Hybrid Systems Modeling of Donor T-Cell Responses and Graft-Versus-Host-Disease After Posttransplantation...

The optimal post-transplant cyclophosphamide (PTCy) dose to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplant (HCT) is undefined. Data from a novel murine HLA-haploidentical HCT model suggested that PTCy has a dose-dependent effect associated with its efficacy in preventing GVHD, including reduced proliferation of conventional CD4⁺Foxp3^- T-helper cells (Th) at Day 7, followed by the preferential expansion of regulatory CD4⁺CD25⁺Foxp3⁺ T cells (Tregs) at Day 21 after HCT. To better quantify the impact of the PTCy dose, we built a hybrid quantitative systems pharmacology (hybrid systems) model consisting of: (1) simulated pharmacokinetics of PTCy and its metabolites; (2) the donor immune system; and (3) a neural network mapping drug exposure and T-cell profiles to clinical scores of acute GVHD. Data were collected from murine MHC-haploidentical HCT studies of PTCy from 0 to 100 mg/kg/day on Days 3 and 4 after transplantation of donor cells. The final model successfully captured time-varying changes in donor Tcytotoxic CD8⁺ T cells (Tc), Th, and Tregs up to Day 21. The clinical score for GVHD was associated with numerous descriptors, with the immediately preceding GVHD score, body weight, PTCy dose, and donor Treg concentration in the blood and in the liver having the greatest contribution. This hybrid systems model quantitatively captures the beneficial impact of PTCy on Tc, Th, Tregs, and acute GVHD after HCT. The mediation through PTCy and metabolite concentrations and Tc, Th, and Treg numbers is underlined, and the model may be further used to refine and improve PTCy regimens.