Phase I/II Trial of a Combination of Anti-CD3/CD7 Immunotoxins for Steroid-Refractory Acute Graft-versus-Host Disease.
Acute graft-versus-host disease
Allogenic hematopoietic stem cell transplantation
Immunotoxin
Journal
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
ISSN: 1523-6536
Titre abrégé: Biol Blood Marrow Transplant
Pays: United States
ID NLM: 9600628
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
26
08
2018
accepted:
25
10
2018
pubmed:
7
11
2018
medline:
8
2
2020
entrez:
7
11
2018
Statut:
ppublish
Résumé
Effective therapies for treating patients with steroid-refractory acute graft-versus-host-disease (SR-aGVHD), particularly strategies that reduce the duration of immunosuppression following remission, are urgently needed. The investigated immunotoxin combination consists of a mixture of anti-CD3 and anti-CD7 antibodies separately conjugated to recombinant ricin A (CD3/CD7-IT), which induces in vivo depletion of T cells and natural killer (NK) cells and suppresses T cell receptor activation. We conducted a phase I/II trial to examine the safety and efficacy of CD3/CD7-IT in 20 patients with SR-aGVHD; 17 of these patients (85%) had severe SR-aGVHD, and all 20 patients had visceral organ involvement, including 18 (90%) with gastrointestinal (GI) involvement and 5 (25%) with liver involvement. A validated 2-biomarker algorithm classified the majority of patients (11 of 20) as high risk. On day 28 after the start of CD3/CD7-IT therapy, the overall response rate was 60% (12 of 20), with 10 patients (50%) achieving a complete response. The 6-month overall survival rate was 60% (12 of 20), including 64% (7 of 11) classified as high risk by biomarkers. The 1-week course of treatment with CD3/CD7-IT caused profound but transient depletion of T cells and NK cells, followed by rapid recovery of the immune system with a diverse TCR Vβ repertoire, and preservation of Epstein-Barr virus- and cytomegalovirus-specific T cell clones. Furthermore, our results indicate that CD3/CD7-IT appeared to be safe and well tolerated, with a relatively low prevalence of manageable and reversible adverse events, primarily worsening of hypoalbuminemia, microangiopathy, and thrombocytopenia. These encouraging results suggest that CD3/CD7-IT may improve patient outcomes in patients with SR-aGVHD.
Identifiants
pubmed: 30399420
pii: S1083-8791(18)30691-8
doi: 10.1016/j.bbmt.2018.10.020
pmc: PMC6595479
mid: NIHMS1036469
pii:
doi:
Substances chimiques
Immunotoxins
0
Types de publication
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
712-719Subventions
Organisme : NCI NIH HHS
ID : P01 CA039542
Pays : United States
Informations de copyright
Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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