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

Periodic Reporting for period 2 - RESTORE (NEURONAL SELF-RENEWAL BY ANTIGEN-SPECIFIC TOLERIZATION IN MULTIPLE SCLEROSIS REINSTALLING THE BALANCE BETWEEN INFLAMMATION AND REGENERATION)

Reporting period: 2019-07-01 to 2020-12-31

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system for which no cure is available. It is the leading cause of non-traumatic disabling neurological disease in young adults with more than 500,000 people affected in Europe. Since MS strikes during the primary productive time of one’s personal and professional life, it leads to a major physical and socio-economic burden to the patient, family and society. Therefore, new therapeutic interventions with improved efficacy over existing drugs and good tolerability are warranted. As chronic inflammatory processes drive the neurodegeneration, we hypothesize that improved clinical outcome depends on restoring the balance between inflammation and the remaining capacity of neuronal self-renewal. In this perspective, cell therapy that specifically targets the damaging immune reactions that cause MS and induce disease-specific tolerance without affecting protective immunity against pathogens and cancer is a promising approach.
Within the AFACTT project (Dec 2013 till Dec 2017), we set-up a collaborative network of European centers working in cell therapy (COST Action BM1305). Centers from 4 different EU countries with 2 additional partners now aim to take the next step and join efforts to bring antigen-specific therapy for MS to the clinic. Our objectives are to evaluate safety, clinical practicality and demonstrate first proof-of-principle of therapeutic efficacy of antigen-specific tolerance-inducing dendritic cells (tolDC) in MS patients in two single-center clinical trials while comparing different modes of tolDC administration. Coordinated patient monitoring and centralized MRI monitoring, including radiological correlates of neurodegeneration, and immunomonitoring will enable us to directly compare results between trials and enable consented biobanking, data safeguarding and accessibility to support future efforts in the field of MS therapy.
Antigen-specific cell therapy has the potential to provide this chronic inflammatory disease with a personalized and effective treatment option. An effective therapy that lowers morbidity by uniting efficacy with reduced occurrence of side effects and less frequent hospitalizations will enhance quality of life of patients as well as dramatically reduce economic burden. This would represent a breakthrough for healthcare in MS.
Our project is at technology readiness level 6 (TRL6). Having successfully gone through animal and pilot studies (TRL5), we are currently investigating the safety and feasibility of tolDC treatment for MS patients in two phase 1 dose-escalating clinical trials.

Today, at the Second Periodic Report, the first and second cohort of ReSToRe’s phase 1 dose-escalation clinical trials, receiving the lowest and intermediate dose of tolDC, were successfully completed. After intense screening procedures, 12 MS patients, meeting all in- and exclusion criteria, were treated with tolDC, demonstrating the first safety- and feasibility-results of this antigen-specific cell therapy product in MS. In addition and after positive advise of the Data Safety Monitoring Board to escalate the dose, the third cohort, receiving the highest dose of tolDC was initiated in Summer 2020, which is currently under treatment. All patients undergo clinical, immunological and MRI assessments according to the protocol. We anticipate to finish the third cohort, 3-months safety follow-up included, by November 2021. Besides the work performed within both clinical trials, ReSToRe focused on organizing meetings for all researchers and stakeholders involved, data management, dissemination and exploitation of the results and the installation of different legal agreements.

At the end of the trials, our goal is to have demonstrated the technology’s readiness for the relevant in vivo environment, validated by the decision that they meet the safety standards in each country and in the EU in general. Our goal is to reach TRL7 at this end, ready to start a second phase of clinical testing.
Although they can lead to life-threatening infections and do not directly address the cause of the disease, most of current therapies for MS are drugs that broadly suppress immunity. Antigen-specific tolerization is different since it aims to target only the pathogenic, autoreactive T cells, while leaving the remainder of the immune system undisturbed thereby providing minimal risk and damage to the host. Hence, advanced therapy medicinal products (ATMP), including tolDC, have the potential to improve the lives of patients suffering from serious conditions where unmet medical needs exist. However, considerable challenges, including regulatory, developer-related and value chain-related hurdles, remain before the widespread use of and the access to these ATMP become a reality. It is therefore our goal to work in a transparent manner to bring these personalized therapies to patients in a safe but expedited manner. Indeed, the translation of cell therapy from the bench to the bedside will be facilitated by achieving increased levels of interaction between the various partners of the developmental value chain.
Also, the opportunity to intervene before the appearance of epitope spreading using antigen-specific therapies in combination with broader immunosuppressive agents should be further explored. For instance, induction of tolerance may be preceded by treatment with biologicals, e.g. alemtuzumab, which can function to reduce autoreactive T cell frequency to a level that can be effectively and permanently suppressed. Strategies that have shown immunosuppressive effects in animal models include the combination of costimulatory blockade reagents and T cell depletion, as well as adoptively transferred Treg. Furthermore, it can be envisaged that ultimately the future of MS therapy will progress towards the development of a combinatorial therapeutic strategy that consists of specific tolerance of autoreactive T cells on the one hand and strategies that promote neurological repair on the other hand. Ultimately, we envisage that ReSToRe will enable the development of a personalized and long-lasting treatment with the potential to tackle the underlying problem permanently or for longer periods of time without compromising protective immunity. A positive impact for patients, their family and overall society is the main objective that we are striving to achieve by minimizing adverse effects and reducing the requirement for life-long therapy. This would represent a breakthrough for healthcare in this chronic disease and mutatis mutandis other autoimmune diseases.
General picture on cell therapy