr-Universität Bochum, Universitätsbibliothek |
Tag: | Open Access Fonds T-cell biology; chimeric antigen receptor; gene expression; lentiviral transduction; lymphocyte proliferation; melphalan; multiple myeloma |
Volume: | 10 |
Issue: | Artikel 568056 |
First Page: | 568056-1 |
Last Page: | 568056-14 |
Note: | Article Processing Charge funded by the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of Ruhr-Universität Bochum. |
Institutes/Facilities: | Marienhospital Herne, Medizinische Klinik III, Hämatologie / Onkologie |
Medizinische Fakultät, Abteilung für Molekulare Gastroenterologische Onkologie | |
Dewey Decimal Classification: | Technik, Medizin, angewandte Wissenschaften / Medizin, Gesundheit |
open_access (DINI-Set): | open_access |
Licence (English): | Creative Commons - CC BY 4.0 - Attribution 4.0 International |