clinical topic updates

Chronic Graft-versus-Host Disease: Biomarkers, Mediators, and Druggable Targets

by David Miklos, MD, PhD

Overview

An improved understanding of chronic graft-versus-host disease (cGVHD) and its pathogenesis has led to the development of novel treatments. Future advancements may be possible using tools to track donor cell expansion and localization.

Expert Commentary

David Miklos, MD, PhD

Professor of Medicine
Chief, Division of BMT and Cellular Therapy
Stanford University Medical Center
Clinical Director, Center for Cancer Cell Therapy
Stanford Medicine
Palo Alto, CA

“The complexities of the immune response in cGVHD occur in many different dimensions, and it may be helpful to think in terms of fluidity and flow. We are interested in targets that represent choke points or valves (ie, targets that might cut off the flow of the immune response).” 

David Miklos, MD, PhD

Currently, all biomarkers for cGVHD are exploratory. It is important to consider not only just biomarkers but also biomarkers that are associated with pharmacodynamic changes that may be druggable. The complexities of the immune response in cGVHD occur in many different dimensions, and it may be helpful to think in terms of fluidity and flow. We are interested in targets that represent choke points or valves (ie, targets that might cut off the flow of the immune response).

GVHD has been classically defined as acute and chronic using a cutoff of 100 days post allogeneic hematopoietic stem cell transplantation. Prior to transplant, it is believed that tissue damage from conditioning regimens may represent an early influence in the development of GVHD. Acute GVHD is understood to be mediated by mature effector T cells from the donor that become activated after encountering alloantigens in the recipient. In cGVHD, shared cooperative B-cell and T-cell responses in the lymph nodes are involved, which likely explains why cGVHD occurs most commonly during the 6 to 12 months after transplantation. Currently druggable targets act at differing points in the relevant pathways. For example, relative to alloantigen recognition, ibrutinib acts upstream at immune receptor activation, whereas ruxolitinib has widespread T-cell inhibitory effects and belumosudil may inhibit peripheral sclerosis further downstream in cGVHD pathogenesis.

In looking to the future of biomarkers and potential targets, a few of the key players include regulatory T cells (Treg cells) and T follicular regulatory cells (Tfr cells). Treg cells are key mediators of immune tolerance that suppress auto- and alloreactive immune responses, and their absence is strongly associated with cGVHD. Tfr cells, which comprise only a small proportion of Treg cells, are also a target of interest and might be druggable. Tfr cells regulate interactions between B cells and T follicular helper cells (Tfh cells) within the germinal center, leading to the production of antibodies that are associated with cGVHD, and antibodies can drive fibrosis through macrophage activation. 

In light of the importance of Treg cells, BCL6 and CXCR4 are potential targets of particular interest. The transcription factor BCL6 is at the center of gene regulation in Tfh cell biology, and the inhibition of this pathway has been shown to have a dramatic effect on cGVHD in a preclinical model. CXCR4, which is a binding molecule that Treg cells use to enter lymph nodes, is another interesting potential target. That is, given that the exponential growth and expansion of cGVHD occur in the lymph nodes (spurred on by the T-cell help, the cytokine environment, and the architecture of the lymph nodes), the following question arises: Might we eliminate this dramatic expansion by keeping the Tfh cells out of the lymph nodes? This is the Tfh cell–CXCR4 idea.

The biomarkers and targets in cGVHD that have been developed thus far represent important steps forward; however, advancements in both preclinical biology and correlative science are needed and will likely stem from an improved capacity to account for single-cell immune response complexity and tracking the fluidity of the immune effector cells in cGVHD pathogenesis. It is likely that the path forward will involve genetically labeling individual cells in a barcoded fashion, just like we do with single-cell RNA analyses. This would facilitate tracking the maturation and disposition of donor cells in the host, enabling us to determine which cell phenotypes dominate and localize at the site of cGVHD.

References

Choi J, Crotty S. Bcl6-mediated transcriptional regulation of follicular helper T cells (TFH). Trends Immunol. 2021;42(4):336-349. doi:10.1016/j.it.2021.02.002

Crossland RE, Perutelli F, Bogunia-Kubik K, et al. Potential novel biomarkers in chronic graft-versus-host disease. Front Immunol. 2020;11:602547. doi:10.3389/fimmu.2020.602547

Dudreuilh C, Basu S, Scottà C, Dorling A, Lombardi G. Potential application of T-follicular regulatory cell therapy in transplantation. Front Immunol. 2020;11:612848. doi:10.3389/fimmu.2020.612848

Forcade E, Kim HT, Cutler C, et al. Circulating T follicular helper cells with increased function during chronic graft-versus-host disease. Blood. 2016;127(20):2489-2497. doi:10.1182/blood-2015-12-688895

Giaccone L, Faraci DG, Butera S, et al. Biomarkers for acute and chronic graft versus host disease: state of the art. Expert Rev Hematol. 2021;14(1):79-96. doi:10.1080/17474086.2021.1860001

Lelas A, Greinix HT, Wolff D, Eissner G, Zivko Pavletic S, Pulanic D. Von Willebrand factor, factor VIII, and other acute phase reactants as biomarkers of inflammation and endothelial dysfunction in chronic graft-versus-host disease. Front Immunol. 2021;12:676756. doi:10.3389/fimmu.2021.676756

Paz K, Flynn R, Du J, et al. Small-molecule BCL6 inhibitor effectively treats mice with nonsclerodermatous chronic graft-versus-host disease. Blood. 2019;133(1):94-99. doi:10.1182/blood-2018-03-839993

Ren H-G, Adom D, Paczesny S. The search for drug-targetable diagnostic, prognostic and predictive biomarkers in chronic graft-versus-host disease. Expert Rev Clin Immunol. 2018;14(5):389-404. doi:10.1080/1744666x.2018.1463159

Whangbo JS, Antin JH, Koreth J. The role of regulatory T cells in graft-versus-host disease management. Expert Rev Hematol. 2020;13(2):141-154. doi:10.1080/17474086.2020.1709436

Zeiser R. Advances in understanding the pathogenesis of graft-versus-host disease. Br J Haematol. 2019;187(5):563-572. doi:10.1111/bjh.16190

Zeiser R, Sarantopoulos S, Blazar BR. B-cell targeting in chronic graft-versus-host disease. Blood. 2018;131(13):1399-1405. doi:10.1182/blood-2017-11-784017

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