Most allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients receive peripheral blood stem cell grafts resulting in a 30%–70% incidence of chronic graft-versus-host disease (cGVHD), a major cause of mortality and morbidity in long-term survivors. While systemic steroids remain the standard of care for first-line therapy, patients may require long-term administration, and those with steroid-resistant or refractory cGVHD have a worse prognosis. Although durable and deep responses with second-line therapies can be achieved in some patients, there remains an urgent need for new therapies. In this study, we evaluated the efficacy of IRX4204, a novel agonist that activates RXRs and is in clinical trials for cancer treatment to prevent and treat cGVHD in two complementary murine models. In a major histocompatibility complex mismatched, non-sclerodermatous multiorgan system model with bronchiolitis obliterans, IRX4204 prevented and reversed cGVHD including associated pulmonary dysfunction with restoration of germinal center T-follicular helper: T-follicular regulatory cell balance. In a minor histocompatibility antigen disparate sclerodermatous model, IRX4204 treatment significantly prevented and ameliorated skin cGVHD by reducing Th1 and Th17 differentiation due to anti-inflammatory properties. Together, these results indicate that IRX4204 is a promising therapeutic option to treat cGVHD with bronchiolitis obliterans or sclerodermatous manifestations.
Bibliographical noteFunding Information:
BB receives remuneration as an advisor to Kamon Pharmaceuticals, Five Prime Therapeutics, Regeneron Pharmaceuticals, Magenta Therapeutics, and BlueRock Therapeuetics; research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences, Abbvie, the Leukemia and Lymphoma Society, the Children’s Cancer Research Fund, and the KidsFirst Fund and is a cofounder of Tmunity. Author MS is shareholder, officer, and director of the company Io Therapeutics, Inc., which is developing IRX4204 for commercialization.The reviewer DW has declared a past co-authorship with one of the authors BB at the time of review.
We thank Jamie Panthera for excellent animal husbandry. This work was supported by grants from the National Institutes of Health, National Institute of Allergy and Infectious Diseases P01 AI056299, R01 AI034495, and T32 AI007313 (FM), and National Heart, Lung, and Blood Institute R01 HL56067 (BB). GT was supported by the Canadian Institutes of Health Research (CIHR) fellowship.
Copyright © 2022 Thangavelu, Zaiken, Mohamed, Flynn, Du, Rhee, Riddle, Aguilar, Panoskaltsis-Mortari, Sanders and Blazar.
- germinal center B cells
- Retinoid X Receptors
- Graft vs Host Disease/drug therapy
- Bronchiolitis Obliterans
- Germinal Center
- Th17 Cells/metabolism
PubMed: MeSH publication types
- Journal Article