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
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.
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.
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.