CALEC Cell Therapy Repairs Corneal Damage in Phase I Study

Researchers headed by a team at Mass Eye and Ear, Harvard Medical School, reported positive data from a Phase I clinical study evaluating a stem cell treatment known as cultivated autologous limbal epithelial cell transplantation (CALEC), in patients with significant chemical burns in one eye. Results from the study, reported in Science Advances, showed treatment to be safe and well tolerated in four patients who were followed for 12 months. The CALEC recipients experienced restored cornea surfaces, with two trial participants able to undergo subsequent corneal transplant, and two reporting significant improvements in vision without additional treatment.

The Phase I study was designed to determine preliminary safety and feasibility before advancing to a second phase of the trial, and the researchers consider the newly reported early findings to be promising. On the basis of these initial results the team started recruiting for a second phase of the trial that will investigate longer-term safety and efficacy in greater numbers of patients.

“Our early results suggest that CALEC might offer hope to patients who had been left with untreatable vision loss and pain associated with major cornea injuries,” said principal investigator Ula Jurkunas, MD, associate director of the Cornea Service at Mass Eye and Ear and an associate professor of ophthalmology at Harvard Medical School. “Cornea specialists have been hindered by a lack of treatment options with a high safety profile to help our patients with chemical burns and injuries that render them unable to get an artificial cornea transplant. We are hopeful with further study, CALEC can one day fill this crucially needed treatment gap.”

Jurkunas is senior author of the team’s published report, which is titled “Cultivated autologous limbal epithelial cell (CALEC) transplantation: Development of manufacturing process and clinical evaluation of feasibility and safety.”

People who experience chemical burns and other eye injuries may develop limbal stem cell (LSC) deficiency, an irreversible loss of cells on the tissue surrounding the cornea. These patients experience permanent vision loss, pain and discomfort in the affected eye. “When limbal stem cells (LSCs) become dysfunctional or deficient, the cornea is unable to maintain its surface epithelial integrity and LSC deficiency (LSCD) develops,” the authors wrote. And without limbal cells and a healthy eye surface, patients are unable to undergo artificial cornea transplants, the current standard of vision rehabilitation.

Existing treatment strategies have limitations and associated risks, and the CALEC procedure aims to address through its unique approach of using a small amount of a patient’s own stem cells that can then be grown and expanded to create a sheet of cells that serves as a surface for normal tissue to grow back. According to the authors, despite landmark studies describing an autologous stem cell approach over the past 25 years and similar methods being utilized in Europe, no U.S. research team had successfully developed a manufacturing process and quality control tests that met FDA requirements or showed any clinical benefit.

“Before CALEC, techniques for culturing autologous and allogeneic limbal epithelial cells for treatment of LSCD used a variety of manufacturing procedures and substrates on which the cells are grown, ranging from petrolatum gauze, contact lenses, fibrin, keratin, silk fibroin, and collagen,” the investigators noted. “However, despite landmark publications describing this approach decades ago, no previous clinical studies have evaluated cultivated LSC grafting in the United States.

The CALEC process involves carrying out a small biopsy to take stem cells from a patient’s healthy eye, and then expand and grow these cells on a graft, via what the team calls an innovative manufacturing process at the Connell and O’Reilly Families Cell Manipulation Core Facility at Dana-Farber Cancer Institute. After two to three weeks, the CALEC graft is then then sent back to Mass Eye and Ear and transplanted into the eye with corneal damage. “… we developed cultivated autologous limbal epithelial cells (CALEC) using an innovative xenobiotic-free, serum-free, antibiotic-free, two-step manufacturing process for LSC isolation and expansion onto human amniotic membrane with rigorous quality control in a good manufacturing practices facility,” the researchers commented. “… our study presents the development of a critical technologic innovation that allowed the first-in-human trial of CALEC…”

In the Phase I study reported, five patients with chemical burns to one eye were enrolled and biopsied. Four received CALEC; a series of quality control tests determined the cells in the fifth patient were unable to adequately expand. The CALEC patients were tracked for 12 months.

CALEC Surgery [Mass Eye and Ear]

The first patient treated, a 46-year-old male, experienced a resolution of his eye surface defect, which primed him to undergo an artificial cornea transplant for vision rehabilitation. The second, a 31-year-old male, experienced a complete resolution of symptoms with vision improving from 20/40 to 20/30. The third, a 36-year-old male, had his corneal defect resolved and his vision improved from hand motion—only being able to see broad movements like waving—to 20/30 vision. The fourth, a 52-year-old male, initially did not have a successful biopsy that resulted in a viable stem cell graft. After re-attempting CALEC three years later, he underwent a successful transplant and his vision improved from hand motion to being able to count fingers. He then received an artificial cornea.

“It was challenging to develop a process for creating limbal stem cell grafts that would meet the FDA’s strict regulatory requirements for tissue engineering,” said Ritz, executive director of the Connell and O’Reilly Families Cell Manipulation Core Facility at Dana-Farber and professor of medicine at Harvard Medical School. “Having developed and implemented this process, it was very gratifying to see encouraging clinical outcomes in the first cohort of patients enrolled on this clinical trial.”

The authors further noted in their paper, “In summary, the initial phase of this trial has established feasibility of the product manufacturing method with no immediate safety concerns, enabling a second recruitment phase to provide longer term safety and efficacy data on more patients.”

The researchers are now finalizing this next phase of the clinical trial in 15 CALEC patients who will be tracked for 18 months to better determine the procedure’s overall efficacy. The hope is that CALEC can one day become a treatment option for patients who previously had to endure long-term deficits when existing treatment options were not an option given the severity of their injuries. “If successful, this first use of CALEC in the United States will serve as a stepping stone for establishing cellular therapy products as viable options for patients with LSCD.”

The CALEC procedure is patent pending, and Jurkunas and Dana have equity in Ocucell, a company interested in developing cell-based therapies for the eye.

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