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Administration of CD4+CD25highCD127FoxP3+ Regulatory T Cells for Relapsing-Remitting Multiple Sclerosis: A Phase 1 Study

Abstract

Background

Multiple sclerosis (MS) is an immune-mediated disease in which autoimmune T conventional (Tconv) cells break the blood–brain barrier and destroy neurons of the central nervous system. It is hypothesized that CD4+CD25highCD127FoxP3+ T regulatory (Treg) cells may inhibit this destruction through suppressive activity exerted on Tconv cells.

Methods

We present the results of a phase 1b/2a, open-label, two-arm clinical trial in 14 patients treated with autologous Treg cells for relapsing-remitting MS. The patients received either expanded ex vivo Treg cells intravenously (intravenous [IV] group, n = 11; dose 40 × 106 Treg cells/kg of body weight) or freshly isolated Treg cells intrathecally (intrathecal [IT] group, n = 3; dose 1.0 × 106 Treg cells). Importantly, patients were not treated with any other disease-modifying drugs for at least 6 months before the recruitment and during the follow-up.

Results

No severe adverse events were observed. Self-assessed quality of life (EuroQol–5 Dimensions [EQ-5D] form) did not change and did not differ significantly between the groups. A total of 12 relapses were noted in five intravenously treated patients, who had from one to three attacks per year. Three out of ten participants who completed the trial in the IV group deteriorated more than 1 point on the Expanded Disability Status Scale (EDSS) during the follow-up. At the same time, no patients in the IT group experienced a relapse or such a deterioration in the EDSS. No significant differences were found in the Multiple Sclerosis Functional Composite (MSFC) scale in both the IV and IT groups. Magnetic resonance imaging (MRI) scans revealed a significantly lower change in the T2 lesion volume in the IT group compared to the IV group. The increase in the number of new T2 lesions during the follow-up was significant for the IV group only. There were no significant changes in the level of Treg cells or Tconv cells in the peripheral blood throughout the follow-up or between the groups. Interestingly, Treg cells in all patients consisted of two different phenotypes: peripheral Treg cells Helios(−) (≈ 20%) and thymic Treg cells Helios(+) (≈ 80%). The analysis of the cytokine pattern revealed higher levels of transforming growth factor-α and proinflammatory factors MCP3, CXCL8, and IL-1RA in the IT group compared with the IV group.

Conclusions

No serious adverse events were reported in the 14 patients with MS treated with Treg cells in this study. The results suggest that IT administration is more promising than IV administration. Because of the low number of patients recruited, the statistical results may be underpowered and further studies are necessary to reach conclusions on efficacy and safety.

Trial registration

EudraCT: 2014-004320-22; registered 18 November 2014.

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Acknowledgements

We thank to Prof. Maciej Juryńczyk from University of Oxford/Medical University of Łódź for critical review of the manuscript and Mrs. Anita Dobyszuk and Mrs. Grażyna Gniłka from Medical University of Gdańsk Medical Centre for their perfect assistance with laboratory and clinical procedures.

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Authors

Corresponding author

Correspondence to Piotr Trzonkowski.

Ethics declarations

Funding

The study was supported by the National Centre for Research and Development, Poland (grant no STRATEGMED1/233368/1/NCBR/2014 to PT).

Conflict of interest

PT and KC are co-inventors of patents related to the presented content. PT is a stakeholder and board member of POLTREG venture. Medical University of Gdańsk received payment for the license to the presented content. AJ, AJC, AK, BK, DIG, ES, JK, JS, KK, MG, MGrz, MK, MZ, PG, PŁ, and WN have no conflicts of interest relevant to the contents of this article.

Ethics approval

The study was conducted according to the Declaration of Helsinki principles. The protocol has been registered in the EudraCT database under the number 2014-004320-22 and received approval from the Institutional Review Board of the Medical University of Gdańsk (no. NKBBN/414/2012 and NKBBN/414-163/2017).

Consent to participate

Written informed consent was received from all the participants at recruitment, before any medical procedure was commenced.

Consent for publication

All the patients signed written consent that the data obtained in the study could be used for scientific publications, provided the data are anonymized.

Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Author contributions

KC was the principal investigator and contributed to the study design, protocol writing, data collection, analysis, interpretation, and writing and reviewing the report. DIG was a head of the R&D team and contributed to the study design, cell preparation, data collection, analysis, and writing and reviewing the report. AJ contributed to the study design, protocol writing, MRI data collection, analysis, interpretation, and writing and reviewing the report. MZ contributed to lab assays, data collection, and interpretation. PŁ contributed to patient care, data collection, and interpretation. MG contributed to the cell preparation, data collection, analysis, and reviewing the report. MGrz contributed to MRI data collection, analysis, and interpretation. KK contributed to patient care, data collection, and interpretation. AK contributed to MRI data collection, analysis, and interpretation. PG contributed to patient care, data collection, and interpretation. AJC contributed to clinical assessment, and data collection. JS and JK contributed to the cell preparation, data collection, and analysis. MK contributed to patient care, data collection, and interpretation. BK, WN, and ES contributed to study design, data collection, and interpretation and reviewed the report. PT is the guarantor of the study, and supervised the whole process and contributed to the study design, protocol writing, cell preparation, data collection, analysis, interpretation, and writing and reviewing the report.

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Chwojnicki, K., Iwaszkiewicz-Grześ, D., Jankowska, A. et al. Administration of CD4+CD25highCD127FoxP3+ Regulatory T Cells for Relapsing-Remitting Multiple Sclerosis: A Phase 1 Study. BioDrugs 35, 47–60 (2021). https://doi.org/10.1007/s40259-020-00462-7

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