NEW YORK & MELBOURNE, Australia—Mesoblast Ltd. has announced that MD Anderson Cancer Center (MDACC) in Texas and the U.S. National Institutes of Health (NIH) will fund a clinical trial combining Mesoblast’s two synergistic proprietary technologies, mesenchymal precursor cell (MPC)-based expansion and ex-vivo fucosylation of hematopoietic stem cells (HSCs) for cord blood transplantation in cancer patients. The trial will provide clinical data on whether the combination of these two technologies synergistically facilitates more rapid cord blood HSC engraftment for bone marrow transplant patients than can be achieved by either technology alone.
Many patients with advanced blood cancers, such as acute myeloid leukemia, require a stem cell transplant to repopulate bone marrow HSCs after treatment with high-dose chemotherapy. Patients typically undergo transplant with blood stem cells taken from the bone marrow or peripheral blood of a donor with a matched tissue type. However, it can be difficult to find a matched donor, especially for patients who are part of a racial or ethnic minority. While transplants using cord blood-derived stem cells do not require the same degree of donor matching as blood and marrow, this approach has had limited success in the past, due to the low yield of stem cells in cord blood and their reduced ability to localize within the recipient’s bone marrow.
Ex-vivo fucosylation is the addition of the sugar fucose to surface receptors on cells, including HSCs and mesenchymal lineage stem cells. This process modifies receptors on these cells by adding carbohydrate or sugar sequences, which allows them to be recognized by and bound to their ligands present on endothelial cells lining blood vessels in inflamed tissues and in human bone marrow. As a result, such modified cells demonstrate enhanced homing properties to bone marrow or to tissues that are inflamed. Mesoblast has exclusively licensed the ex-vivo fucosylation technology, which was developed at Harvard Medical School by Dr. Robert Sackstein, for use with HSCs and with allogeneic mesenchymal lineage cells. This cell-targeting technology resulted in engraftment of systemically infused human HSCs into mouse bone marrow at a rate 10 times that of unmodified human HSCs.
The number of allogeneic bone marrow transplants performed globally each year could be substantially increased beyond the current 30,000 for cancer and non-cancer indications if safe and effective alternative sources of allogeneic HSCs are available, such as cord blood, for patients who cannot find a matched donor.
DDNews spoke with Silviu Itescu, CEO and managing director at Mesoblast, who says, “If this is a successful trial, it will mean that cord blood transplants will be available for everyone who doesn’t have a related donor—around 60,000 people.”
According to Itescu, the primary problem with bone marrow transplants is the lack of donors. There’s a high risk with unrelated donors, and a greatly increased chance of infection, due to the time period it takes to see if the graft works.
Unfortunately, cord blood transplants are associated with prolonged engraftment times due to insufficient numbers and inadequate homing capacity of cord blood HSCs, adversely impacting their clinical outcomes. The strategy of combining Mesoblast’s proprietary technologies using MPC-based expansion plus ex-vivo fucosylation of cord blood HSCs aims to overcome the two key limitations to using cord blood for rapid, early engraftment and bone marrow reconstitution in adult bone marrow transplant patients. This novel clinical strategy has the potential to significantly increase the number of patients who can receive unrelated donor transplants.
Previously, Mesoblast conducted a Phase 2 clinical trial which demonstrated that transplantation of HSCs from MPC-expanded cord blood resulted in a reduced engraftment time, from a median of 24 days for placebo-treated cells to a median of 15 days for co-cultured cells. Separately, another Phase 2 clinical study showed that transplantation of fucosylated, but non-expanded, cord blood HSCs also resulted in a reduced median engraftment time of 17 days. More recently, preclinical results from a group led by Dr. Elizabeth J. Shpall, director of the Cell Therapy Laboratory and a professor in the Department of Stem Cell Transplantation at MDACC, where MPC-based expansion and ex-vivo fucosylation technologies were combined, showed a very rapid engraftment time of approximately seven days.
“Mesoblast has previously worked with MDACC, where we provided Dr. Shpall with our technology as part of a clinical protocol that expanded cord blood precursors in a Phase 2 clinical trial,” says Itescu. “This new trial will be funded by the NIH and MD Anderson, and Mesoblast is funding the cells and the enzymes used.”
“It was exciting to do the first study with Shpall, and we were able to significantly reduce the engraftment time to around 15 days. Shpall then reduced engraftment time to seven days with the proprietary technologies in mouse models,” Itescu adds. “Now with this new trial, we’ll see whether the combined techniques will help get the technologies to work on human models in a similar time.”
“Our data suggest that combining Mesoblast’s MPC-based HSC expansion and ex-vivo fucosylation technologies may be the optimal clinical strategy for rapid engraftment of cord blood transplants, potentially making cord blood transplantation a real option for many desperate patients who cannot find a suitable alternative,” said Shpall.
If the results of the combination study are positive, Mesoblast’s proprietary ex-vivo fucosylation technology may be incorporated into the company’s Phase 3 program of MPC-expanded HSCs.
As of the publication of this article, the trial was only waiting for the Investigational New Drug clearance to come from the FDA, which seemed likely begin in late January, according to Itescu, adding, “If we see great results in as few as 10 patients, we would then be able to talk to the FDA about fast-tracking this treatment.”
The recent 21st Century Cures Act, signed into law on Dec. 13, has created a pathway for fast approval for new regenerative medicine therapy cell products. As Itescu says, “Mesoblast has already in place a Phase 3 program, agreed to with the FDA, on using the MPCs to expand cord transplants. We are considering amending the program to include fucolysation, and we believe that kind of a trial would be approved for an accelerated pathway under the new act. We’re very excited—the fucolysation technology has applications beyond this specific one, so not only might it work for bone marrow transplants, it may work for bringing down inflammation in other conditions, such as Crohn’s and diabetes.”