Minnelide suppresses GVHD and enhances survival while maintaining GVT responses
Allogeneic hematopoietic stem cell transplantation (aHSCT) can cure patients with otherwise fatal leukemias and lymphomas. However, the benefits of aHSCT are limited by graft-versus-host disease (GVHD). Minnelide, a water-soluble analog of triptolide, has demonstrated potent anti-inflammatory and anti-tumor activity in several pre-clinical models and has proven both safe and efficacious in clinical trials for advanced gastro-intestinal malignancies. Here, we tested the effectiveness of Minnelide in preventing acute GVHD as compared to cyclophosphamide post-aHSCT (PTCy). Strikingly, we found Minnelide improved survival, weight loss and clinical scores in an MHC-mismatched model of aHSCT. These benefits were also apparent in minor MHC-matched aHSCT and xenogeneic HSCT models. Minnelide was comparable to PTCy in terms of survival, GVHD clinical score and colonic length. Notably, in addition to decreased donor T cell infiltration early post-HSCT, several regulatory cell populations including Tregs, ILC2s and MDSCs in the colon were increased which together may account for Minnelide's GVHD suppression post-HSCT. Importantly, Minnelide GVHD prevention was accompanied by preservation of graft-versus-tumor (GVT) activity. As Minnelide possesses anti-AML activity and is being applied in clinical trials, together with the present findings, we conclude that this compound might provide a new approach for AML patients undergoing aHSCT.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
JCI insight - (2024) vom: 11. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Copsel, Sabrina N [VerfasserIn] |
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| Links: |
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| Themen: |
Cellular immune response |
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| Anmerkungen: |
Date Revised 11.04.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1172/jci.insight.165936 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370920996 |
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| 520 | |a Allogeneic hematopoietic stem cell transplantation (aHSCT) can cure patients with otherwise fatal leukemias and lymphomas. However, the benefits of aHSCT are limited by graft-versus-host disease (GVHD). Minnelide, a water-soluble analog of triptolide, has demonstrated potent anti-inflammatory and anti-tumor activity in several pre-clinical models and has proven both safe and efficacious in clinical trials for advanced gastro-intestinal malignancies. Here, we tested the effectiveness of Minnelide in preventing acute GVHD as compared to cyclophosphamide post-aHSCT (PTCy). Strikingly, we found Minnelide improved survival, weight loss and clinical scores in an MHC-mismatched model of aHSCT. These benefits were also apparent in minor MHC-matched aHSCT and xenogeneic HSCT models. Minnelide was comparable to PTCy in terms of survival, GVHD clinical score and colonic length. Notably, in addition to decreased donor T cell infiltration early post-HSCT, several regulatory cell populations including Tregs, ILC2s and MDSCs in the colon were increased which together may account for Minnelide's GVHD suppression post-HSCT. Importantly, Minnelide GVHD prevention was accompanied by preservation of graft-versus-tumor (GVT) activity. As Minnelide possesses anti-AML activity and is being applied in clinical trials, together with the present findings, we conclude that this compound might provide a new approach for AML patients undergoing aHSCT | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Cellular immune response | |
| 650 | 4 | |a Immunology | |
| 650 | 4 | |a Stem cell transplantation | |
| 650 | 4 | |a Transplantation | |
| 700 | 1 | |a Garrido, Vanessa T |e verfasserin |4 aut | |
| 700 | 1 | |a Barreras, Henry |e verfasserin |4 aut | |
| 700 | 1 | |a Bader, Cameron S |e verfasserin |4 aut | |
| 700 | 1 | |a Pfeiffer, Brent |e verfasserin |4 aut | |
| 700 | 1 | |a Mateo-Victoriano, Beatriz |e verfasserin |4 aut | |
| 700 | 1 | |a Wolf, Dietlinde |e verfasserin |4 aut | |
| 700 | 1 | |a Gallardo, Miguel |e verfasserin |4 aut | |
| 700 | 1 | |a Paczesny, Sophie |e verfasserin |4 aut | |
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| 700 | 1 | |a Benjamin, Cara L |e verfasserin |4 aut | |
| 700 | 1 | |a Villarino, Alejandro |e verfasserin |4 aut | |
| 700 | 1 | |a Saluja, Ashok K |e verfasserin |4 aut | |
| 700 | 1 | |a Levy, Robert B |e verfasserin |4 aut | |
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