Abstract
PURPOSE: In this first-in-human, phase I, GVHD prevention trial (NCT02891603), we combine pacritinib (PAC), a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL6 activity. We evaluate the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation.
PATIENTS AND METHODS: The preclinical efficacy and immune modulation of PAC/SIR were investigated in xenogeneic GVHD. Our phase I trial followed a 3+3 dose-escalation design, including dose level 1 (pacritinib 100 mg daily), level 2 (pacritinib 100 mg twice daily), and level 3 (pacritinib 200 mg twice daily). The primary endpoint was to identify the lowest biologically active and safe dose of pacritinib with SIR/TAC (n = 12). Acute GVHD was scored through day +100. Allografts included 8/8 HLA-matched related or unrelated donor peripheral blood stem cells.
RESULTS: In mice, we show that dual JAK2/mTOR inhibition significantly reduces xenogeneic GVHD and increases peripheral regulatory T cell (Treg) potency as well as Treg induction from conventional CD4+ T cells. Pacritinib 100 mg twice a day was identified as the minimum biologically active and safe dose for further study. JAK2/mTOR inhibition suppresses pathogenic Th1 and Th17 cells, spares Tregs and antileukemia effector cells, and exhibits preliminary activity in preventing GVHD. PAC/SIR/TAC preserves donor cytomegalovirus (CMV) immunity and permits timely engraftment without cytopenias.
CONCLUSIONS: We demonstrate that PAC/SIR/TAC is safe and preliminarily limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2712-2722 |
| Number of pages | 11 |
| Journal | Clinical cancer research : an official journal of the American Association for Cancer Research |
| Volume | 27 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 15 2021 |
Bibliographical note
Funding Information:The Flow Cytometry, USF Comparative Medicine and Vivarium, Analytic Microscopy, Biostatistics, and Tissue Cores at Moffitt/USF were utilized in completing this work. The core facilities are supported partially by the Moffitt Cancer Center Support Grant, P30-CA076292. The University of Minnesota Research Animal Resource and Flow Cytometry Resource were also used to complete this work. This work was supported by R01 HL133823 (to B.C. Betts) and R50 CA211447 (to H.R. Lawrence).
Funding Information:
J. Pidala reports personal fees from CTI Biopharma during the conduct of the study, as well as personal fees from Syndax, Amgen, and Regeneron outside the submitted work. K. Walton reports grants from R01 HL133823 during the conduct of the study. N. Bejanyan reports personal fees from Magenta therapeutics outside the submitted work. T. Nishihori reports other from Karyopharm and Novartis outside the submitted work. F. Khimani reports grants from Bristol Myers Squibb outside the submitted work. L.PerezreportsgrantsfromR01HL133823(toB.C.Betts)duringtheconductof thestudy. R.G. Faramand reports grants from Kite/Gilead outside the submitted work. E.M. Sagatys reports grants from NIH/NHLBI during the conduct of the study. S.G. Holtan reports other from Incyte, Generon, CSL Behring, and BristolMyersSquibboutsidethesubmitted work. N.J. Lawrence reports a patent for WO2017156527A1 pending and a patent for U.S. Patent, 7960434 issued and licensed to GLG Pharma. H.R. Lawrence reports a patent for U.S. Patent, 7960434 issued and licensed to GLG Pharma and a patent for WO2017156527A1 issued to none. C. Anasetti reports a patent for WO 2017/058950 A l issued. S.M. Sebti reports grants from NIH during the conduct of the study. B.C. Betts reports grants from NHLBI, nonfinancial support from CTI BioPharma, and other from a patent for WO2017058950A1 during the conduct of the study. B.C. Betts also reports personal fees from Incyte outside the submitted work, as well as a patent for WO2015120436A2 pending. No disclosures were reported by the other authors.
Publisher Copyright:
© American Association for Cancer Research.
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
