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Towards a dendritic cell-based vaccine for the treatment of multiple sclerosis (MS): interim safety data of the first dose cohort of the MS-tolDC phase I clinical trial

Nathalie Cools1, 2*, Silvia Presas-Rodríguez3, 4, Maria José Mansilla5, 6, Judith Derdelinckx1, 7, Wai Ping Lee1, Griet Nijs2, Maxime De Laere1, Inez Wens1, Patrick Cras7, Paul Parizel8, Wim Van Hecke9, Annemie Ribbens9, Geert Adams10, Marie-Madeleine Couttenye11, Juan Navarro-Barriuso5, 6, Aina Teniente-Serra5, 6, Bibiana Quirant-Sánchez5, 6, Ascension Lopez-diaz De Cerio12, Susana Inogés12, Felipe Prosper13, 14, Catharina C. Gross15, Heinz Wiendl15, S. Marieke Van Ham16, Anja Ten Brinke16, Herman Verheij17, Anke Kip17, Ana Marian Barriocanal18, Anna Massuet-Vilamajó19, Niel Hens20, 21, Zwi Berneman1, 2, Eva Martínez-Cáceres5, 6, Cristina M. Ramo-Tello3 and Barbara M. Willekens1, 7*
  • 1 Laboratory of Experimental Hematology, University of Antwerp, Belgium
  • 2 Center for Cellular Therapy and Regenerative Medicine, Antwerp University Hospital, Belgium
  • 3 Hospital Germans Trias i Pujol, Spain
  • 4 Departamento de Medicina, Facultad de Medicina, Universidad Autónoma de Barcelona, Spain
  • 5 Hospital Germans Trias i Pujol, Spain
  • 6 Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona, Spain
  • 7 Antwerp University Hospital, Department of Neurology, Belgium
  • 8 Department of Radiology, Antwerp University Hospital, Belgium
  • 9 Icometrix (Belgium), Belgium
  • 10 C-Clear Partners, Belgium
  • 11 Department of Nephrology, Antwerp University Hospital, Belgium
  • 12 Clinica Universidad de Navarra, Spain
  • 13 Área de Terapia Celular, Clínica Universidad de Navarra, Spain
  • 14 Centro de Investigación Médica Aplicada (CIMA), Spain
  • 15 Klinik für Allgemeine Neurologie, Universitätsklinikum Münster, Germany
  • 16 Sanquin Diagnostic Services, Netherlands
  • 17 Lygature, Netherlands
  • 18 Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Spain
  • 19 Hospital Germans Trias i Pujol, Spain
  • 20 Centre for the Evaluation of Vaccination , University of Antwerp, Belgium
  • 21 Center for Statistics, University of Hasselt, Belgium

Introduction: The therapeutic armamentarium for multiple sclerosis (MS) has increased exponentially in the past years. However, higher treatment efficiency comes with larger safety risks and several of current treatments are associated with treatment-related, sometimes life-threatening, adverse events. Cell therapy shows great potential as treatment for MS aiming to establish permanent antigen-specific immune tolerance towards the causative triggers. In this context, a promising approach to restore immune tolerance and treat MS is antigen-specific tolerization with autologous myelin peptide-loaded tolerogenic dendritic cells (tolDC). Proof-of-concept has been demonstrated both in vitro and in the EAE animal model [1; 2; 3; 4]. In this study, we aim to demonstrate safety and feasibility of clinical grade autologous tolDC in active MS patients following intradermal administration. Methods: In a phase I clinical trial [5], active MS patients are included according to predefined in- and exclusion criteria (clinicaltrials.gov NCT02618902). Autologous monocytes are extracted via a leukapheresis procedure and cultured in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4 and 1α,25 dihydroxyvitamin D3, according to predefined procedures in accordance with good manufacturing practices (GMP). Following stimulation with an inflammatory cytokine cocktail for 48 hours on day 4, tolDC are harvested, loaded with 7 immunodominant myelin antigens (MBP13-32, MBP111-129, MBP154-170, PLP139-154, MOG1-20, MOG35-55 and MBP83-99), and cryopreserved. Separate aliquots of the cell product are saved for quality control and quality assurance (QC/QA). Six administrations at predefined intervals are planned in 3 cohorts receiving incremental doses of tolDC, according to a best-of-five design. For safety, the number of adverse events (AE) and relapses, neurological disability, and magnetic resonance imaging (MRI) endpoints will be assessed. Secondary outcome measures include other clinical and MRI endpoints. Immunological monitoring is performed and quality of life is assessed. In the first dose cohort, patients receive 6 injections with 5 x 106 tolDC each. Results: Until August 20, 2018, 8 patients have been screened, of which 4 were eligible to be included in the clinical trial. 1 of the 4 investigational products did not comply with the release criteria and was destroyed. Three patients received the tolDC-based treatment and are currently in the treatment and safety follow-up phase. Two of the 3 patients were diagnosed with relapsing remitting MS (1 male and 1 female), and 1 patient with primary progressive MS. The age ranged between 30 and 39 years. Disease duration from symptom onset varies between 2 and 13 years. EDSS at baseline ranged between 1.5 and 2.5. To date, no serious adverse events have been reported and most adverse events were considered to be treatment unrelated, except for mild local reactions seen at the injection site. Two patients experienced a mild MS relapse. Both relapses did not fulfill the protocol defined criteria for confirmed MS relapse. Conclusions: The interim results of the first dose cohort of the MS-tolDC phase I clinical trial did not show an important safety signal to date. Further treatment and follow-up of patients in the first dose cohort is ongoing. Enrollment of patients in the second dose cohort in accordance with the protocol can only start after evaluation of the first dose cohort by the Data Safety Monitoring Board.

