In vivo T cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: a first-in-disease trial
Divya T Koura, John T Horan, Amelia A Langston, Muna Qayed, Aneesh Mehta, Hanna J Khoury, R Donald Harvey, Yvonne Suessmuth, Cynthia Couture, Jennifer Carr, Audrey Grizzle, Heather R Johnson, Jennifer A Cheeseman, Jason A Conger, Jennifer Robertson, Linda Stempora, Brandi E Johnson, Aneesah Garrett, Allan D Kirk, Christian P Larsen, Edmund K Waller, Leslie S Kean, Divya T Koura, John T Horan, Amelia A Langston, Muna Qayed, Aneesh Mehta, Hanna J Khoury, R Donald Harvey, Yvonne Suessmuth, Cynthia Couture, Jennifer Carr, Audrey Grizzle, Heather R Johnson, Jennifer A Cheeseman, Jason A Conger, Jennifer Robertson, Linda Stempora, Brandi E Johnson, Aneesah Garrett, Allan D Kirk, Christian P Larsen, Edmund K Waller, Leslie S Kean
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.
Keywords: Allogeneic transplantation; Costimulation blockade; Graft-versus-host disease prophylaxis.
Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Source: PubMed