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
Affiliations
Joseph Pidala
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Francisca Beato
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA
Jongphil Kim
Biostatistics, Moffitt Cancer Center, Tampa, FL, USA
Brian Betts
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Heather Jim
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, FL, USA
Elizabeth Sagatys
Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL, USA
John E. Levine
Tisch Cancer Institute, the Icahn School of Medicine at Mt. Sinai, New York, NY, USA
James L.M. Ferrara
Tisch Cancer Institute, the Icahn School of Medicine at Mt. Sinai, New York, NY, USA
Umut Ozbek
Tisch Cancer Institute, the Icahn School of Medicine at Mt. Sinai, New York, NY, USA
Ernesto Ayala
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Marco Davila
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Hugo F. Fernandez
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Teresa Field
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Mohamed A. Kharfan-Dabaja
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Divis Khaira
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Farhad Khimani
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Frederick L. Locke
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Asmita Mishra
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Michael Nieder
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Taiga Nishihori
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Lia Perez
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Marcie Riches
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
Claudio Anasetti
Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA;Oncologic Sciences, College of the Medicine at University of South Florida, Tampa, FL, USA
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.)
