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NEURONAL SELF-RENEWAL BY ANTIGEN-SPECIFIC TOLERIZATION IN MULTIPLE SCLEROSIS REINSTALLING THE BALANCE BETWEEN INFLAMMATION AND REGENERATION

CORDIS provides links to public deliverables and publications of HORIZON projects.

Links to deliverables and publications from FP7 projects, as well as links to some specific result types such as dataset and software, are dynamically retrieved from OpenAIRE .

Deliverables

Documentation of adverse effects in the first cohort receiving the lowest dose of tolDC

Adverse events will be summarized by presenting for each cohort, the number and proportion of patients having any adverse event. All AE and special reporting situations, whether serious or non-serious, occurring during the study will be reported to the data and safety monitoring board by study-site personnel within 24 hours of their knowledge of the event. The investigators will report these events to the regulatory authorities and the independent ethics committee that approved the protocol.

Certificates of clinical training

We aim at implementing standardized clinical monitoring procedures for peptide-loaded tolDC and training study staff on clinical monitoring to affirm harmonization and standardization will be started prior beginning the clinical trial. Prior to commencement of the clinical trial, P1 (UA), P2 (UZA) and P4 (ICS) will organize seminars for all personnel involved in the clinical trial, a specialized training program for neurologists on diagnosis, patient enrolment, correct documentation and data collection, samples collection and follow up.

Report on the overall safety and tolerability of tolDC therapy

The overall goal of the ReSToRe project is to assess the safety and tolerability and demonstrate first proof-of-concept of administering clinical-grade vitamin D3-treated tolDC loaded with myelin-derived peptides via different administration routes to treat a well-defined subpopulation of MS patients. At this timepoint, assessment of safety and tolerability will be possible based on data gathered through standardized clinical, radiological and immunological evaluation of tolDC therapy in MS.

Stakeholder committee evaluation report (2)

A second stakeholder committee evaluation report will be prepared by month 42

Stakeholder committee evaluation report (1)

Timely communication among the various stakeholders is critical to ensure patient safety in clinical trials. In order to spread awareness and information about the project and its results beyond the research community with the public as a whole, we envisage to install a stakeholder committee that will consist of experts from major interest groups that are interested in receiving exposure to the project and are willing to exchange knowledge relating to ReSToRe’s communication and operation, i.e. representatives from patient organizations (including patients and their families), the investigators, institutional review board/ethics committee, and the scientific, medical and business community. The stakeholder committee will be informed regularly per e-mail and in organized meetings about the progress of the project and will supervise the research and the dissemination material. On the other hand, the members of the stakeholder committee will provide the project with an opportunity to receive external validation of approach and results, whilst supporting networks and associations thereby amplifying the outreach of ReStoRe’s dissemination plan. By involving the stakeholder committee from the start to the end of the project, we will ensure a high quality level of all actions.

Plans for dissemination and exploitation of the results

The applicants strongly believe in collaboration and dissemination of knowledge keeping in mind the patients best interests Dissemination will be carried out as soon as possible with due regard to the interests of all partners Dissemination and exploitation plans will be drafted following the requirements of the EC

Stakeholder committee evaluation report (3)

A final stakeholder committee evaluation report will be prepared by month +60

Report on overall study monitoring

Although data entry necessarily is a local responsibility for each participating center in order to respect the protection of the patient's identity, study monitoring by an ISO-certified specialised company or (academic) CRO will guarantee coherent clinical data acquisition and harmonisation at all sites.

Report on clinical trial design and voluntary harmonization procedure

"All documents needed for regulatory and ethical approval to proceed to the second stage of the outlined clinical trials will be submitted to the CTFG in order to obtain a harmonised assessment for the proposed clinical trial application. As a result we anticipate to obtain a single opinion and one ""all approvals package""."

Reporting of adverse effects of intradermal vs. intranodal administration of tolDC to investigators, data safety monitoring board and regulatory authorities

We anticipate timely, accurate, and complete reporting and analysis of safety information. Adverse events will be summarised by presenting for each cohort, the number and proportion of patients having an adverse event.

