Latest Clinical: "Rejection Response" in 62 Children Was Relieved by Stem Cell Drugs

Written by: Yang, Fujian Medical University

Expert review: Professor Li Jing, Affiliated Hospital of Jiangsu University

Recently, the Spanish research team published their latest research in the journal Stem Cells Translational Medicine[1], a multicenter sympathetic drug delivery clinical trial using mesenchymal stem cells (MSCs) in 62 steroid-resistant graft-versus-host disease (GVHD) children, and the results showed that MSCs treatment is a safe and effective means of treating refractory GVHD. This can lead to a significant proportion of patients' disease relief.

Mesenchymal stem cell drugs for GVHD

At present, a number of stem cell drugs for graft-versus-host disease are being developed around the world, and mesenchymal stem cell drugs for this indication have been approved for marketing in Japan and Canada in 2015 and 2012, respectively. In our country, mesenchymal stem cells are written into the 2021 "chronic GVHD" expert consensus, and the application of MSC occupies an important position in this expert consensus for the prevention of cGVHD.

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently an effective means of treating various blood system diseases, and despite careful matching before transplantation, the occurrence and development of graft-versus-host disease (GVHD) often hinders the success of HSCT and becomes a serious complication.

According to statistics[2], about 50% of patients receiving HSCT develop GVHD. However, only 30%-50% of patients respond to first-line treatment with steroids, and other second-line treatments are not yet widely recognized. Therefore, for those patients with GVHD who do not respond to immunosuppressant therapy such as steroids, it is necessary to explore more effective and safer treatment options.

In recent years, mesenchymal stem cells (MSCs) have gradually been introduced into the treatment of GVHD, a class of pluripotent stem cells with a wide range of immunomodulatory properties, such as inhibiting the activation of T cells and B cells, increasing the number of regulatory T cells and inducing the release of anti-inflammatory cytokines. In addition, MSCs have low immunogenicity and do not require matching when used with allogenes [1]. Therefore, MSCs are well suited for regulating the over-stressed immune response in patients with GVHD.

Clinically confirmed: mesenchymal stem cells significantly alleviate the disease

The study, which lasted from 2008 to 2018, was conducted simultaneously in multiple centers in Spain, and 62 steroid-resistant patients with GVHD (acute GVHD 46, chronic GVHD 16), of which 45 men (7 children) and 17 women (2 children) underwent allogeneic bone marrow and/or fat mesenchymal stem cell transplantation, cells were infused intravenously at doses of 1 × 10^6/kg, and each patient received an average of 4 infusions (range: 1-12 times). Clinical response was assessed 4 weeks after the first infusion and followed up was continued. The results are as follows:

NO.1| Safety and tolerability assessment of MSCs infusions

In the adult population, 1 case had a cardiac arrest during the first infusion, recovered by cardiopulmonary resuscitation and intravenous epinephrine, without sequelae. The patient was then treated with 3 more MSCs without any adverse reactions. Other adverse effects such as syncope, induration and pain at the infusion site, and infection. None of the adverse events occurred in the pediatric group. Therefore, the infusion of MSCs is generally safely tolerated.

NO.2| Evaluation of clinical response after MSCs infusion

An evaluation of clinical response 4 weeks after the first MSCs infusion showed an overall response rate of 58.69% (27/46) in patients with acute GVHD and 62.50% (10/16) in patients with chronic GVHD.

NO.3| Survival time analysis after MSCs infusion

In patients with acute GVHD, patients in the complete response group gradually discontinued their original supportive care within 6 to 8 weeks. The median survival (608 days) in the remission group was higher than in the no-response group (25 days) (P

The effective rate in the remission group after 2 years was 51.85% (14 of the 27 patients still survived), and the response group was 0% (0 of the 20 patients survived) (P

The overall survival rate was 70% in the remission group after 2 years (7 of 10 patients were still alive), and the overall survival rate was 16.67% in the non-remission group (1 in 6 patients survived) (P=0.008). In addition, subgroup analysis showed that the overall survival rate of patients under 18 years of age at 2 years (55.55%, 5 out of 9 patients survived) was better than that of patients over 18 years old (32.07%, 17 out of 53 patients survived) (P=0.045).

Mesenchymal stem cell therapy for GVHD can be expected in the future

The multicenter sympathetic dosing clinical trial in Spain was one of the largest studies using MSCs for the treatment of refractory GVHD with steroid resistance after allogeneic hematopoietic stem cell transplantation, and the results showed that MSCs were generally well tolerated and had satisfactory response rates, consistent with the results of previous clinical trials [4] and meta-analyses [5] conducted by the research team.

These results support the use of MSCs as a safe and effective treatment for refractory GVHD, which can lead to a significant proportion of patients' disease relief and increased probability of survival.

However, there are also some problems to be solved, such as at what time of disease progression should BE involved in MSCs treatment, whether it needs to be combined with conventional drug treatment, etc. The solution of these problems requires the joint efforts of researchers! The prospect of mesenchymal stem cell therapy is promising!

bibliography:

[1] Macías-Sánchez MDM, Morata-Tarifa C, Cuende N, et al. Mesenchymal Stromal Cells for Treating Steroid-Resistant Acute and Chronic Graft Versus Host Disease: A Multicenter Compassionate Use Experience [published online ahead of print, 2022 Mar 28]. Stem Cells Transl Med. 2022;szac003.

https://pubmed.ncbi.nlm.nih.gov/35348788/

[2] MacMillan ML, Weisdorf DJ, Wagner JE, et al. Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems. Biol Blood Marrow Transplant. 2002;8( 7):387-394.

https://pubmed.ncbi.nlm.nih.gov/12171485/

[3] Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105(4):1815-1822.

https://pubmed.ncbi.nlm.nih.gov/15494428/

[4] Jurado M, De La Mata C, Ruiz-García A, et al. Adipose tissue-derived mesenchymal stromal cells as part of therapy for chronic graft-versus-host disease: A phase I/II study. Cytotherapy. 2017;19(8):927-936.

https://pubmed.ncbi.nlm.nih.gov/28662983/

[5] Morata-Tarifa C, Macías-Sánchez MDM, Gutiérrez-Pizarraya A, Sanchez-Pernaute R. Mesenchymal stromal cells for the prophylaxis and treatment of graft-versus-host disease-a meta-analysis. Stem Cell Res Ther. 2020;11(1):64. Published 2020 Feb 18.

https://pubmed.ncbi.nlm.nih.gov/32070420/