In Vivo T Cell Costimulation Blockade with Abatacept for Acute Graft-versus-Host Disease Prevention: A First-in-Disease Trial

Abstract

We performed a first-in-disease trial of in vivo CD28:CD80/86 costimulation blockade with abatacept for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation (HCT). All patients received cyclosporine/methotrexate plus 4 doses of abatacept (10 mg/kg/dose) on days -1, +5, +14, +28 post-HCT. The feasibility of adding abatacept, its pharmacokinetics, pharmacodynamics, and its impact on aGVHD, infection, relapse, and transplantation-related mortality (TRM) were assessed. All patients received the planned abatacept doses, and no infusion reactions were noted. Compared with a cohort of patients not receiving abatacept (the StdRx cohort), patients enrolled in the study (the ABA cohort) demonstrated significant inhibition of early CD4(+) T cell proliferation and activation, affecting predominantly the effector memory (Tem) subpopulation, with 7- and 10-fold fewer proliferating and activated CD4(+) Tem cells, respectively, at day+28 in the ABA cohort compared with the StdRx cohort (P < .01). The ABA patients demonstrated a low rate of aGVHD, despite robust immune reconstitution, with 2 of 10 patients diagnosed with grade II-IV aGVHD before day +100, no deaths from infection, no day +100 TRM, and with 7 of 10 evaluable patients surviving (median follow-up, 16 months). These results suggest that costimulation blockade with abatacept can significantly affect CD4(+) T cell proliferation and activation post-transplantation, and may be an important adjunct to standard immunoprophylaxis for aGVHD in patients undergoing unrelated-donor HCT.

Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

“…Unlike the hyperacute GVHD cohorts, recipients prophylaxed with combinatorial therapies (either with standard-of-care tacrolimus plus methotrexate [Tac/MTX], or Siro plus CTLA4-Ig [Siro/CTLA4-Ig]) 7,8 successfully suppressed hyperacute GVHD. Thus, in the first several weeks posttransplant, both the Tac/Mtx and Siro/CTLA4-Ig cohorts controlled the clinical symptoms of disease ( Figure 1B-C).…”

CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire

“…Both studies were institutional review board-approved and conducted between 2010 and 2013, as previously described. 23 Patient and transplant characteristics are shown in Table 1. Patients were analyzed prospectively for CMV reactivation by polymerase chain reaction (PCR), and those that reactivated CMV (.300 copies per mL whole blood) were treated with antiviral therapy according to institutional standards.…”

“…All patients received myeloablative pretransplant conditioning and unmanipulated unrelated-donor allografts. 23 Immune reconstitution was monitored in detail in all patients onstudy, and revealed an extremely wide variability in the pace and character of their immune reconstitution, for which the heterogeneity was most prominent in the CD8…”

“…To determine the factors that were contributing to this variability, we performed univariate analysis of the following patient characteristics and posttransplant complications ( Table 2): patient sex, age, donor age, degree of donor/recipient HLA matching, relapse, posttransplant GVHD prophylaxis regimen (cyclosporine/methotrexate vs cyclosporine/methotrexate/abatacept), 23 grade II-IV aGVHD, moderate-severe cGVHD, infections (including respiratory viruses and bacterial infections), and CMV reactivation. Univariate analysis with the Kendall t-b test (for binary variables) or with the Spearman rank test (for continuous variables) was used to determine which variables were positively correlated with elevated CD8…”

Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

“…[26] Further, addition of abatacept to CSA/MTX standard aGVHD prophylaxis was investigated in a pilot clinical trial involving 10 patients transplanted from unrelated donors. [91] Only two patients developed grade II-IV acute GVHD. A phase II multicentre randomized trial of abatacept combined with calcineurin inhibition and MTX after unrelated donor alloHSCT is currently ongoing in the United States (ClinicalTrials.gov#NCT01743131).…”