Documentation of adverse effects in the third cohort receiving the highest dose of peptide-loaded tolDC

Adverse events will be summarized by presenting for each cohort the number and proportion of patients having any adverse event All AE and special reporting situations whether serious or nonserious occurring during the study will be reported to the data and safety monitoring board by studysite personnel within 24 hours of their knowledge of the event The investigators will report these events to the regulatory authorities and the independent ethics committee that approved the protocol

Documentation of adverse effects in the second cohort receiving the intermediate dose of peptide-loaded tolDC

Adverse events will be summarized by presenting for each cohort, the number and proportion of patients having any adverse event. All AE and special reporting situations, whether serious or non-serious, occurring during the study will be reported to the data and safety monitoring board by study-site personnel within 24 hours of their knowledge of the event. The investigators will report these events to the regulatory authorities and the independent ethics committee that approved the protocol.

Data Management Plan

A data management plan describing the data management life cycle for the data to be collected processed andor generated by ReSToRe will be drafted according to the Guidelines on FAIR Data Management in Horizon 2020 In brief the data management plan will contain details on the incidental findings policy as well as detailed information on the procedures that will be implemented for data collection storage protection retention sharing merging reuse andor destruction The plan will also include a privacy impact assessment In other words items that will be addressed in the data management plan include What data will be collected generated What standards will be used be generated What data will be exploited What data will be sharedmade open How will data be curated and preserved

Dissemination materials (2)

ReSToRe will create and publish the public dissemination material via its website, project brochures, newsletters (twice a year), etc.. An update will be provided together with the second report on status of posting results.

Dissemination materials

ReSToRe will create and publish the public dissemination material via its website, project brochures, newsletters (twice a year), etc.. An update will be provided together with the first report on status of posting results.

Dissemination materials (3)

ReSToRe will create and publish the public dissemination material via its website, project brochures, newsletters (twice a year), etc.. An update will be provided together with the final report on status of posting results.

Project website, including internal section for partners

As part of ReSToRe's dissimination strategy, a website will be set up to promote public dissimination of project activities and research results. A private section for partners will also be included.

Training for all personnel involved in the clinical trial

Prior to commencement of the clinical trial, P1 (UA), P2 (UZA) and P4 (ICS) will organize seminars for all personnel involved in the clinical trial, a specialized training program for neurologists on diagnosis, patient enrolment, correct documentation and data collection, samples collection and follow up. Regarding set-up and support for standardized and centralized use of MRI (WP6), IcoMetrix (P7) will provide the MRI protocol, operation manuals for acquisition and upload and training of the centers for acquisition and data transfer.

Assessment of effect of safety and clinical outcome measures following administration of peptide-loaded tolDC

Having completed the safety and proof-of-concept comparison of intradermal vs. intranodal routes of administration, at this point, we will be able to assess the safety profile and clinical effects of peptide-loaded tolDC treatment in MS.

Demonstration of maximum tolerated dose of tolDC

By month 39, results of the dose-escalation study (WP3) will allow the identification of the maximum tolerated dose of tolDC.

Midterm recruitment report

In order to anticipate problems with patient recruitment, patient inclusion will be closely followed during the project and risk-mitigation measures are in place when needed.

Publications

Transfection of Vitamin D3-Induced Tolerogenic Dendritic Cells for the Silencing of Potential Tolerogenic Genes. Identification of CSF1R-CSF1 Signaling as a Glycolytic Regulator

Author(s): María José Mansilla; Iñigo González-Larreategui; Neus Figa-Martín; Jaume Barallat; Federico Fondelli; Ares Sellés-Rius; Bibiana Quirant-Sánchez; Aina Teniente-Serra; Eva Martínez-Cáceres
Published in: International Journal of Molecular Sciences, Issue 7, 2021, ISSN 1422-0067
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
DOI: 10.3390/ijms22147363

Made to Measure: Patient-Tailored Treatment of Multiple Sclerosis Using Cell-Based Therapies.

Author(s): Inez Wens; Ibo Janssens; Judith Derdelinckx; Megha Meena; Barbara Willekens; Nathalie Cools
Published in: International Journal of Molecular Sciences, Issue 1, 2021, ISSN 1422-0067
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
DOI: 10.3390/ijms22147536

Safety and immunological proof-of-concept following treatment with tolerance-inducing cell products in patients with autoimmune diseases or receiving organ transplantation: A systematic review and meta-analysis of clinical trials

Author(s): Barbara Willekens; Inez Wens; Kristien Wouters; Patrick Cras; Nathalie Cools
Published in: Autoimmunity reviews, Issue 2, 2021, ISSN 1568-9972
Publisher: Elsevier BV
DOI: 10.1016/j.autrev.2021.102873

Guidelines for analysis of low-frequency antigen-specific T cell results: Dye-based proliferation assay vs 3H-thymidine incorporation

