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

• Published in: Biology of blood and marrow transplantation Vol. 19; no. 11; pp. 1638 - 1649
• Main Authors: Koura, Divya T, Horan, John T, Langston, Amelia A, Qayed, Muna, Mehta, Aneesh, Khoury, Hanna J, Harvey, R. Donald, Suessmuth, Yvonne, Couture, Cynthia, Carr, Jennifer, Grizzle, Audrey, Johnson, Heather R, Cheeseman, Jennifer A, Conger, Jason A, Robertson, Jennifer, Stempora, Linda, Johnson, Brandi E, Garrett, Aneesah, Kirk, Allan D, Larsen, Christian P, Waller, Edmund K, Kean, Leslie S
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2013
• Subjects: Abatacept; Acute Disease; Adolescent; Adult; Aged; Allogeneic transplantation; Costimulation blockade; Feasibility Studies; Female; Graft vs Host Disease - prevention & control; Graft-versus-host disease prophylaxis; Hematology, Oncology and Palliative Medicine; Hematopoietic Stem Cell Transplantation - methods; Humans; Immunoconjugates - therapeutic use; Immunosuppressive Agents - therapeutic use; Male; Middle Aged; T-Lymphocytes - immunology; Transplantation Conditioning - methods; Transplantation, Homologous; Young Adult; Graft-versus-host disease prophylaxis; Costimulation blockade; Allogeneic transplantation
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/j.bbmt.2013.09.003

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.