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In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation
Pidala, J., Beato, F., Kim, J., Betts, B., Jim, H., Sagatys, E., Levine, J. E., Ferrara, J. L., Ozbek, U., Ayala, E., et al
Haematologica. 2017
Abstract
T helper 1 and T helper 17 lymphocytes mediate acute graft vs. host disease. 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 biologic impact and clinical outcomes following IL-12/IL-23p40 neutralization using ustekinumab. 30 patients received peripheral blood mobilized hematopoietic cell transplantation from HLA-matched sibling or unrelated donors, received sirolimus plus tacrolimus as graft vs. host disease prophylaxis, and were randomized to ustekinumab vs. placebo with 1:1 allocation after stratification by donor type. The primary endpoint of the trial was the mean % Treg 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 day 30 and 90 after transplantation was polarized with significant reduction in IL-17 and IFN-gamma production and increase in IL-4. No toxicity attributed to ustekinumab was observed. Overall survival and NIH moderate/severe chronic graft vs. host disease-, relapse-free survival were significantly improved among ustekinumab-treated patients. No significant improvements were observed in acute or chronic graft vs. host disease, 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. This trial was registered as NCT01713400.