Author(s): Daniela Di Blasi, Iris Claessen, Annelies W. Turksma, Josine van Beek, Anja ten Brinke
Published in: Journal of Immunological Methods, Issue 487, 2020, Page(s) 112907, ISSN 0022-1759
Publisher: Elsevier BV
DOI: 10.1016/j.jim.2020.112907

Ways Forward for Tolerance-Inducing Cellular Therapies- an AFACTT Perspective

Author(s): Anja ten Brinke, Marc Martinez-Llordella, Nathalie Cools, Catharien M. U. Hilkens, S. Marieke van Ham, Birgit Sawitzki, Edward K. Geissler, Giovanna Lombardi, Piotr Trzonkowski, Eva Martinez-Caceres
Published in: Frontiers in Immunology, Issue 10, 2019, ISSN 1664-3224
Publisher: Frontiers Media S.A
DOI: 10.3389/FIMMU.2019.00181

Paving the way towards an effective treatment for multiple sclerosis: advances in cell therapy

Author(s): M. J. Mansilla, S. Presas-Rodríguez, A. Teniente-Serra, I. González-Larreategui, B. Quirant-Sánchez, F. Fondelli, N. Djedovic, D. Iwaszkiewicz-Grześ, K. Chwojnicki, Đ. Miljković, P. Trzonkowski, C. Ramo-Tello, E. M. Martínez-Cáceres
Published in: Cellular & Molecular Immunology, Issue 18/6, 2021, Page(s) 1353-1374, ISSN 1672-7681
Publisher: Nature Publishing Group
DOI: 10.1038/s41423-020-00618-z

Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration

Author(s): Barbara Willekens, Silvia Presas-Rodríguez, MJ Mansilla, Judith Derdelinckx, Wai-Ping Lee, Griet Nijs, Maxime De Laere, Inez Wens, Patrick Cras, Paul Parizel, Wim Van Hecke, Annemie Ribbens, Thibo Billiet, Geert Adams, Marie-Madeleine Couttenye, Juan Navarro-Barriuso, Aina Teniente-Serra, Bibiana Quirant-Sánchez, Ascensión Lopez-Diaz de Cerio, Susana Inogés, Felipe Prosper, Anke Kip, Herman Ve
Published in: BMJ Open, Issue 9/9, 2019, Page(s) e030309, ISSN 2044-6055
Publisher: BMJ Publishing Group
DOI: 10.1136/bmjopen-2019-030309

Vitamin D3-Induced Tolerogenic Dendritic Cells Modulate the Transcriptomic Profile of T CD4+ Cells Towards a Functional Hyporesponsiveness.

Author(s): Juan Navarro-Barriuso; Juan Navarro-Barriuso; María José Mansilla; María José Mansilla; Bibiana Quirant-Sánchez; Bibiana Quirant-Sánchez; Aina Teniente-Serra; Aina Teniente-Serra; Cristina Ramo-Tello; Eva M. Martínez-Cáceres; Eva M. Martínez-Cáceres
Published in: Frontiers in Immunology, Issue 1, 2021, ISSN 1664-3224
Publisher: Frontiers Media S.A.
DOI: 10.3389/fimmu.2020.599623

Combined Therapy of Vitamin D3-Tolerogenic Dendritic Cells and Interferon-β in a Preclinical Model of Multiple Sclerosis

Author(s): Bibiana Quirant-Sánchez; María José Mansilla; Juan Navarro-Barriuso; Silvia Presas-Rodríguez; Aina Teniente-Serra; Federico Fondelli; Cristina Ramo-Tello; Eva Martínez-Cáceres
Published in: Biomedicines, Vol 9, Iss 1758, p 1758 (2021), Issue 8, 2021, ISSN 2227-9059
Publisher: MDPI AG
DOI: 10.3390/biomedicines9121758

MAP7 and MUCL1 Are Biomarkers of Vitamin D3-Induced Tolerogenic Dendritic Cells in Multiple Sclerosis Patients

Author(s): Juan Navarro-Barriuso, María José Mansilla, Bibiana Quirant-Sánchez, Alicia Ardiaca-Martínez, Aina Teniente-Serra, Silvia Presas-Rodríguez, Anja ten Brinke, Cristina Ramo-Tello, Eva M. Martínez-Cáceres
Published in: Frontiers in Immunology, Issue 10, 2019, ISSN 1664-3224
Publisher: Frontiers in Immunology
DOI: 10.3389/fimmu.2019.01251

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