Phase I Clinical Trial Evaluating Abatacept in Patients with Steroid-Refractory Chronic Graft Versus Host Disease
Year: 2017
Type: article
Study design: Clinical Trial
Abstract: Introduction: Steroid-refractory GVHD remains a major source of morbidity and mortality following allogeneic transplantation. Activated T cells driven by alloantigen stimulation play a critical role in the pathophysiology of chronic GVHD (cGVHD). As such, inhibition of T cell activation through co-stimulation blockade has therapeutic potential. Abatacept, a selective co-stimulatory modulator, binds to CD80 and CD86, down-modulating T cell CD28-mediated co-stimulation. We conducted a phase I clinical trial to evaluate the safety, clinical and immune effects of Abatacept in steroid-refractory cGVHD. Methods: The study followed a 3 + 3 design with two escalating Abatacept doses to determine the maximum tolerated dose (MTD): 3 mg/kg and 10 mg/kg. Abatacept was administered for 6 doses. Doses 1-3 were given at 2-week intervals and doses 4-6 were given at 4-week intervals. Inclusion criteria included recipients of allogeneic stem cell transplantation with myeloablative or reduced intensity conditioning, with cGVHD defined by NIH consensus criteria. Peripheral blood was examined to assess Abatacept's effect on PD-1 T cell expression and T cell IFNϒ and IL-10 production. Results: 17 subjects were treated, 1 of which withdrew consent. 3 were treated at a dose of 3 mg/kg and 3 were treated with 10 mg/kg, without DLT. 10 patients were treated on an expansion cohort (10 mg/kg). Abatacept-related adverse events included: grade 1 diarrhea (n = 2), fatigue (n = 2), rash (n = 1), and skin pain (n = 1); grade 2 gastritis (n = 1) and pain (n = 1); grade 3 pulmonary infection (n = 3); and grade 4 pulmonary infection (n = 1). Of the 16 evaluable patients, 7 (44%) achieved a clinical PR defined by improvement in 2 disease systems per the 2011 NIH consensus criteria. Abatacept resulted in a 51.3% reduction in prednisone usage in clinical responders with a mean baseline dose of 27 mg compared to 14 mg, 1 month following the 6th dose (P = .01). In clinical responders, PD-1 expression on circulating CD4+ and CD8+ T cells increased from a mean of 3.4% and 2.7%, respectively at baseline to a mean of 8.9% and 7.6%, respectively at 1 month following dose 6 (n = 3; P < .05). In contrast, no change in PD-1 expression was observed in non-responders. A shift from Th1 to Th2 cytokine secretion was observed in clinical responders, with a mean 2.8 fold decrease in IFNϒ and a mean 2.5 fold increase in IL-10 (n = 4). Conclusion: Abatacept is well-tolerated and resulted in both the improvement in NIH cGVHD scores in 44% of patients and a decrease in prednisone dose. An increase in PD-1 expression and a skewing toward Th2 cytokines was observed in clinical responders. Based on this promising data, a phase II trial has been initiated.
Authors: Myrna R. Nahas, Robert J. Soiffer, Edwin P. Alyea, Jon E. Arnason, Robin Joyce, Joseph H. Antin, Vincent T. Ho, Dina Stroopinsky, James D. Levine, Malgorzata McMasters, Salvia Jain, Ayad Hamdan, Dimitrios Tzachanis, Mary Paty Bryant, Emma Logan, Josie Bazemore, Jeremy Stewart, Amy Joyce, Susan Stephenson, Abigail Washington, Leandra Cole, Athalia Pyzer, Rebecca Karp Leaf, David E. Avigan, Jacalyn Rosenblatt
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2590175272