Advances in the biology of chronic GVHD

Understanding pathways allows more diverse and more specific therapeutic approaches for cGVHD

• Therapeutic targets (e.g., ROCK2) and microbiome-derived protection from cGVHD may be explored

In this presentation, Dr. Mohty provided insights into the biology and pathophysiology of cGVHD and suggested diagnostic biomarkers and therapeutic targets for its management, based on published scientific evidence.

Definition of cGVHD (Schoemans HM, et al. 2018)

• While the historical perception was that acute GVHD (aGVHD) occurs in the first three months after transplant and cGVHD thereafter, a consensus was provided to capture various cGVHD entities including an overlap cGVHD

• Manifestations of aGVHD are limited to skin, liver, and GI tract, while manifestations of cGVHD (meeting NIH 2014 diagnostic criteria) cover a wider list^*

• Undefined other cGVHD includes atypical signs and symptoms of alloreactivity falling outside the NIH 2014 diagnostic criteria

Pathophysiology of cGVHD and role of T and B cells
 

• Finke J, et al. 2009 reported that the addition of ATG-F to GVHD prophylaxis lowered the incidence of cGVHD (limited/extensive and extensive) vs control by depleting the T cells
• Meyer E, et al. 2022 showed that Orca-T, an engineered allograft, resulted in high GVHD- free and relapse-free survival (at one year) following myeloablative conditioning for hematological malignancies vs CIBMTR control (71% vs 34%)
  • Incidence of moderate to severe cGVHD (as per NIH Consensus Grading) through day +365 was reduced with Orca-T vs CIBMTR control (5% vs 38%)
• As per Dr Mohty, the risk factors† for cGVHD analyzed by Flowers M, et al. 2011 highlight its pathophysiology including HLA mismatching, minor HLA antigen, number of T cells, insult by the conditioning regimen and GVHD prophylaxis regimen, and thymic damage and immune reconstitution
• To avoid cGVHD, a normal immune reconstitution needs to be achieved. However, transplant patients can suffer from other complications highlighted by Cooke KR, et al. 2017 where the T cells can be impacted leading to immune dysregulation and abnormal proliferation of alloreactive T cells
• Injury to the thymus and the subsequent T cell recovery especially the naïve T helper cells plays an important role in T cell reconstitution (Gaballa A, et al. 2020)
• An unbalanced reconstitution of donor-derived regulatory T cells (Tregs) as well as effector/ conventional T cells (Tcons) and CD8 T cells, observed after nine months of transplant, was associated with cGVHD (Alho AC, et al. 2016)
  • Thymic damage prevented recovery of naïve Tregs
• Findings from McManigle W, et al. 2019 highlighted that in cGVHD, after allogeneic HCT, B cell recovery occurs under constant exposure to chronic alloantigen and a high B-cell activating factor: B cells ratio, leading to altered peripheral B-cell with constitutive activation and survival signaling
• Also, as shown by Zorn E, et al. 2004, after allogeneic SCT, T cell response, was blocked by anti-DRB1501; recognized endogenously processed peptide on female and male dendritic cells; and was followed by B cell response
• Mikios DB, et al. 2004 examined the magnitude of antibody responses to recombinant DBY and DBX and found anti-DBY response to be higher in male patients with female donors vs male patients with male donors
• Sarvaria A, et al. 2016 demonstrated that IL-10+ regulatory B cells, enriched in cord blood, may protect against cGVHD after cord blood transplantation
• In general, the pathophysiology of cGVHD as per Cookee KR, et al. 2016 involves:
  • Phase 1: Acute inflammation, tissue injury, and involves innate immunity
  • Phase 2: Chronic inflammation and dysregulated immunity and involves adaptive immune system (including T cells, B cells, antigen-presenting cells, NK cells, and regulatory cells: Tregs, Bregs, and Tr1 cells)
  • Phase 3: Marks aberrant tissue repair and fibrosis and involves innate and adaptive immunity

Therapeutic targets for cGVHD
 

• Dr. Mohty mentioned the therapeutic targets that could be considered while managing cGVHD
• He highlighted ROCK2^‡, a critical regulator of immune modulation and fibrosis, and an emerging therapeutic target in cGVHD which can be effectively inhibited by drugs (Zannin-Zhorav A, et al. 2021)
• Microbiota and dysbiosis in local organs after HCT can influence GVHD. Findings from Markey KE, et al. 2020 showed that microbe-derived short-chain fatty acids butyrate and propionate at day 100 were associated with protection from cGVHD

Diagnostic biomarkers for cGVHD
 

• The cGVHD biomarkers can aid in refining diagnosis, anticipating severity, and in guiding treatment
• Evaluation of diagnostic biomarker values (Cuvellier GDE, et al. 2023) have shown that:
  • At the onset of cGVHD, various populations of T cells^§ decreased, indicating thymic damage, whereas various cytokines and chemokines increased indicating effector T cell recruitment and cGVHD tissue damage
  • Similar patterns of biomarkers were seen at the onset of moderate-severe GVHD except for a decrease in NKreg cells
• Assessment of cGVHD risk at three months after HCT identified cGVHD biomarkers including some key molecules including CXCL9, and fibrotic biomarkers like MMP3 and DKK3 (Logan BR, et al. 2023)