Periodic Reporting for period 4 - RESTORE (NEURONAL SELF-RENEWAL BY ANTIGEN-SPECIFIC TOLERIZATION IN MULTIPLE SCLEROSIS REINSTALLING THE BALANCE BETWEEN INFLAMMATION AND REGENERATION)
Berichtszeitraum: 2022-07-01 bis 2023-06-30
Multiple sclerosis (MS) is a neurodegenerative inflammatory disease affecting the central nervous system. Striking individuals during their most productive years, both personally and professionally, MS imposes a significant physical and socio-economic burden on patients, their families, and society at large. Despite the increasing number of approved disease-modifying treatments for MS, a definitive cure remains elusive. Consequently, there is an urgent need for innovative therapeutic interventions that surpass existing drugs in efficacy and tolerability.
Given that chronic inflammatory processes drive neurodegeneration, our hypothesis posited that an improved clinical outcome relies on restoring the delicate balance between inflammation and the inherent capacity for neuronal self-renewal. In line with this perspective, we proposed in current EU-funded Horizon 2020 project the evaluation of a cell therapy that targets specific immune reactions responsible for MS, inducing disease-specific tolerance while preserving protective immunity against pathogens and cancer—an auspicious approach.
Our efforts focused on assessing the safety, clinical viability, and initial proof-of-principle for the therapeutic efficacy of antigen-specific tolerance-inducing dendritic cells (tolDC) in MS patients. Conducted through two phase I, open-label, dose-escalation, single-center clinical trials, we scrutinised two modes of tolDC administration. Rigorous patient monitoring, centralised MRI evaluations, including radiological markers of neurodegeneration, and immunomonitoring facilitated direct comparisons across trials. Simultaneously, we prioritised consented biobanking, data security, and accessibility to fortify future MS therapy endeavours. In Belgium (NCT02618902) and Spain (NCT02903537), 18 patients (9 per trial) underwent treatment with tolDC, either intradermally or intranodally. Notably, there were no significant differences in adverse events (AE) between cohorts or trial sites, and no serious adverse events were reported. The administration of tolDC, whether intradermal or intranasal, proved safe, feasible, and well-tolerated, prompting regulatory approval for a phase II clinical trial.
Given that chronic inflammatory processes drive neurodegeneration, our hypothesis posited that an improved clinical outcome relies on restoring the delicate balance between inflammation and the inherent capacity for neuronal self-renewal. In line with this perspective, we proposed in current EU-funded Horizon 2020 project the evaluation of a cell therapy that targets specific immune reactions responsible for MS, inducing disease-specific tolerance while preserving protective immunity against pathogens and cancer—an auspicious approach.
Our efforts focused on assessing the safety, clinical viability, and initial proof-of-principle for the therapeutic efficacy of antigen-specific tolerance-inducing dendritic cells (tolDC) in MS patients. Conducted through two phase I, open-label, dose-escalation, single-center clinical trials, we scrutinised two modes of tolDC administration. Rigorous patient monitoring, centralised MRI evaluations, including radiological markers of neurodegeneration, and immunomonitoring facilitated direct comparisons across trials. Simultaneously, we prioritised consented biobanking, data security, and accessibility to fortify future MS therapy endeavours. In Belgium (NCT02618902) and Spain (NCT02903537), 18 patients (9 per trial) underwent treatment with tolDC, either intradermally or intranodally. Notably, there were no significant differences in adverse events (AE) between cohorts or trial sites, and no serious adverse events were reported. The administration of tolDC, whether intradermal or intranasal, proved safe, feasible, and well-tolerated, prompting regulatory approval for a phase II clinical trial.
To establish the safety, tolerability, and feasibility of intradermal (id, MS-tolDC) and intranodal (in, TOLERVIT-MS) administration of tolDC in active MS patients, we conducted two phase I, open-label, dose-escalation, single-center clinical trials.
Clinical-grade vitamin D3-treated autologous tolDC were manufactured under GMP conditions, starting from leukapheresis. Following loading with seven myelin-derived peptides (MBP13-32, MBP111-129, MBP154-170, PLP139-154, MOG1-20, MOG35-55, and MBP83-99), cell aliquots were cryopreserved. In a dose escalation study, three cohorts received a total of six administrations of 5, 10, or 15x106 tolDC per vaccine. The first four tolDC products were administered with a 2-week interval, while the last two had a 4-week interval. Safety assessments included recording adverse events (AE), relapses, neurological disability, and magnetic resonance imaging (MRI) endpoints. Secondary outcome measures included additional clinical and MRI endpoints, with exploratory outcomes involving immunological monitoring and quality of life assessments.
In Belgium (NCT02618902) and Spain (NCT02903537), 18 patients were included and treated with id (n=9) or in (n=9) tolDC, respectively. Each cohort exhibited a similar number of AE, with no statistically significant differences observed between sites or cohorts. Importantly, no serious adverse events were reported.
In conclusion, both intradermal (id) and intranodal (in) administration of tolDC proved to be safe, feasible, and well-tolerated. Regulatory authorities have approved a phase II clinical trial, and as of now, all approvals for the phase 2 clinical trial application have been obtained. This positive response has been affirmed by National competent authorities and institutional review boards in Spain and Belgium. Patient inclusion and treatment for the phase 2 clinical trial are anticipated to commence in Q1 2024.
