Jacopo Mariotti
Daniel H. Fowler
Stefania Bramanti
Steve Z. Pavletic- 1Bone Marrow Transplantation (BMT) and Cell Therapy Unit, IRCCS Humanitas Research Hospital, Rozzano, Italy
- 2Rapa Therapeutics, Rockville, MD, United States
- 3Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
Editorial on the Research Topic
Controversies and expectations for prevention and treatment of graft-versus-host-disease: a biological and clinical perspective
Acute and chronic Graft-versus-Host-Disease (GVHD) remain the major contributors to transplantation related deaths and the most significant barrier to the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) (1). Despite prophylactic treatments with immunosuppressive agents, approximately 30-50% of transplantation recipients develop GVHD and, among them, at least 30% do not respond or relapse to front-line treatment and eventually die (2, 3). In this Research Topic, the authors have reviewed current options for prevention and treatment of GVHD and proposed new strategies to enhance available approaches in this field.
Watkins et al. provided a biological and clinical perspective of current platforms and future strategies for GVHD prophylaxis. The authors first summarized main risk factors contributing to GVHD onset and subsequently analyzed how current and new options for GVHD prophylaxis can affect them. The authors provided a detailed review of recent evidence on the employment of antithymocyte globulin (ATG) (4), post-transplant cyclophosphamide (PT-CY) (5) and anti CD80/CD86, abatacept (6), in the setting of matched related (MRD), matched (MUD) and mismatched (7/8) unrelated, and haploidentical donor transplants. Eventually they proposed personalized strategies based on different clinical situations, where we may need to optimize our GVHD preventive platform based on: underlying disease (high risk of relapse vs. non-malignant disease); risk of graft failure; or need of achieving rapid immune reconstitution to reduce infectious risks. Recent advances achieved with experimental strategies involving manipulation of the graft by CD45RA+ T cell depletion (7) or Treg cell enrichment (Orca-T) (8) are also discussed.
Several questions remain on the table: can we optimize GVHD prophylaxis by combining available immunosuppressive drugs or by building on existing platforms with manipulated T cell add-back? Can we identify whether it is better to employ one drug or another to avoid a particular worrisome subset of GVHD presentation? The articles by Weng et al. and Huang et al. has set the stage to answer these questions. Lung chronic GVHD (cGVHD) is one of the most life threatening side effects after allo-HSCT. Weng et al. described a significant reduction of bronchiolitis obliterans syndrome (BOS) in patients receiving haploidentical transplant (Haplo-SCT) and recognized that this effect is mainly mediated by ATG use. This finding is in agreement with one of the first observations on the role of ATG at diminishing cGVHD for MUD transplants whereby ATG infusion was associated with a significant reduction of post-transplant lung dysfunction (9). It is tempting to speculate that early post-transplant depletion of type 17 T cells (Th17) is one of the main mechanisms underpinning this beneficial late effect mediated by ATG, as this mechanism is thought to contribute to the recent impressive results achieved by the ROK2 inhibitor, belumosudil, for the treatment of cGVHD, particularly lung cGVHD (10). Huang et al. has also brought new life to basiliximab, a well-known anti-IL2 receptor monoclonal antibody, that had failed to improve the front-line treatment of acute GVHD (11). Huang et al. described a very low incidence of acute (aGVHD) and cGVHD (15% and 12%, respectively) by the combination of ATG and basiliximab. It is possible that an early usage of basiliximab eliminates highly replicating IL-2 dependent donor-specific alloreactive T cells immediately after Allo-HSCT, thereby paralleling one of the PT-Cy mechanistic effects. In a large retrospective EBMT study, the combination of ATG and PT-Cy in the setting of Haplo-SCT was tested by several authors and was recently associated with a lower incidence of cGVHD and a higher rate of engraftment compared with the use of PTCy alone (12). The work by Huang et al. underlined once again that using a lower dose of ATG (≤ 6 mg/kg) achieves an efficacious level of immunosuppression while sparing important side effects, such as infections (CMV) or disease relapse. In this sense, usage of lower doses of ATG was recently appropriately recommended by an international consensus panel (13).
