Amir Ahmed Toor, MD
Bone Marrow Transplant Program
Massey Cancer Center
Current clinical practice in allogeneic stem cell transplantation (SCT) is to identify donors based on the degree of human leukocyte antigen (HLA) matching. With this practice, immunosuppressive regimens are chosen using stochastic models based on the probability of disease relapse or development of graft-versus-host disease (GVHD).
Now, investigators at Virginia Commonwealth University Massey Cancer Center are developing dynamical models that may allow clinicians to move beyond simple HLA matching to personalize immunosuppressive regimens and thus improve donor selection.
This approach will hopefully lead to better clinical outcomes and the ability to bring more patients to transplant by reducing the likelihood of GVHD and other complications. Already, a clinical trial has been initiated based on the dynamical systems model of transplant outcomes (NCT02593123), and its results will further help guide an understanding of GVHD pathogenesis.
The emerging model grew out of studies conducted at VCU Massey Cancer Center that uncovered a large body of antigenic variation between transplant donors and recipients for which HLA matching does not account. This research was done using next-generation DNA sequencing to examine the exomes of stem cell transplant donor-recipient pairs (DRPs).
Figure 1. Evolution of State in Dynamical Versus Stochastic Systems
In dynamical model (top), deterministic growth of T cells over time leads to the successive states of the patient (eg, GVHD present or not). In the stochastic system, outcome probability changes with changing state of the system, and cannot be predetermined beyond a certain level of precision due to random influences.
Using matrix mathematics, a computer program has been developed that allows simulation of SCT donor T-cell response to recipient antigens.
The computational output from this program appears to correlate with clinical outcomes in stem cell transplant recipients, thus enabling clinicians to develop immunosuppressive regimens based on the antigenic variation in each DRP.
Understanding GVHD Biology
Allogeneic SCT recipients are susceptible to the competing risks of GVHD, opportunistic infections, and relapsed primary malignancy. The common variable in all of these clinical outcomes is donor-derived immune reconstitution whereby recipient antigens, specifically minor histocompatibility antigens (mHAs), are recognized by nontolerant, donor-derived T cells.
Clinical manifestations of GVHD are mixed, with either an acute, rapidly progressive phenotype, or a more indolent, chronic phenotype. In the former, the skin, gastrointestinal tract, and the liver are frequent targets; in the latter, skin, mucosal surfaces, muscle, fascia, lungs, and liver are commonly involved.
GVHD occurrence, while potentially life threatening, is often associated with maintenance of cancer remission, presumably through donor T-cell recognition of tumor-associated and normal recipient antigens on the malignant cells. The treatment of GVHD, on the other hand, can predispose patients to opportunistic infections, which threaten survival.