The Clinical Trial
A major objective of the VISICORT project is to carry out a clinical trial in which a cell therapy designed to modify the immune system is administered to patients receiving a full-thickness corneal transplant who are at high risk for rejection.
The cells to be tested, which have been shown to improve the outcomes of other diseases caused by abnormal immune responses, are called mesenchymal stromal cells (MSCs) or, simply “stromal cells”. They are grown from the bone marrow of healthy adult volunteers and stored frozen until needed.
The primary purpose of the VISICORT trial will be to demonstrate, in a small number of carefully screened patients, that this cell therapy can be given safety and tolerably as an intravenous injection during the week before a high-risk corneal transplant.
If this first-stage (Phase 1b) trial goes well, the therapy can then be tested for its potential to reduce the risk of corneal transplant rejection in a larger (Phase 2) trial. The VISICORT clinical trial received regulatory and ethical approval in 2019.
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Diseases of the cornea (the clear part of the front of the eye that allows light through the pupil to the retina) are one of the most common causes of visual loss and blindness worldwide and, when severe, require a corneal transplant to restore sight. Although the healthy cornea is protected from damage by the immune system, corneal transplants may be damaged by immune-mediated rejection, which remains the leading cause of corneal transplant failure. This is a particularly challenging problem in high-risk corneal transplant recipients, such as those with previous transplant failures due to rejection or those with eye diseases that cause intense inflammation of the cornea and/or growth of blood vessels into the cornea.
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The Research Behind the Trial
Laboratory research studies carried out by members of the VISICORT consortium and others have given strong evidence that MSCs grown from the bone marrow of a healthy donor who is unrelated to the corneal transplant donor have the potential to significantly reduce the risk of acute rejection through immunomodulatory mechanisms when given during the week prior to transplantation as two intravenous doses to high-risk corneal transplant recipients. In the VISICORT clinical trial, we refer to this cell therapy as “allogeneic human bone marrow-derived MSCs” or “allo-hBM-MSC” for short. To facilitate being able to give the cells around the time of a transplant, the cells are packaged into individual doses and frozen (cryopreserved) until needed – an approach often referred to as “off-the-shelf stromal cell therapy”.
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The Trial Sites
The stromal cell therapy for the trial is manufactured at the Centre for Cell Manufacturing at the National University of Ireland Galway. This is also the coordinating site for the VISICORT project [details about the cell manufacturing site and the process can be found here].
The clinical centre at which the trial and transplant procedures is being performed is Department of Ophthalmology at the world-renowned Charité University Hospital, Berlin, Germany. The trial is led by VISICORT partner, Prof. Uwe Pleyer, an internationally recognised expert in corneal disease and transplantation.
The clinical trial is being coordinated by VISICORT partner, Charité Research Organisation (CRO), a contract research organisation that was founded in collaboration with Charité Medical University, Berlin and specialises in conducting early phase clinical studies of novel therapies in patients and healthy volunteers.
The Trial Design and Patient Safety
The stromal cell therapy product for the trial is derived from the bone marrow of human leukocyte antigen (HLA)‐unmatched healthy adult donors.
Similar cell therapy products have been shown the be safe in a large number of clinical trials for other medical conditions involving abnormal immune responses, including trials involving multiple intravenous doses. While the overall number of patients treated with stromal cells to date is still relatively small (several thousand) when compared to certain drug classes, the consistency of the safety signal in many independent trials using multiple manufacturers and modes of delivery has been reassuring. Nonetheless, if stromal cell therapies are to be proven effective in people receiving high-risk corneal transplants, it will be essential to prove their safety, tolerability and feasibility in this specific clinical setting. That is a primary objective of the VISICORT clinical trial.
Other aspects of the trial, however, will also bring the potential to better understand how the stromal cell therapy influences immune responses following transplantation.
Click here to read about the trial design in more detail.
Eight patients needing a second or greater corneal transplant are planned to be included in 2 groups or cohorts. This trial will include both female and male subjects. The total duration of the trial for each patient will be approximately 13 weeks (not included screening and enrolment period). It is also planned to follow all trial patients in the Charité University Hospital Ophthalmology Department for long-term outcomes.
Click here to read about the trial inclusion criteria in more detail.
In the future, new cellular and molecular therapies have the potential to achieve rejection-free survival of corneal transplants without the need for prolonged treatment with immunosuppressive drugs (a state called “immune tolerance”) even in high-risk grafts.
To work toward this goal, carefully performed clinical trials such as the VISICORT trial, that bring together the expertise of ophthalmologists/eye surgeons, research scientists, specialists in cell manufacturing and experts in clinical trial design and coordination will be essential.
Most importantly, the voluntary participation of patients in pioneering trials such is the most significant contribution toward achieving better long-term outcomes for all corneal transplant recipients.