From the Guidelines
CAR-T cell therapy is not currently approved for treating Graft-versus-Host Disease (GVHD), though research in this area is ongoing. The primary concern with using CAR-T cells in GVHD is that they might exacerbate the condition by increasing inflammatory responses 1. GVHD is typically treated with corticosteroids (like prednisone at 1-2 mg/kg/day), calcineurin inhibitors (tacrolimus or cyclosporine), antithymocyte globulin, or JAK inhibitors (ruxolitinib) 1.
Current Treatment Approaches
- Corticosteroids are the mainstay of initial treatment for GVHD, often used in conjunction with a T-cell inhibitor (cyclosporine or tacrolimus) 1.
- In cases of corticosteroid-refractory GVHD, numerous therapies have been studied, including cyclophosphamide, biologics, and photopheresis, with varied success depending on the tissues involved and the severity of the disease 1.
- Management of GVHD can be optimized by providing coordinated care from a multidisciplinary team, preferably in medical centers with access to specialized transplant services 1.
Experimental Approaches
- Some research explores using regulatory T cells (Tregs) modified with CARs to suppress GVHD, potentially targeting specific tissues affected by GVHD while preserving beneficial graft-versus-tumor effects 1.
- The use of allogeneic CAR-T cells, which could offer an 'off-the-shelf' approach, is also being investigated, but graft-versus-host disease and host rejection remain major barriers 1.
- Genome editing strategies, such as CRISPR-Cas, could potentially be used to prevent or delay the rejection of CAR-T cells by the recipient's immune system or to boost CAR-T-cell efficacy by knocking out T cell inhibitory receptors or signaling molecules 1.
Clinical Practice
- Patients with GVHD should continue to receive standard therapies while these novel approaches are being investigated.
- Clinical trials are needed to establish the safety and efficacy of CAR-T cell therapy in GVHD before it can be recommended for clinical practice.
From the Research
Role of CAR T cells in Treating GVHD
- CAR T cells can be used to prevent and treat Graft-Versus-Host Disease (GVHD) by targeting specific cells involved in the disease pathogenesis, such as CD83+ cells 2.
- Human CD83-targeted CAR T cells have been shown to eradicate pathogenic CD83+ target cells, increase the ratio of regulatory T cells to allo-activated Tconvs, and provide durable prevention of xenogeneic GVHD 2.
- CAR T-cell therapy can also trigger GVHD, especially in patients who have undergone allogeneic hematopoietic cell transplantation (allo-HCT), highlighting the need for careful management and monitoring 3, 4.
Alternative Approaches to Prevent GVHD
- Developing methods to disrupt endogenous TCR of allogeneic CAR-T cells using gene editing tools to prevent GVHD is an active area of research, but it also raises concerns about off-target activity and genotoxicities 5.
- Alternative cell types, such as γδ-T, iNKT, virus-specific T, double negative T cells, and MAIT cells, killer cells (NK and CIK cells), non-lymphocytic cells (neutrophils and macrophages), stem/progenitor cells, and cell-free extracellular vesicles, are being explored as potential substitutes for αβ-T cells to reduce the risk of GVHD 5.
Treatment of GVHD after CAR T-cell Therapy
- Extracorporeal photopheresis (ECP) has been shown to be a promising strategy for the treatment of GVHD after CAR T-cell therapy, with the ability to reduce alloreactivity without hampering CAR T-cell functionality 3, 6.
- ECP can selectively induce apoptosis, enrich naive and central memory CAR-T cells, and modulate the cytokine milieu to promote immune tolerance, making it a potential therapeutic approach for GVHD after CAR T-cell therapy 6.