The emergence of novel cell therapy technologies has led to questions about the necessity of human leukocyte antigen matching (HLA matching) in the development of potential “universal” allogeneic cell therapies. After all, if you can eliminate alloreactive responses, what role would HLA matching play?
Martin Maiers, MS, is the Vice President of Biomedical Informatics for our research arm, the CIBMTR® (Center for International Blood and Marrow Transplant Research®). He and his team develop and use software and analytical methods to predict factors that can impact outcomes for patients who receive an allogeneic cell therapy.
Martin Maiers, MA, Vice President of Biomedical Informatics, CIBMTR
He believes that HLA matching will continue to be relevant for allogeneic cell therapies. In fact, he says it may become one of the most important aspects of precision medicine. A review of the historical role of HLA in allogeneic cell therapies helps demonstrate why.
HLA matching improves allogeneic cell therapy outcomes
HLAs are proteins found on the surface of most human cells. They play an important role in modulating immune response. Immune cells use HLAs to identify one’s own cells from invading microbes and viruses. A properly functioning immune system will attack those cells that don’t match the body’s HLA profile.
This immune response has several important implications. These implications apply to the development of allogeneic cellular therapies and in hematopoietic stem cell transplant (HSCT). HSCT was one of the first allogeneic cell therapies. They include:
- Graft-versus-host disease (GVHD), where the donor cells attack the patient’s cells because they do not match the “self” HLA pattern.
- Graft rejection, where the patient’s immune system attacks the transplanted donor cells, leading to graft failure.
Due to these potential after-effects, the identification of HLA type has played a critical role in matching donors with patients in need of life-saving allogeneic HSCT.
When physicians conducted the first transplants in the 1950s, the rate of transplant success was low. Allogeneic HSCT success improved dramatically once consideration of HLA type became part of the transplant process.
HLA matching improves cord blood transplant outcomes
Similarly, the use of cord blood as a donor cell source was another important innovation in the field of transplant. Cord blood made it possible for a patient without a family match to find a donor source. There has been a lot of debate about the matching level required when using cord blood as a donor source.
Recent research indicates that HLA matched cord blood can lead to faster engraftment times and a lower risk of GVHD.
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Will HLA-matching history repeat itself again?
As companies develop next-generation cell therapies, HLA matching could play an important role in a number of leading-edge therapeutics and cellular therapies.
“In the next 10 years, HLA matching may become one of the most important aspects of precision medicine and will play an essential role in drug development,” Maiers said. “The role of HLA matching today is limited to particular procedures and treatments, like bone marrow transplant.”
The implications for HLA matching are enormous. These implications are not only in the development of cellular therapies, but also across the field of drug development. Some cancer drugs pharmaceutical companies are currently developing have a component that corresponds to HLA type, Maiers explained.
“Organizations who are creating these drugs may be able to use information about HLA type even when developing these non-cell-based therapies,” Maiers said. For example, a recent paper published in Nature Medicine demonstrated that HLA type plays a role in the efficacy of some cancer therapies, like immune checkpoint inhibitors, have in treating disease.
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In another modality, natural killer (NK) cells used in combination with monoclonal antibodies have shown promise recently as an approach to treating diseases like lymphoma. NK therapies have been described as an “off-the-shelf” therapy, in that they don’t require matching with a patient. But it’s possible that matching NK cells could lead to better outcomes for patients as well.
One consideration with “universal” therapies relates to graft rejection. Donor-specific anti-HLA antibodies (DSA) have shown increased risk for graft failure in both solid organ and HSCT. This has potential to impact the efficacy of newer cell therapies where there is some indication that persistence of these cells is critical to avoiding relapse.
Historical data could help determine therapy success probability
Though the region of the genome that codes for HLA type is well-characterized, determining HLA type remains a complex process with many unknowns. As the importance of HLA grows in relation to the development of new therapies, one of our primary objectives at Be The Match BioTherapies® is providing historical data and search algorithms to ensure patients receive the therapies with the most probability for success.
“Finding an HLA match is a probabilistic system. Our goal is to manage uncertainty when it comes to HLA matching,” Maiers said. “As genomic sequencing technologies become more accurate and more affordable, we will be able to gain an even more precise indication of a person’s HLA type.”
In the future, HLA will likely play a larger role in the development and administration of cancer therapies. At Be The Match BioTherapies, our partnership with the CIBMTR helps to provide therapy developers with the evidence-based resources necessary to navigate, and ultimately reduce, the uncertainties associated with HLA matching as they develop new allogeneic cellular therapies.