Although treatment of aGVHD has recently improved after the introduction of ruxolitinb as standard therapy for the steroid refractory subset (14, 15), a great deal of work remains, as delineated by the contributions of Pan et al. and Bojanic et al. Specifically, Pan et al., through their T-cell transcriptomic studies, has identified extensive activation of glycolysis pathways in T cells before aGVHD onset. In particular, TCR, mTORC1, MYC, Hedgehog and Wnt/ß-catenin pathways were significantly enriched and may represent master regulators of metabolic reprogramming of T cells involved in aGVHD onset. These findings provide new potential targets to treat or prevent aGVHD. Glycolysis and metabolic reprogramming were shown to be of great relevance for T cell differentiation and persistence. For instance, GSK-3b/Wnt signaling is involved in T stem cell memory differentiation (TSCM) (16), which are not only relevant for long-lived anti-tumor effect but are also involved in acute (17) and chronic (18) GVHD development. Moreover, WNT pathway inhibitors were recently found to prevent experimental sclerodermatous cGVHD in pre-clinical models (19). Altogether, there is strong evidence supporting to test Wnt or glycolysis inhibitors as potential agents to prevent or treat GVHD in the near future. Finally, Bojanic et al. have extensively reviewed extracorporeal photopheresis (ECP) as an immunomodulatory treatment for cGVHD. By exploring T cell and biomarkers changes to highlight ECP response, the authors not only provide new tools to monitor or predict response to ECP in GVHD patients, but most importantly pave the way for new experimental approaches combining ECP with other immunomodulatory drugs. For instance, promising results were recently shown by combining ECP and ruxolitinib for the treatment of steroid refractory cGVHD, particularly BOS (20). Such combinations therapy holds promise as a future backbone of new strategies capable of eliminating problematic cases of GVHD. In another article of our Research Topic, Pinto et al. showed that Resolvin D1 represents an important gene involved in bone regeneration both by promoting osteoblast differentiation and reducing osteoclastogenesis. These mechanisms are not only important in the field of bone allograft regeneration, but may be of relevance in the setting of GVHD. Acute and chronic GVHD may target atypical organ sites such as the bone marrow (BM) niche (21), resulting in poor graft function and increased risk of death due to infection or hemorrhage. BM T-cell infiltration, endothelial damage and a reduced number of osteoblasts represent a hallmark of GVHD-mediated BM attack. Strategies capable of overcoming such GVHD side effects are relatively lacking, and currently only include TPO mimetics or atorvastatin. Pinto et al. provides a new potential target in order to treat T cell-mediated BM damage.
Author contributions
JM performed literature research and wrote the manuscript, SB, DF, SP revised the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of interest
Author DF was employed by the company Rapa Therapeutics.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Pavletic S, Fowler D. Are we making progress in GVHD prophylaxis and treatment? Hematol Am Soc Hematol Educ Program (2012) 2012:251–64. doi: 10.1182/asheducation.V2012.1.251.3798879
2. Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American society of blood and marrow transplantation. Biol Blood Marrow Transplant (2012) 18:1150–63. doi: 10.1016/j.bbmt.2012.04.005
3. Lee SJ, Nguyen TD, Onstad L, Bar M, Krakow EF, Salit RB, et al. Success of immunosuppressive treatments in patients with chronic graft-versus-Host disease. Biol Blood Marrow Transplant (2018) 24:555–62. doi: 10.1016/j.bbmt.2017.10.042
4. Kröger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, et al. Antilymphocyte globulin for prevention of chronic graft-versus-Host disease. N Engl J Med (2016) 374:43–53. doi: 10.1056/NEJMoa1506002
5. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant (2008) 14:641–550. doi: 10.1016/j.bbmt.2008.03.005
6. Watkins B, Qayed M, McCracken C, Bratrude B, Betz K, Suessmuth Y, et al. Phase II trial of costimulation blockade with abatacept for prevention of acute GVHD. J Clin Oncol (2021) 39:1865–77. doi: 10.1200/JCO.20.01086
