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Cell Therapy & Immunotherapy
In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation
Ferrata Storti Foundation
Joseph Pidala,1,2 Francisca Beato,1 Jongphil Kim,3 Brian Betts,1,2 Heather Jim,1,4 Elizabeth Sagatys,5 John E. Levine,6 James L.M. Ferrara,6 Umut Ozbek,6 Ernesto Ayala,1,2 Marco Davila,1,2 Hugo F. Fernandez,1,2 Teresa Field,1,2 Mohamed A. Kharfan-Dabaja,1,2 Divis Khaira,1,2 Farhad Khimani,1,2
Frederick L. Locke,1,2 Asmita Mishra,1,2 Michael Nieder,1,2 Taiga Nishihori,1,2 Lia Perez,1,2 Marcie Riches,1,2 and Claudio Anasetti1,2
Haematologica 2018 Volume 103(3):531-539
1Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL; 2Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL; 3Biostatistics, Moffitt Cancer Center, Tampa, FL; 4Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, FL; 5Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL and 6Tisch Cancer Institute, the Icahn School of Medicine at Mt. Sinai, New York, NY, USA
ABSTRACT
T-helper 1 and T-helper 17 lymphocytes mediate acute graft-versus- host disease (GvHD). Interleukin 12 is critical for T-helper 1 differ- entiation and interleukin 23 for T-helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40). In a randomized, blinded, placebo-controlled trial, we examined the biological impact and clinical outcomes following IL-12/IL-23p40 neutralization using ustekinumab. Thirty patients received peripheral blood mobilized hematopoietic cell transplantation (HCT) from HLA-matched sibling or unrelated donors, received sirolimus plus tacrolimus as GvHD prophylaxis, and were randomized to ustekinumab versus placebo with 1:1 allocation after stratification by donor type. The primary end point of the trial was the mean percentage (%) T-regulatory (Treg) cells on day 30 post HCT. Ustekinumab was delivered by subcutaneous injection on day -1 and day +20 after trans- plantation. On day 30 post transplant, no significant difference in % Treg was observed. Ustekinumab suppressed serum IL-12/IL-23p40 lev- els. Host-reactive donor alloresponse at days 30 and 90 after transplan- tation was polarized with significant reduction in IL-17 and IFN-γ pro- duction and increase in IL-4. No toxicity attributed to ustekinumab was observed. Overall survival and National Institute of Health moderate/severe chronic GvHD-free, relapse-free survival were signifi- cantly improved among ustekinumab-treated patients. No significant improvements were observed in acute or chronic GvHD, relapse, or non-relapse mortality. These data provide first evidence that IL-12/IL- 23p40 neutralization can polarize donor anti-host alloresponse in vivo and provide initial clinical efficacy evidence to be tested in subsequent trials. (Trial registered at clinicaltrials.gov identifier: 01713400.)
Introduction
Differentiation of CD4+ T cells into distinct lineages [Th1, Th2, Th17, T-regula- tory (Tregs)] is co-ordinated by specific cytokine programs.1-3 IL-12 plays a key role in Th1 differentiation, and IL-23 stabilizes the Th17 phenotype. These cytokines share a common p40 subunit. Previous data have implicated Th1 and Th17 in acute graft-versus-host disease (GvHD) pathogenesis,4-6 and demonstrated that regulatory Tregs control alloreactivity.7 In experimental systems, disruption of Tbet and ROR t transcription factors,8 or neutralization of IL-12/IL-23p40, reduces Th1 and Th17 differentiation, increases Th2 and Tregs, and reduces GvHD mortality.
Clinical translation of this work is made possible through neutralization of IL- 12/IL-23p40 using the monoclonal antibody ustekinumab (Stelara, Janssen Biotech Inc.), which is approved for therapy of plaque psoriasis, psoriatic arthritis, and
Correspondence:
joseph.pidala@moffitt.org
Received: April 20, 2017.
Accepted: December 6 2017. Pre-published: December 14, 2017.
doi:10.3324/haematol.2017.171199
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/3/531
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