title: In vivo T cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: a first-in-disease trial.
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.
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Divya T
authors.initials: DT
authors.lastname: Koura
authors.forename: John T
authors.initials: JT
authors.lastname: Horan
authors.forename: Amelia A
authors.initials: AA
authors.lastname: Langston
authors.forename: Muna
authors.initials: M
authors.lastname: Qayed
authors.forename: Aneesh
authors.initials: A
authors.lastname: Mehta
authors.forename: Hanna J
authors.initials: HJ
authors.lastname: Khoury
authors.forename: R Donald
authors.initials: RD
authors.lastname: Harvey
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Suessmuth
authors.forename: Cynthia
authors.initials: C
authors.lastname: Couture
authors.forename: Jennifer
authors.initials: J
authors.lastname: Carr
authors.forename: Audrey
authors.initials: A
authors.lastname: Grizzle
authors.forename: Heather R
authors.initials: HR
authors.lastname: Johnson
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Cheeseman
authors.forename: Jason A
authors.initials: JA
authors.lastname: Conger
authors.forename: Jennifer
authors.initials: J
authors.lastname: Robertson
authors.forename: Linda
authors.initials: L
authors.lastname: Stempora
authors.forename: Brandi E
authors.initials: BE
authors.lastname: Johnson
authors.forename: Aneesah
authors.initials: A
authors.lastname: Garrett
authors.forename: Allan D
authors.initials: AD
authors.lastname: Kirk
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Kean
mesh_terms: D000069594:Abatacept; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D005240:Feasibility Studies; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology*; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept
keywords: Allogeneic transplantation; Costimulation blockade; Graft-versus-host disease prophylaxis