TY - JOUR
T1 - Phase I/II trial of a combination of anti-CD3/CD7 immunotoxins for steroid-refractory acute graft-versus-host disease
AU - Groth, Christoph
AU - van Groningen, Lenneke F J
AU - Matos, Tiago R
AU - Bremmers, Manita E
AU - Preijers, Frank W M B
AU - Dolstra, Harry
AU - Reicherts, Christian
AU - Schaap, Nicolaas P M
AU - van Hooren, Eric H G
AU - IntHout, Joanna
AU - Netea, Mihai G
AU - Masereeuw, Rosalinde
AU - Levine, John E
AU - Morales, George
AU - Ferrara, James L
AU - Blijlevens, Nicole M A
AU - van Oosterhout, Ypke V J M
AU - Stelljes, Matthias
AU - van der Velden, Walter J F M
N1 - Copyright © 2018. Published by Elsevier Inc.
PY - 2019/4
Y1 - 2019/4
N2 - 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- and NK-cells and suppresses T-cell receptor activation. We conducted a phase I/II trial in order 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; 18 gastrointestinal (GI) (90%) and 5 liver (25%) involvement. A validated two biomarker algorithm classified the majority of patients (11/20) as high-risk. On day 28 after the start of CD3/CD7-IT, the overall response rate was 60% (12/20), with 10 patients (50%) achieving a complete response; moreover, the 6-month overall survival rate was 60% (12/20), including 64% (7/11) classified as high risk by biomarkers. The one-week treatment course with CD3/CD7-IT caused profound but transient depletion of T- and NK-cells, followed by rapid recovery of the immune system with a diverse TCR Vβ repertoire, and preservation of EBV- and CMV-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. This trial was registered at www.clinicaltrials.gov as #NCT02027805.
AB - 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- and NK-cells and suppresses T-cell receptor activation. We conducted a phase I/II trial in order 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; 18 gastrointestinal (GI) (90%) and 5 liver (25%) involvement. A validated two biomarker algorithm classified the majority of patients (11/20) as high-risk. On day 28 after the start of CD3/CD7-IT, the overall response rate was 60% (12/20), with 10 patients (50%) achieving a complete response; moreover, the 6-month overall survival rate was 60% (12/20), including 64% (7/11) classified as high risk by biomarkers. The one-week treatment course with CD3/CD7-IT caused profound but transient depletion of T- and NK-cells, followed by rapid recovery of the immune system with a diverse TCR Vβ repertoire, and preservation of EBV- and CMV-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. This trial was registered at www.clinicaltrials.gov as #NCT02027805.
KW - Immunotoxin
KW - Acute graft-versus-host disease
KW - Allogenic hematopoietic stem cell transplantation
U2 - 10.1016/j.bbmt.2018.10.020
DO - 10.1016/j.bbmt.2018.10.020
M3 - Article
C2 - 30399420
SN - 1083-8791
VL - 25
SP - 712
EP - 719
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 4
ER -