In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation

Joseph Pidala, Francisca Beato, Jongphil Kim, Brian Betts, Heather Jim, Elizabeth Sagatys, John E Levine, James L M Ferrara, Umut Ozbek, Ernesto Ayala, Marco Davila, Hugo F Fernandez, Teresa Field, Mohamed A Kharfan-Dabaja, Divis Khaira, Farhad Khimani, Frederick L Locke, Asmita Mishra, Michael Nieder, Taiga Nishihori, Lia Perez, Marcie Riches, Claudio Anasetti, Joseph Pidala, Francisca Beato, Jongphil Kim, Brian Betts, Heather Jim, Elizabeth Sagatys, John E Levine, James L M Ferrara, Umut Ozbek, Ernesto Ayala, Marco Davila, Hugo F Fernandez, Teresa Field, Mohamed A Kharfan-Dabaja, Divis Khaira, Farhad Khimani, Frederick L Locke, Asmita Mishra, Michael Nieder, Taiga Nishihori, Lia Perez, Marcie Riches, Claudio Anasetti

Abstract

T-helper 1 and T-helper 17 lymphocytes mediate acute graft-versus-host disease (GvHD). Interleukin 12 is critical for T-helper 1 differentiation 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 transplantation. On day 30 post transplant, no significant difference in % Treg was observed. Ustekinumab suppressed serum IL-12/IL-23p40 levels. Host-reactive donor alloresponse at days 30 and 90 after transplantation was polarized with significant reduction in IL-17 and IFN-α production 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 significantly 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).

Trial registration: ClinicalTrials.gov NCT01713400.

Copyright© 2018 Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
Pharmacokinetic and pharmacodynamics measurements. (A) Concentration of anti-IL-12/IL-23p40 antibody over time post hematopoietic stem cell transplantation (HCT). (B) Concentration of circulating IL-12/IL-23p40 over time post HCT.
Figure 2.
Figure 2.
Donor responder cell cytokine production after stimulation with host or 3rd-party stimulators. *IFN-γ ELISPOT and supernatant cytokines (IL-4, IL-17) shown as in (A), (B) and (C). P-values for comparison by Mann-Whitney test.
Figure 3.
Figure 3.
Regulatory T cell (Treg) numbers and suppressive function at 30 days post HCT. (A) number of peripheral blood Treg/total CD4+ T cells at day 30 post HCT; (B) absolute number of Treg/μL at day 30 post-HCT. (C) Representative Treg suppression assay, demonstrating reduced proliferation of T-responder cells in presence of escalating Treg:T-effector ratio; D) absolute Treg numbers to achieve IC-25.
Figure 4.
Figure 4.
Comparison of clinical outcomes for ustekinumab versus placebo-treated subjects. (A) Cumulative incidence of grade II–IV acute graft-versus-host disease (GvHD). (B) Cumulative incidence of Naitonal Institutes of Health (NIH) moderate/severe chronic GvHD. (C) Cumulative incidence of malignancy relapse. (D) Cumulative incidence of non-relapse mortality. (E) Overall survival. (F) NIH moderate/severe chronic GvHD-, relapse-free survival (Conditional Random Fields Score, CRFS). *P-value for comparisons of cumulative incidence by Gray method; P-value for survival plots by log-rank test.
Figure 5.
Figure 5.
Serum concentration of ST2 and REG3α at day 7 post-HCT.

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Source: PubMed

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