Acknowledgements

BW was supported by a research fellowship of the University of Antwerp (UA) and holds a clinical PhD fellowship from the Research Foundation Flanders (FWO 1701919N). This work was supported by the Methusalem Funding Program from the UA, an applied biomedical research project of the Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT-TBM 140191), Belgian Charcot Foundation and the EU Horizon 2020 research and innovation program, grant agreement 779316

References

[1] W.-P. Lee, B. Willekens, P. Cras, H. Goossens, E. Martínez-Cáceres, Z.N. Berneman, and N. Cools, Immunomodulatory Effects of 1, 25-Dihydroxyvitamin D3 on Dendritic Cells Promote Induction of T Cell Hyporesponsiveness to Myelin-Derived Antigens. Journal of Immunology Research 2016 (2016). [2] M.J. Mansilla, C. Selles-Moreno, S. Fabregas-Puig, J. Amoedo, J. Navarro-Barriuso, A. Teniente-Serra, L. Grau-Lopez, C. Ramo-Tello, and E.M. Martinez-Caceres, Beneficial effect of tolerogenic dendritic cells pulsed with MOG autoantigen in experimental autoimmune encephalomyelitis. CNS neuroscience & therapeutics 21 (2015) 222-30. [3] M.J. Mansilla, R. Contreras-Cardone, J. Navarro-Barriuso, N. Cools, Z. Berneman, C. Ramo-Tello, and E.M. Martinez-Caceres, Cryopreserved vitamin D3-tolerogenic dendritic cells pulsed with autoantigens as a potential therapy for multiple sclerosis patients. Journal of neuroinflammation 13 (2016) 113. [4] D. Raich-Regue, L. Grau-Lopez, M. Naranjo-Gomez, C. Ramo-Tello, R. Pujol-Borrell, E. Martinez-Caceres, and F.E. Borras, Stable antigen-specific T-cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients. European journal of immunology 42 (2012) 771-82. [5] B. Willekens, J. Derdelinckx, P. Cras, P. Parizel, E. Martinez-Caceres, C. Ramo-Tello, W. Van Hecke, A. Ribbens, Z. Berneman, and N. Cools, Study Protocol for MS tolDC: a phase I clinical trial of a personalized" Negative" Dendritic Cell-based Vaccine for the Treatment of Multiple Sclerosis, MULTIPLE SCLEROSIS JOURNAL, SAGE PUBLICATIONS LTD 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND, 2016, pp. 777-777.

Keywords: Multiple Sclerosis, cell therapy, dendritic cell, Clinical Trial, Phase I (drug development)

Conference: Belgian Brain Congress 2018 — Belgian Brain Council, LIEGE, Belgium, 19 Oct - 19 Oct, 2018.

Presentation Type: e-posters

Topic: NOVEL STRATEGIES FOR NEUROLOGICAL AND MENTAL DISORDERS: SCIENTIFIC BASIS AND VALUE FOR PATIENT-CENTERED CARE

Citation: Cools N, Presas-Rodríguez S, Mansilla M, Derdelinckx J, Lee W, Nijs G, De Laere M, Wens I, Cras P, Parizel P, Van Hecke W, Ribbens A, Adams G, Couttenye M, Navarro-Barriuso J, Teniente-Serra A, Quirant-Sánchez B, Lopez-diaz De Cerio A, Inogés S, Prosper F, Gross CC, Wiendl H, Van Ham S, Ten Brinke A, Verheij H, Kip A, Barriocanal A, Massuet-Vilamajó A, Hens N, Berneman Z, Martínez-Cáceres E, Ramo-Tello CM and Willekens BM (2019). Towards a dendritic cell-based vaccine for the treatment of multiple sclerosis (MS): interim safety data of the first dose cohort of the MS-tolDC phase I clinical trial. Front. Neurosci. Conference Abstract: Belgian Brain Congress 2018 — Belgian Brain Council. doi: 10.3389/conf.fnins.2018.95.00060

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Received: 23 Aug 2018; Published Online: 17 Jan 2019.

* Correspondence:
Prof. Nathalie Cools, Laboratory of Experimental Hematology, University of Antwerp, Edegem, Antwerp, Belgium, nathalie.cools@uza.be
MD. Barbara M Willekens, Antwerp University Hospital, Department of Neurology, Antwerp, Belgium, Barbara.Willekens@uza.be