7. Bleakley M, Sehgal A, Seropian S, Biernacki MA, Krakow EF, Dahlberg A, et al. Naive T-cell depletion to prevent chronic graft-Versus-Host disease. J Clin Oncol (2022) 40:1174–85. doi: 10.1200/JCO.21.01755
8. Oliai C, Hoeg RT, Pavlova A, Gandhi A, Muffly L, Metha RS, et al. Precision-engineered cell therapy orca-T demonstrates high relapse-free survival at 1 year while reducing graft-Versus-Host disease and toxicity. Blood (2022) 140(Supplement 1):654–6. doi: 10.1182/blood-2022-165654
9. Bacigalupo A, Lamparelli T, Barisione G, Bruzzi P, Guidi S, Alessandrino PE, et al. Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant (2006) 12:560–5. doi: 10.1016/j.bbmt.2005.12.034
10. DeFilipp Z, Kim HT, Yang Z, Noonan J, Blazar BR, Lee SJ, et al. Clinical response to belumosudil in bronchiolitis obliterans syndrome: a combined analysis from 2 prospective trials. Blood Adv (2022) 6:6263–70. doi: 10.1182/bloodadvances.2022008095
11. Cahn JY, Bordigoni P, Tiberghien P, Milpied N, Brion A, Widjenes J, et al. Treatment of acute graft-versus-host disease with methylprednisolone and cyclosporine with or without an anti-interleukin-2 receptor monoclonal antibody. a multicenter phase III study. Transplantation (1995) 60:939–42. doi: 10.1097/00007890-199511000-00010
12. Battipaglia G, Labopin M, Blaise D, Diez-Martin JL, Bazarbachi A, Vitek A, et al. Impact of the addition of antithymocyte globulin to post-transplantation cyclophosphamide in haploidentical transplantation with peripheral blood compared to post-transplantation cyclophosphamide alone in acute myelogenous leukemia: a retrospective study on behalf of the acute leukemia working party of the European society for blood and marrow transplantation. Transplant Cell Ther (2022) 28:587.e1–7. doi: 10.1016/j.jtct.2022.06.006
13. Bonifazi F, Rubio MT, Bacigalupo A, Boelens JJ, Finke J, Greinix H, et al. Rabbit ATG/ATLG in preventing graft-versus-host disease after allogeneic stem cell transplantation: consensus-based recommendations by an international expert panel. Bone Marrow Transplant (2020) 55:1093–102. doi: 10.1038/s41409-020-0792-x
14. Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-Host disease. N Engl J Med (2020) 382:1800–10. doi: 10.1056/NEJMoa1917635
15. Carniti C, Gimondi S, Vendramin A, Recordati C, Confalonieri D, Bermema A, et al. Pharmacologic inhibition of JAK1/JAK2 signaling reduces experimental murine acute GVHD while preserving GVT effects. Clin Cancer Res (2015) 21:3740–9. doi: 10.1158/1078-0432.CCR-14-2758
16. Gattinoni L, Zhong XS, Palmer DC, Ji Y, Hinrichs CS, Yu Z, et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med (2009) 15:808–13. doi: 10.1038/nm.1982
17. Tkachev V, Furlan SN, Watkins B, Panoskaltsis-Mortari A, Blazar BR, Kean L. T Stem cell memory dynamics during acute graft-Versus-Host disease. Blood (2015) 126:3079. doi: 10.1182/blood.V126.23.3079.3079
18. Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG. Host-reactive CD8+ memory stem cells in graft-versus-host-disease. Nat Med (2005) 11:1299–305. doi: 10.1038/nm1326
19. Zhang Y, Shen L, Dreißigacker K, Zhu H, Trinh-Minh T, Meng X, et al. Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease. Blood (2021) 137:2403–16. doi: 10.1182/blood.2020008720
20. Maas-Bauer K, Kiote-Schmidt C, Bertz H, Apostolova P, Wäsch R, Ihorst G, et al. Ruxolitinib-ECP combination treatment for refractory severe chronic graft-versus-host disease. Bone Marrow Transplant (2021) 56:909–16. doi: 10.1038/s41409-020-01122-8
Keywords: graft verses host disease, transplantation, allogeneic, combination (combined) therapy, review
Citation: Mariotti J, Fowler DH, Bramanti S and Pavletic SZ (2023) Editorial: Controversies and expectations for prevention and treatment of graft-versus-host-disease: a biological and clinical perspective. Front. Immunol. 14:1212756. doi: 10.3389/fimmu.2023.1212756
Received: 26 April 2023; Accepted: 27 April 2023;
Published: 15 May 2023.
Edited and Reviewed by:
Antoine Toubert, Université Paris Cité, FranceCopyright © 2023 Mariotti, Fowler, Bramanti and Pavletic. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jacopo Mariotti, amFjb3BvLm1hcmlvdHRpQGh1bWFuaXRhcy5pdA==
†These authors have contributed equally to this work and share last authorship