Cell Therapy Could Reduce Bone-Marrow Transplant, Radiation Injury Complications
A cell-therapy approach first discovered at the UW Carbone Cancer Center (UWCCC) in 2009 may reduce complications from bone marrow transplant (BMT) and radiation injury in the future, according to a new study.
The cells, called MEMs, are a distinct subset of macrophages, a type of immune cell. In the study, UWCCC researchers Dr. Peiman Hematti and Dr. Christian Capitini showed that MEMs reduce inflammation, improve wound healing and increase overall survival in a pre-clinical mouse model of graft versus host disease (GVHD) – a major complication of BMT – and in a mouse model of radiation injury.
Both GVHD and radiation injury can severely affect patients by inducing too much of an inflammatory immune response, and can lead to death if uncontrolled.
"Our discoveries in this work could have major implications in not only alleviating major complications of bone-marrow transplantation but also a much bigger potential in radiation medicine," Hematti said.
A promising therapy to suppress GVHD has involved infusing patients with cells known as MSCs. However, in large clinical trials MSCs unfortunately appear to work no better than standard drug therapies. Hematti and Capitini’s study shows that MEMs, in which macrophages are grown in the lab and “educated” by MSCs to mature into MEMs, may be the improvement physicians and patients have been looking for.
“When we discovered MEMs in 2009, people began realizing that macrophages are a major component of the potential beneficial effects of MSC therapy to treat GVHD,” Hematti said. “But back then, we didn’t have Christian. He is an expert in GVHD models and transplantation, and when he joined UW I found the collaborator I needed to move MEMs forward.”
Working together, Hematti and Capitini’s first step in this new study was to characterize MEMs, especially in comparison to other macrophages. They looked at the cells’ gene expression, in collaboration with Dr. Sandeep Dave, a genomic specialist at Duke University.
“They have a completely unique profile compared to the regular macrophages we encounter,” Capitini said. “We found many different pathways that seem to go along with a theme of tissue repair and wound healing, so there were hints that these cells could be useful in an anti-inflammatory setting. But you don’t know until you look at the mouse models.”
So next, they moved the MEM work into a mouse model of GVHD, in which mice typically die within several weeks after receiving BMT. Just as the mice were beginning to show signs of GVHD, the researchers treated them with one round of MSCs, MEMs or no additional cells. Mice that received no cellular therapy or MSCs survived less than one week after treatment, but half of mice in the MEM group were alive after 50 days.
The researches then tested MEMs in a mouse model of radiation toxicity. Radiation toxicity after radiotherapy, accidental nuclear events or intentional nuclear attacks are a major medical issue. In this model, there were higher survival rates if mice were treated with a single infusion of MEMs as compared to MSCs or standard macrophages. Capitini said they would next test if multiple rounds of infusions showed a greater benefit in both radiation and GVHD models.
“With MSCs, we think that they are educating macrophages in the body to become MEMs, but the cells get diluted,” Hematti said. “Here, we expect that if we take macrophages and grow and educate them in the lab, then we can give a lot more of the good cells back to the patient.”
Hematti is working with several groups of collaborators on campus and at other universities to further study the potential of these cells in other disease models. Also, Hematti and Capitini are applying for an Investigational New Drug (IND) designation from the FDA for the MEMs. If approved, they expect to bring MEMs to clinical trials in the next few years.
"As we’re expanding the number of cancers that are getting transplanted, we need better GVHD therapies," Capitini said.
The study was published online in the journal Biology of Blood and Marrow Transplantation and featured in a commentary in the journal highlighting the importance of the findings. It was funded in part by a pilot grant co-funded by UW ICTR and UWCCC (NIH/NCATS UL1TR000427 and NIH/NCI P30 CA014520), NIH/NCI K08 CA174750, the Don Anderson GVHD Fund and the Crystal Carney Fund for Leukemia Research. This discovery has been filed for a patent by WARF.
Date Published: 04/12/2017