EU-MSC2 meeting report: shaping the future of MSC therapy
In this report, Katerina Apelt, Brigitte Wieles and Melissa van Pel discuss the key findings from the EU-MSC2 meeting (5–6 September 2019, Leiden, The Netherlands) and the state of the mesenchymal stem cell field.
EU-MSC2 is a bi-annual event, organized by the Leiden University Medical Center (The Netherlands), that assembles researchers, clinicians and cell product developers working within EU-sponsored research consortia, with a focus on mesenchymal stromal cell (MSC) therapy for immune-related disorders and tissue regeneration.
The main objective of the meeting is to enhance knowledge-sharing between EU research groups working in the MSC therapy domain and learn from each other’s successes and failures.
Three events have been organized, attended by regulators from the European Medicines Agency (Amsterdam, The Netherlands), national competent authorities, industry and members of a total of 17 EU-sponsored consortia. The event has so far provided excellent opportunities for networking, exploring new funding opportunities and dissemination of results contributing to MSC knowledge-sharing, research and development.
The 2019 edition (5–6 September, Leiden, The Netherlands) focused on product harmonization, product potency and patient monitoring, clinical trial design and the regulatory landscape. These topics were presented by experts in the field, followed by a poll in which participants could voice their opinion on a number of statements.
First, a simple question was posed related to the use of MSCs as a starting material (Figure 1). Bone marrow was the favorite tissue source for MSC manufacturing according to 54% of the participants, while 33% and 13% preferred adipose tissue and umbilical cord, respectively, broadly reflecting the tissue sources used for MSC manufacturing in the clinical trials the consortia are involved in.
Product potency and patient monitoring
MSC immunogenicity was discussed with a focus on the formation of donor-specific antibodies important in solid organ transplantation. One study showed that presensitized patients were more prone to generate donor-specific antibodies, but these were shown to disappear over time. Another study showed no formation of donor-specific antibodies to third party MSCs. The capacity of patient leukocytes to kill donor MSCs was presented as a potential donor-eligibility test for MSCs in graft-versus-host disease. The increase in PGE2 levels after MSC infusion could be an early marker for patient response to MSC therapy.
The audience was questioned on the clinical relevance of potency assays for MSC product release, whether a single potency assay is sufficient to cover all immune modulation therapies and the importance of the patient microenvironment for a successful cell therapy. The majority felt that a potency assay may be clinically relevant but that multiple assays are needed to cover all immune-related disorders.
Furthermore, 67% disagreed with the statement that the patient microenvironment alone is the single determinant of therapy outcome (Figure 2). The substantial percentage of ‘I don’t know’ responses is indicative of an uncertainty about the mechanism of action in immunomodulatory MSC therapy. Interestingly, tools to study the mechanisms of action were presented. These included tools for imaging MSC and MSC-derived factors in pre-clinical models, such as bioluminescence imaging, gold nanostars and optoacoustic imaging.
Results from a number of clinical trials were presented, including:
- SCIENCE – allogeneic adipose tissue-derived MSCs for ischemic heart failure,
- VISICORT – MSC-based therapy in corneal transplantation,
- NEPHSTROM – MSCs to treat diabetic nephropathy,
- RESPINE – MSCs to treat degenerative disc disease,
- RETHRIM – MSCs in graft-vs-host disease,
- MSC therapy in kidney transplantation and in the treatment of lung emphysema.
A number of EU-sponsored clinical trials suffer from low accrual of patients. It is therefore of no surprise that the audience largely agreed (93%) with the statement that we tend to overestimate the number of patients that can be recruited for a trial. The majority of the audience (76%) also felt that hospital exemptions do not stand in the way of proper clinical trials and market authorization (MA).
An investigator’s perspective on current regulations of advanced therapeutic medical products (ATMPs) and a physician’s view on the clinical application and reimbursement of ATMPs without MA were discussed.
92% of the audience agreed that MAs should not be the single route to bring ATMPs to patients (Figure 3). From this, we can conclude that hospital exemptions may also be a way to bring ATMPs to patients; however, hospital exemptions may increase clinical experience but provide only limited information regarding the mechanism of action and product efficacy.
A lot of consortia have limited experience in obtaining regulatory approval for clinical trials. Delay of the projects could be attributed to underestimating the requirements for release packages and the quality standards of the cell therapy product itself, which is reflected by the majority of the audience agreeing they underestimate these requirements.
The meeting was concluded by looking forward to the future of MSC therapy. There was consensus on the need for harmonization and standardization in MSC immune therapy. Furthermore, the majority of the audience expect that induced pluripotent stem cell-derived MSCs (iMSCs) are the future as they may provide an unlimited and standardized MSC source.