Mesenchymal Stem Cells and Graft-versus-Host Disease

Graft host disease is a battle between two immune systems

The above short story is about graft-versus-host disease (graft-versus-host disease, GVHD ). This is the most important complication after allogeneic hematopoietic stem cell transplantation. It is a systemic disease with multi-system damage (skin, esophagus, gastrointestinal tract, liver, etc.), and it is one of the important causes of death.

Since the 1990s, hematopoietic stem cell transplantation therapy has made rapid progress. It can cure a wide range of diseases, and the treatment method is safer and more effective. It has become an important means of curing a variety of benign and malignant blood diseases and genetic diseases.

GVHD also occurs, and its immune rejection is mainly mediated by donor T cells, which attack transplant cells through T cells, and even cause death of the patient in severe cases.

The first-line drugs for the treatment of GVHD are adrenal corticosteroids, but the curative effect of adrenal corticosteroids alone is limited, and the effective rate is about 50%. There is currently no standard second-line regimen for the treatment of GVHD, which usually requires long-term combination with other immunosuppressive drugs. For some GVHD, the therapeutic effects of commonly used drugs, including first-line and second-line drugs, are not satisfactory.

Can MSCs be mediators?

The immunomodulatory properties of mesenchymal stromal cells (MSCs) make it possible for them to be used as a clinical treatment for GVHD. Related studies in recent years have shown that MSCs can play an immunomodulatory role by inhibiting the proliferation of lymphocytes, inhibiting the differentiation, maturation and function of antigen-presenting cells, inhibiting the formation of CTL, and increasing the proportion of regulatory T cells.

Clinically, the application of MSCs in the prevention and treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation has remarkable effects. The first successful application was: MSCs for the treatment of severe steroid- and cyclosporine-resistant graft-versus-host disease in a 9-year-old boy. The world's first stem cell therapy drug is Prochymal .

In 2002, "British Journal of Hematology" (Br JHaematol) published Lee et al. co-transplanted MSCs and haploidentical HSCs for the first time, showing the effect of promoting engraftment and reducing acute graft-versus-host disease (aGVHD).

In 2004, Le Blanc et al[1] first tried to use MSCs to treat a patient with steroid-resistant grade IV intestinal and liver acute graft-versus-host disease ( aGVHD) , and the results were remarkable. Subsequently, multiple treatment centers successively applied MSCs to treat GVHD[2-4].

In 2008, the United States "Leukemia" magazine (Leukemia) published a preliminary randomized controlled clinical study by Ning et al., who found that co-infusion of MSCs and HSCs transplantation can reduce the incidence of acute graft-versus-host disease (aGVHD). In the same year, the European Society for Bone Marrow Transplantation recommended MSCs as one of the second-line treatments for acute graft-versus-host disease (aGVHD). Therefore, the reduction and treatment of MSCs on the incidence of aGVHD after hematopoietic stem cell transplantation has gained the consensus of most experts.

In 2009, the failure of the phase 3 clinical trial of Prochymal (bone marrow-derived MSCs) in the treatment of refractory GVHD was a catastrophic event in the clinical application of MSCs, which almost negated the clinical efficacy of MSCs.

In 2010, "Biology of Blood and Marrow Transplantation" (Biology of Blood and Marrow Transplantation) published that Baron et al performed reduced-dose preconditioning transplantation on 20 patients with incomplete HLA matching of donors and recipients, and infused third-party MSCs at the same time , the study found that MSCs can reduce aGVHD-related mortality.

In 2015, a systematic review and meta-analysis evaluating the response and survival of MSCs in the treatment of steroid-resistant aGVHD was published in The Lancet Haematology. A total of 628 documents were found in the study, and 610 documents were excluded after reading the documents. Six of the most valuable studies provided data for the primary outcome analysis (119 patients). The 6-month survival rate after MSCs treatment was 63% (95% CI 50-74, I2=41%). It indicated that injection of MSCs is a feasible treatment for steroid-resistant acute GVHD. [5]

In early 2018, Mesoblast announced that the Phase 3 clinical trial of MSC-100-IV (remestemcel-L), a candidate allogeneic mesenchymal stem cell product for the treatment of children with steroid-refractory acute graft-versus-host disease (aGVHD), was completed on the 28th The overall response rate (ORR, complete response + partial response) successfully reached the primary clinical endpoint. [6]

A total of 55 children enrolled in the phase 3 trial had an ORR of 69% at day 28, a statistically significant increase (p=0.0003) from the protocol-defined historical control rate of 45%. Among patients who received at least one infusion and were followed for 100 days (n=50), the mortality rate was 22%. This is in stark contrast to the 70% mortality rate at day 100 in patients who did not respond to initial steroid therapy.

Treatment guidelines in the UK and the EU recommend MSCs as third-line therapy for acute GVHD grades 2–4. However, because there are no mature commercial MSCs products in the United States, the American Society for Blood and Marrow Transplantation (ASBMT) did not include MSCs in the treatment guidelines.

Warm reminder: When GVHD patients are seriously threatened and conventional treatments such as hormones are ineffective, they can refer to the standards of the United Kingdom and the European Union and try mesenchymal stem cell therapy, and there may be a chance of survival.

Side news : By the way, it is said that domestic clinical trials of MSCs for the treatment of GVHD have been going on for a long time, and new drugs will be declared soon.