α1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease

Abstract

Corticosteroid resistance after acute graft-versus-host disease (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation. Current immunosuppressive therapies for SR-aGVHD provide marginal effectiveness because of poor response or excessive toxicity, primarily from infection. α₁-Antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by downmodulating inflammation and increasing ratios of regulatory (T_reg) to effector T cells (T_effs). In this prospective multicenter clinical study, we sought to determine the safety and response rate of AAT administration in SR-aGVHD. Forty patients with a median age of 59 years received intravenous AAT twice weekly for 4 weeks as first-line treatment of SR-aGVHD. The primary end point was overall response rate (ORR), the proportion of patients with SR-aGVHD in complete (CR) or partial response by day 28 without addition of further immunosuppression. Treatment was well tolerated without drug-related adverse events. A significant increase in serum levels of AAT was observed after treatment. The ORR and CR rates by day 28 were 65% and 35%, respectively, and included responses in all aGVHD target organs. At day 60, responses were sustained in 73% of patients without intervening immunosuppression. Infectious mortality was 10% at 6 months and 2.5% within 30 days of last AAT infusion. Consistent with preclinical data, correlative samples showed an increase in ratio of activated T_regs to T_effs after AAT treatment. These data suggest that AAT is safe and may be potentially efficacious in treating SR-aGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01700036.

Figure 1.

ORR. The percentage of patients who experienced an overall response (primary end point) as defined by the sum of patients with SR-aGVHD achieving CRs and PRs after initiation of AAT. NR, nonresponder; Prog, progression.

Figure 2.

OS. Survival from time of initiation of AAT for SR-aGVHD in the entire cohort (n = 40) (A) and those who received ≥8 doses (solid) or <8 doses (hatched) (B).

Figure 3.

AAT increases proportion of activated T_regs to effector memory T cells. T_regs, T_reg subsets (naïve and activated), conventional T cells (T_conv), and T_conv subsets (naïve, central memory, effector, and effector memory) were analyzed by FACS at enrollment before AAT administration (T_regs, n = 7; T_conv, n = 9) and after 2 (T_regs, n = 6; T_conv, n = 9) and 4 weeks (T_regs, n = 5; T_conv, n = 6) of AAT treatment. (A) Fold change of T_regs (CD4⁺CD25⁺Foxp3⁺ lymphocytes) expressed as a percentage of CD4⁺ helper T (T_h) cells (number of T_regs/number of viable CD4⁺ lymphocytes) at 2 and 4 weeks after AAT treatment relative to prior treatment. (B) Fold change of activated T_h cells (CD4⁺CD25⁺Foxp3^loCD45⁻ lymphocytes), naïve T_regs (CD4⁺CD25⁺Foxp3^loCD45⁺ lymphocytes), or activated T_regs (CD4⁺CD25⁺Foxp3^hiCD45⁻ lymphocytes) expressed as a percentage of total T_regs at time points after AAT treatment relative to that observed at enrollment. (C) Fold change of cytotoxic T cells (viable CD3⁺CD8⁺CD4⁻), with naïve (CCR7⁺CD45RA⁺), central memory (CCR7⁺CD45RA⁻), effector (CCR7⁻CD45RA⁻), and effector memory (CCR7⁻CD45RA⁺) cells expressed as a percentage of total cytotoxic T cells at time points after AAT treatment relative to that observed at enrollment. Data represent mean values, and the error bars represent the standard errors of the mean. *P < .05.

Figure 4.

AAT levels. Serum levels of AAT were measured in patients with SR-aGVHD at enrollment before administration of ATT and in paired samples obtained at 2, 4, and 8 weeks after the start of AAT treatment. AAT administration was completed after 4 weeks. Median values are depicted. Error bars represent standard deviations. *P = .01; **P < .01. N, number of paired samples at a given time point.