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. α-Antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by downmodulating inflammation and increasing ratios of regulatory (T) to effector T cells (Ts). 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 Ts to Ts 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.

RNA-seq of Human T-Cells After Hematopoietic Stem Cell Transplantation Identifies Linc00402 as a Novel Regulator of T-Cell Alloimmunity

“…Flow cytometry analysis was performed with fluorescently-labeled monoclonal antibodies to mouse CD4-APC (GK1.5, BioLegend) or CD8a-PE (53-6.7, BioLegend) or human CD3-PE (UCHT1, BioLegend), CD4-APC (SK3, BioLegend), and CD8a-PE (HIT8a, BiioLegend), as described previously ( 40 ). Dead cells were stained with Live/Dead Fixable Near-IR (ThermoFisher).…”

Treatment and unmet needs in steroid-refractory acute graft-versus-host disease

“…α 1 -Antitrypsin α 1 -Antitrypsin (AAT), a circulating protease inhibitor produced by the liver, is implicated in several aspects of immune regulation: It inactivates serine proteases from neutrophils and macrophages, induces IL-10, and suppresses plasma proinflammatory cytokines (Table 2) [89]. In murine models, AAT reduced the severity of aGVHD, reducing inflammatory cytokines and increasing the ratio of Tregs to effector T cells-this led to a phase 2 clinical trial in patients with SR-aGVHD (NCT01700036).…”

“…Forty patients received 60 mg/kg AAT intravenously every 4 days for up to 4 weeks. At day 28, ORR and CR rates were 65% and 35%, respectively [89]. There is an ongoing early-access clinical study (NCT03172455), and AAT is also being investigated as prophylaxis for SR-aGVHD (NCT03459040).…”

Acute Graft‐versus‐Host Disease: Emerging Insights and Updates into Detection, Prevention, and Treatment

“…75 Recent small phase I and II studies demonstrated that complete responses were achievable when AAT was administered as salvage therapy. 75,76 A prospective dose-finding study used AAT in a cohort of patients (N=12) presenting with grades III or IV GI only, or GI with liver, acute GVHD who failed steroid treatment. An initial loading dose of AAT 90 mg/kg intravenous on day 1 was given followed by seven maintenance doses on days 3, 5, 7, 9, 11, 13, 15 of either 30-60 mg/kg/day depending on the dosing cohort.…”

“…Administration of AAT appeared to be well tolerated, although infection was reported in 32.5% of patients, making AAT another potential treatment to consider for steroid-refractory disease. 76…”