In addition to the clinical trial efforts, ReSToRe has focused on organising meetings for researchers and stakeholders, data management, dissemination, exploitation of results, and the establishment of legal agreements. The findings from the phase I clinical trial were disseminated through presentations at reputable international meetings, including the 18th International Congress of Immunology 2023 and the 9th Joint ECTRIMS-ACTRIMS Meeting 2023.
Clinical-grade vitamin D3-treated autologous tolDC were manufactured under GMP conditions, starting from leukapheresis. Following loading with seven myelin-derived peptides (MBP13-32, MBP111-129, MBP154-170, PLP139-154, MOG1-20, MOG35-55, and MBP83-99), cell aliquots were cryopreserved. In a dose escalation study, three cohorts received a total of six administrations of 5, 10, or 15x106 tolDC per vaccine. The first four tolDC products were administered with a 2-week interval, while the last two had a 4-week interval. Safety assessments included recording adverse events (AE), relapses, neurological disability, and magnetic resonance imaging (MRI) endpoints. Secondary outcome measures included additional clinical and MRI endpoints, with exploratory outcomes involving immunological monitoring and quality of life assessments.
In Belgium (NCT02618902) and Spain (NCT02903537), 18 patients were included and treated with id (n=9) or in (n=9) tolDC, respectively. Each cohort exhibited a similar number of AE, with no statistically significant differences observed between sites or cohorts. Importantly, no serious adverse events were reported.
In conclusion, both intradermal (id) and intranodal (in) administration of tolDC proved to be safe, feasible, and well-tolerated. Regulatory authorities have approved a phase II clinical trial, and as of now, all approvals for the phase 2 clinical trial application have been obtained. This positive response has been affirmed by National competent authorities and institutional review boards in Spain and Belgium. Patient inclusion and treatment for the phase 2 clinical trial are anticipated to commence in Q1 2024.
In addition to the clinical trial efforts, ReSToRe has focused on organising meetings for researchers and stakeholders, data management, dissemination, exploitation of results, and the establishment of legal agreements. The findings from the phase I clinical trial were disseminated through presentations at reputable international meetings, including the 18th International Congress of Immunology 2023 and the 9th Joint ECTRIMS-ACTRIMS Meeting 2023.
While current therapies for multiple sclerosis (MS) often pose the risk of life-threatening infections and primarily focus on immune suppression without directly addressing the root cause of the disease, a paradigm shift is presented by antigen-specific tolerization. Unlike broad immunosuppressive drugs, this approach aims to selectively target only the pathogenic, autoreactive T cells, leaving the rest of the immune system intact, thereby minimizing risks and potential damage to the host. Advanced therapy medicinal products (ATMP), such as tolDC, hold tremendous potential to enhance the lives of patients facing serious conditions with unmet medical needs. However, substantial challenges, spanning regulatory, developer-related, and value chain-related obstacles, must be overcome before widespread access to these ATMP becomes a reality. Our commitment was to work transparently, expediting the safe delivery of these personalised therapies to patients.
The translation of cell therapy from laboratory research to clinical application necessitates increased collaboration across the developmental value chain. Intervention before epitope spreading occurs, utilizing antigen-specific therapies in conjunction with broader immunosuppressive agents, presents a promising avenue. For instance, preceding tolerance induction with biologicals like alemtuzumab can effectively reduce autoreactive T cell frequency to a level amenable to permanent suppression. Strategies demonstrating immunosuppressive effects in animal models involve the combination of costimulatory blockade reagents and T cell depletion, as well as the adoptive transfer of Treg.
Looking ahead, the future of MS therapy may evolve into a combinatorial approach, encompassing specific tolerance of autoreactive T cells alongside strategies promoting neurological repair. The vision for ReSToRe is to enable the development of a personalised, enduring treatment capable of addressing the underlying problem either permanently or for extended periods without compromising protective immunity. The primary objective was to minimize adverse effects and reduce the need for lifelong therapy, representing a breakthrough in healthcare for chronic diseases like MS and, by extension, other autoimmune conditions.
The translation of cell therapy from laboratory research to clinical application necessitates increased collaboration across the developmental value chain. Intervention before epitope spreading occurs, utilizing antigen-specific therapies in conjunction with broader immunosuppressive agents, presents a promising avenue. For instance, preceding tolerance induction with biologicals like alemtuzumab can effectively reduce autoreactive T cell frequency to a level amenable to permanent suppression. Strategies demonstrating immunosuppressive effects in animal models involve the combination of costimulatory blockade reagents and T cell depletion, as well as the adoptive transfer of Treg.
Looking ahead, the future of MS therapy may evolve into a combinatorial approach, encompassing specific tolerance of autoreactive T cells alongside strategies promoting neurological repair. The vision for ReSToRe is to enable the development of a personalised, enduring treatment capable of addressing the underlying problem either permanently or for extended periods without compromising protective immunity. The primary objective was to minimize adverse effects and reduce the need for lifelong therapy, representing a breakthrough in healthcare for chronic diseases like MS and, by extension, other autoimmune conditions.