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. 2023 Sep 12;7(17):4886-4902.
doi: 10.1182/bloodadvances.2022007611.

Chronic GvHD NIH Consensus Project Biology Task Force: evolving path to personalized treatment of chronic GvHD

Nataliya P Buxbaum  1 , Gerard Socié  2 , Geoffrey R Hill  3   4 , Kelli P A MacDonald  5 , Victor Tkachev  6   7 , Takanori Teshima  8 , Stephanie J Lee  4 , Jerome Ritz  9 , Stefanie Sarantopoulos  10 , Leo Luznik  11 , Defu Zeng  12 , Sophie Paczesny  13 , Paul J Martin  4 , Steven Z Pavletic  14 , Kirk R Schultz  15 , Bruce R Blazar  16
Affiliations

Chronic GvHD NIH Consensus Project Biology Task Force: evolving path to personalized treatment of chronic GvHD

Nataliya P Buxbaum et al. Blood Adv. .

Abstract

Chronic graft-versus-host disease (cGvHD) remains a prominent barrier to allogeneic hematopoietic stem cell transplantion as the leading cause of nonrelapse mortality and significant morbidity. Tremendous progress has been achieved in both the understanding of pathophysiology and the development of new therapies for cGvHD. Although our field has historically approached treatment from an empiric position, research performed at the bedside and bench has elucidated some of the complex pathophysiology of cGvHD. From the clinical perspective, there is significant variability of disease manifestations between individual patients, pointing to diverse biological underpinnings. Capitalizing on progress made to date, the field is now focused on establishing personalized approaches to treatment. The intent of this article is to concisely review recent knowledge gained and formulate a path toward patient-specific cGvHD therapy.

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Conflict of interest statement

Conflict-of-interest disclosure: G.S. receives renumeration for serving on the advisory board of Equillium Incyte, Novartis, and PharmaCyclic. G.R.H. has consulted for Generon Corporation, NapaJen Pharma, iTeos Therapeutics, and Neoleukin Therapeutics, and has received research funding from Compass Therapeutics, Syndax Pharmaceuticals, Applied Molecular Transport, Serplus Technology, Heat Biologics, Laevoroc Oncology, and iTeos Therapeutics. S.J.L. has consulted for Mallinckrodt, Equillium, and Kadmon; has received research funding from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, and Takeda; serves on the steering committee for Incyte; and has received drug supply from Janssen. J.R. receives research funding from Amgen, Equillium, Kite/Gilead and Novartis; serves on Data Safety Monitoring Committees for AvroBio and scientific advisory boards for Akron Biotech, Clade Therapeutics, Garuda Therapeutics, LifeVault Bio, Novartis, Rheos Medicines, Talaris Therapeutics, and TScan Therapeutics. S.P. holds a patent on “Biomarkers and assays to detect chronic graft-versus-host disease” (US Patent # 10571478 B2). L.L. holds a patent with WindMiL therapeutics; receives grant/research/clinical trial support from Genentech; and is a consultant/advisory board member for Gilead Sciences, Rubius Therapeutics, Precision Biosciences, and Talaris Therapeutics. P.J.M. receives research funding from AltruBio; renumeration as an adviser to Mallinckrodt, Mesoblast, Rigel, Talaris; renumeration as a member of the Data and Safety Monitoring Board for Pfizer, Pediatric Transplantation and Cellular Therapy Consortium; and has received honoraria from Janssen, Mount Sinai School of Medicine, Therakos, Florida Department of Health, and Deutsche Knochenmarkspenderdatei. S.Z.P. receives research support from the Center for Cancer Research at the National Cancer Institute through the National Institutes of Health Intramural Research Program, including Clinical Research Development Agreements with Celgene, Actelion, Eli Lilly, Pharmacyclics and Kadmon. B.R.B. receives renumeration as an adviser to Magenta Therapeutics, BlueRock Therapeutics, Childrens’ Cancer Research Fund, and KidsFirst Fund, and is a cofounder of Tmunity Therapeutics.

Figures

Figure 1.
Figure 1.
Pathophysiological networks and targeted approaches for prevention and treatment of cGvHD. FDA-approved drugs are highlighted within red bubbles. Ag, antigen; AKT, Ak strain transforming; BAFF, B-cell activating factor; BAFF R, BAFF receptor; BCR, B-cell receptor; BLNK, B-cell linker; BTK, Bruton’s Tyrosine Kinase; BTK/ITK, Bruton’s Tyrosine Kinase /IL-2 Inducible T-cell Kinase; CD, cluster of differentiation; FOXP3, forkhead box P3; HSP47, heat shock protein 47; INF-γ, interferon gamma; ITK, IL-2-inducible T-cell kinase; Jakinibs, Janus kinase inhibitors; JAKs, Janus kinases; LCK, lymphocyte-specific protein tyrosine kinase; NOTCH2, Neurogenic locus notch homolog protein 2; NOTCH2 mAb, neurogenic locus notch homolog protein 2 mAb; PI3K, phosphoinositide 3-kinase; pSTAT5, phosphorylated signal transducer and activator of transcription 5; ROCK2, Rho associated coiled-coil containing protein kinase 2; STATs, signal transducers and activators of transcription; SYK, spleen associated tyrosine kinase; TCR, T-cell receptor; TGF-β, transforming growth factor beta; Th, T helper; TNF-α, tumor necrosis factor alpha; Treg, T regulatory cell; VA-lip HSP47, vitamin A coupled liposomal containing small interfering RNA (siRNA) against heat shock protein 47.
Figure 2.
Figure 2.
Summary of the preclinical modeling and clinical studies that led to the development of FDA-approved agents for chronic GvHD. (A) The role of B cells and targeting of B cells in cGvHD. (B) The role of macrophages and targeting of macrophage function in cGvHD. (C) The role of Tregs, in suppressing cGvHD and the development of cGvHD therapies aimed at Treg expansion/improved function. Ab, antibody; BTK, Bruton’s Tyrosine Kinase; CAR Treg, chimeric antigen receptor T regulatory cell; ECP, extracorporeal photopheresis; FoxP3, forkhead box P3; H-Y Ab, antibodies specific for male (Y) antigens; MCP-1, monocyte chemoattractant protein-1; iNKT, invariant NK T cells; ROCK2, Rho associated coiled-coil containing protein kinase 2; sBAFF, soluble B-cell activating factor; SYK, spleen sssociated tyrosine kinase; TNF-α, tumor necrosis factor alpha. Reference citations used: ,,, , ,,,,,,,,,,,,,,,,,,,, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .
Figure 2.
Figure 2.
Summary of the preclinical modeling and clinical studies that led to the development of FDA-approved agents for chronic GvHD. (A) The role of B cells and targeting of B cells in cGvHD. (B) The role of macrophages and targeting of macrophage function in cGvHD. (C) The role of Tregs, in suppressing cGvHD and the development of cGvHD therapies aimed at Treg expansion/improved function. Ab, antibody; BTK, Bruton’s Tyrosine Kinase; CAR Treg, chimeric antigen receptor T regulatory cell; ECP, extracorporeal photopheresis; FoxP3, forkhead box P3; H-Y Ab, antibodies specific for male (Y) antigens; MCP-1, monocyte chemoattractant protein-1; iNKT, invariant NK T cells; ROCK2, Rho associated coiled-coil containing protein kinase 2; sBAFF, soluble B-cell activating factor; SYK, spleen sssociated tyrosine kinase; TNF-α, tumor necrosis factor alpha. Reference citations used: ,,, , ,,,,,,,,,,,,,,,,,,,, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .
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