New computer software is able to identify targets for potential immunotherapies in individual leukemia patients undergoing stem cell transplants, a new study shows.
These results open the door for tailored and highly personalized immune therapies that activate only the leukemia-specific donor cells, leaving the patient’s healthy cells unharmed.
The study, “Computational modeling and confirmation of leukemia-associated minor histocompatibility antigens,” was published in the journal Blood Advances.
Stem cell transplants are one of the most effective treatments for blood cancer patients. However, it comes with a risk of serious graft-versus-host disease (GVHD).
GVHD happens when immune cells from the donor, especially T-cells (cells that fight infections and cancer) are transplanted together with the stem cells and view the recipient’s body as foreign and then react against it.
This is because the patient carries a genetic signature that is different from the donor, producing proteins that are seen as foreign by the donor’s immune system.
Since the cancer cells also display a different protein set, these proteins can serve as markers for their destruction by the donor’s natural defense system. But for that, researchers need to be able to identify proteins that are specific to cancer cells and restricted to the blood so that no other tissues are targeted by the donor’s immune cells.
“If you could identify and activate the immune cells from the stem cell donor that only target leukemia cells, and not normal, healthy cells, that would be a big win,” Ben Vincent, MD, an assistant professor at the University of North Carolina School of Medicine and co-senior author of the study, said in a UNC news release.
Researchers at the UNC Lineberger Comprehensive Cancer Center developed a method that uses genetic sequencing and computer software to predict which genetic sequences in patients lead to a unique set of proteins at the surface of cancer cells (called minor histocompatibility antigens).
They tested their software in a group of 101 myeloid leukemia patients who had undergone stem cell transplants and whose genome had been analyzed for small variations, called single-nucleotide polymorphisms, or SNPs, in protein-coding genes.
Sixty-one patients had acute myeloid leukemia, 25 had chronic myeloid leukemia, 14 had myelodysplastic syndrome, and one patient had myeloproliferative neoplasms.
The UNC computational analysis identified 14 of 18 minor histocompatibility antigens known to occur in leukemia patients. Moreover, they identified a list of 102 new minor histocompatibility antigen targets that could be expressed on leukemia patients cancer cells.
One of the new hits arises due to a single variation in the G-protein-coupled receptor 4 kinase (GRK4) gene. The GRK4 protein is found in leukemia and testis cancer, as well as in other cancer types but has little to no activity in other normal tissues.
Four of nine acute myeloid leukemia patients who had undergone stem cell transplants developed immune responses against GRK4, supporting its potential as a new target for immunotherapies across leukemia patients.
Now, researchers will continue to optimize their software and aim to predict the most common leukemia-associated minor histocompatibility antigens in the U.S. population.
After experimental confirmation of the potential hits, these results support the engineering of donor immune cells to specifically target the proteins present in cancer cells, leaving the patient’s healthy tissues intact.
“We’ve developed a software package that predicts leukemia-specific immune targets in any leukemia patient undergoing a stem cell transplant based on DNA and RNA sequencing and demonstrated that these data can lead to actual targets expressed on leukemia cells,” Vincent said.
“The next step of our work is to use that information for patient-specific therapies to try to improve cure rates without making graft-versus-host disease worse,” he added.
This work was supported by grants from the National Institutes of Health and the National Cancer Institute. Additional funding came from an ASCO Young Investigator Award, and researchers were supported by the University Cancer Research Fund and the UNC Scott Neil Schwirck Fellowship.
