Graft-versus-host disease (GVHD) is counterintuitive
In the weeks and months following a transplant, a major concern is the recipient’s immune system rejecting the “foreign” biological material. But in GVHD, the opposite happens: transplanted tissue unleashes a horde of T cells that spark a cascade of inflammation, within 100 days. Typically, GVHD follows a bone marrow transplant (BMT).
Eighty Percent Mortality
BMT has been used for more than half a century to treat and possibly cure certain cancers and single-gene conditions like sickle cell disease, immune deficiencies, and lysosomal storage diseases. BMT and hematopoietic stem cell (HSC) transplantation also enable a cancer patient to withstand higher doses of chemotherapy or radiation.
Acute GVHD develops in about half of the 30,000 or so patients who receive a BMT from a donor worldwide each year. In children the complication can be particularly fierce. A blistery rash can become so extreme that the skin peels away, as can the intestinal lining, causing abdominal pain, diarrhea, and nausea and vomiting. Hepatitis may develop.
Only 20% of children who have steroid-resistant acute GVHD survive. But a treatment of mesenchymal stromal/stem cells (MSCs), called remestemcel-L (RYONCIL™), from Mesoblast Limited, is boosting survival to the 65-75% range, according to recent clinical trial findings.
On August 13, FDA’s Oncologic Drugs Advisory Committee, an independent panel of experts who take a first peek at phase III clinical trial results, voted overwhelmingly to advise the agency to continue along the path to approval for RYONCIL. FDA’s final meeting is slated for September 30.
“This devastating condition has an extremely poor prognosis and there are no FDA-approved options for children under the age of 12. The clinical studies I have directed have demonstrated the potential for this treatment to fill a significant unmet medical need,” said pediatric transplant physician Joanne Kurtzberg, the Jerome Harris Distinguished Professor of Pediatrics and Professor of Pathology, and Director, Pediatric Blood and Marrow Transplant Program at Duke University Medical Center.
Mesoblast MSCs’ Time Has Come
Like other successful biotechnologies, the deployment of MSCs for a number of indications has been a long time coming. I wrote about them more than 20 years ago, for The Scientist, when Osiris Therapeutics was developing what would become remestemcel-L:
“MSCs are the body’s storehouse of potential spare parts, pockets of unspecialized cells, tucked into a variety of places, that can migrate to an injury and, responding to signals in the milieu, embark on a normal developmental pathway to become what’s needed.”
They’re not as potent (pluripotent) as embryonic stem cells, but are more developmentally flexible than the HSCs that replenish bone marrow.
Despite this history that includes many clinical trials for a variety of conditions with an inflammatory component, FDA has not approved use of MSCs for any indication, although some MSCs are delivered in cord blood transplants, which are approved for certain conditions. Remestemcel-L would be a first.
Three Phase III trials
The three phase III clinical trial results that Mesoblast just presented to FDA had different designs.
The first, a randomized controlled clinical trial, enrolled 260 patients, including 28 children. The effect of the stem cell treatment emerged in an ad-hoc analysis of the 14 youngsters with the most severe GVHD: 9 of 14 (64%) responded for the benchmark of at least 28 consecutive days within 100 days of starting treatment, compared to 5 of 14 (36%) among the control group. However, the overall group, including patients with less severe disease, did not meet the primary endpoint of complete remission for 28 consecutive days.
The second trial design was “real world”: an expanded access protocol, which the agency invokes to greenlight a treatment still under investigation, for compassionate use. Of the 241 kids who’d failed everything, 65% responded for the 28 consecutive days and 66% survived at day 100. “A relatively large cohort of children with the most severe SR-aGVHD and on multiple lines of treatment responded to remestemcel-L in a ‘real-world’ setting,” the researchers write.
But it was the earlier treatments that influenced FDA to require a third and “pivotal” study on participants who had only the initial 28-day course of steroids. These 54 children received two infusions of stem cells a week for four consecutive weeks.
By the end of the period, 38 participants (70.4%) had had either a complete response (16 of 38; all organs clear) or a partial response (22 of 38; organs improving and none worsening). Forty children (74.1%) survived until day 100 and 37 (68.5%) until day 180.
How MSCs Help GvHD
Since MSCs were initially described in 1991, researchers have worked out many of the details of how the cells counter cytokine storms and facilitate healing in various bodily settings. In general, MSCs are distinguished by a characteristic trio of surface markers: CD166, CD105, and CD45.
Remestemcel-L in particular reduces pathogenic inflammation by dampening the expression of receptors for the cytokines tumor necrosis factor alpha (TNF-α) and interleukin-2, which inhibits activation of cytotoxic T cells. See infographic 1 above from Mesoblast on anti-inflammatory mechanisms. The stimulated stem cells also secrete mediators in response to TNF-α that modulate immune responses, tamping down pro-inflammatory cytokines, boosting anti-inflammatory cytokines, and sending signals that recruit anti-inflammatory cells. The response is complex, but suggests efficacy in countering inappropriate inflammation.
Understanding the therapeutic mechanism is critical for regulatory submission as a “biologics license application” (BLA). A cell-based product offers more of a mixed bag of possibilities than a conventional drug, and may exert effects through multiple actions. That’s why manufacturers must file a BLA with FDA.
In their natural niche, the MSCs that comprise Remestemcel-L hug blood vessels, and they come from bone marrow of healthy adults. Each donation can yield potentially thousands of doses that can be frozen and used without tissue matching. The company is establishing a “cell bank” for each donor, but the cells can’t last indefinitely. Maintaining the supply will regularly require new donors.
Remestemcel-L’s Potential COVID Niches Too Including MIS-C
The advanced status of the clinical trials of remestemcel-L for acute GVHD placed it towards the head of the pack of potential treatments for the mother of all cytokine storms (see infographic 2 above from Mesoblast): the ones that accompany COVID-19.
FDA’s expanded access pathway made the cells available to treat 12 COVID-19 patients on ventilators at Mt. Sinai Hospital in New York City in the spring, with encouraging, even if preliminary results. A phase three, double-blind, randomized placebo-controlled trial is now underway for up to 300 patients on ventilators with moderate to severe acute respiratory distress syndrome from COVID-19, the primary cause of death.
Then on July 6, based on encouraging interim news from the GVHD trials, FDA approved remestemcel-L for an expanded use protocol to treat children aged two months to 17 years who have heart and blood vessel damage from multisystem inflammatory syndrome (MIS-C), which is associated with COVID-19. MIS-C also causes fever, diarrhea, abdominal pain, headache, rash, conjunctivitis, difficulty swallowing, and muscle aches. The lungs and kidneys may also fail.
“Kids with multisystem inflammatory syndrome can have a tremendous cytokine storm affecting their heart function. Stem cells introduced into the body by intravenous administration can mitigate the cytokine storm,” said Sunjay Kaushal, PhD, MD, chief of the University of Maryland Congenital Heart Disease Outreach Program. Remestemcel-L, is given in one or two doses within five days to these children.
Results haven’t been released yet. A review article published August 17 in Lancet Infectious Diseases lists only intravenous immunoglobulin, steroids, aspirin, and anticoagulants under “published immunotherapies against MIS-C,” but emphasizes inclusion of affected children in clinical trials on a case-by-case basis.
Let’s hope that the long-term research invested in harnessing MSCs to treat acute steroid-resistant GVHD in children will also pay off for children suffering from the rare complication of the very new COVID-19 and perhaps other diseases in the future.