**6. Summary/conclusions**

The clinical outcome parameters and the kind and amount of MSCs used in the clinical trials we reviewed in this chapter are variable. Most important difference of MSCs used in the clinical trials is whether they are autologous, extracted from the patient's own tissue or allogeneic extracted from health donors. When we reviewed the clinical trials using autologous MSCs trials treating SLE we observed that autologous MSCs did not show much efficacy while allogeneic MSCs regardless of their origins seem to be showing consistently better efficacy in most trials (**Table 1**). The reason for lack of efficacy in autologous use of MSCs is most probably due to their intrinsic abnormalities, and their inability to function at their best capacity. Autologous MSCs may not be functioning due their previous exposure the inflammatory micro environment in SLE or due to their genetic predisposition [79].

Allogeneic mesenchymal stem cell treatment has been shown to be efficacious in the treatment of various systemic lupus erythematosus activity, mainly in refractory lupus nephritis. Allogeneic MSCs, at 1 x 106 /kg seems to be efficacious but the results are not as homogeneous as expected from clinical trials and FDA approval for MSCs use in rheumatologic diseases have been challenging. Heterogeneous results could be due to the heterogenous disease manifestations among patients

*Lupus - Need to Know*

than without it.

patients.

2 × 108

stem cell (hUC-MSC) for the treatment of lupus nephritis (LN) among 18 patients with WHO class III or IV LN. Patients were randomly assigned to hUC-MSC (dose

A pilot study investigated the effect of MSCs on soluble human leukocyte antigen G (s HLA-G) levels 24 hours and 30 days after MSC injection (UC) and reported a negative correlation between the HLA-G levels and clinical SLE activity scores [85]. The levels of s HLA-G were lower in patients with renal involvement

An open label phase II trial the following year reported safety and long-term efficacy of UC MSCs in severe SLE. Wang et al. [86] reported a long-term followup study of allogeneic bone marrow and/or umbilical cord MSC transplantation (MSCT) in severe and drug-refractory systemic lupus erythematosus (SLE) patients. Eighty-one patients were enrolled, and the 5-year overall survival rate was 84% (68/81) after MSCT. At 5-year follow-up, 27% of patients (22/81) were in complete clinical remission and another 7% (6/81) were in partial clinical remission, with a 5-year disease remission rate of 34% (28/81). In total, 37 patients had achieved clinical remission and then 9 patients subsequently relapsed, with 5-year overall rate of relapse of 24% (9/37). SLEDAI scores, serum albumin, complement C3, peripheral white blood cell, and platelet numbers, as well as proteinuria levels, continued to improve during the follow-up. Their results demonstrated that allogeneic MSC treatment is safe and resulted in long-term clinical remission in SLE

Barbado et al. [87] infused three SLE patients with MSCs who were diagnosed with class IV nephritis by kidney biopsies. MSCs were allogeneic MSCs from healthy donors. Total of ninety million cells were infused intravenously into each patient during high and very high activity disease. Patient 1 was treated with cyclophosphamide, azathioprine, methotrexate, mycophenolate and cyclosporine, patient 2 was treated with cyclophosphamide, mycophenolate, rituximab and patient 3 was treated with cyclophosphamide and mycophenolate before MSC treatment. Then, follow-up was performed after 9 months. Proteinuria levels improved significantly during the 1st month and then continued to be sustained in normal levels. Clinical outcome scores such as SLEDAI was perfect for 2 patients while the third SLE patient only had a partial response and the patient could reduce the dose of her current therapies down to 50–60%. Follow up stopped after 9 months SLEDAI scores revealed early, durable, and substantial remissions that were complete for two patients and partial for the third patient and that permitted medication doses to

In 2019 using slightly older patient population with severe SLE (SLEDAI score > =8), Wen et al. [88] also reported efficacy of allogeneic bone marrow and umbilical cord MSC treatment over one year of follow up in those patients that did not have any baseline arthritis or use of cyclophosphamide of hydroxychloroquine

over and above standard immunosuppression [84].

 cells) or placebo. All patients received standard immunosuppressive treatment, which consisted of intravenous methylprednisolone and cyclophosphamide, followed by maintenance oral prednisolone and mycophenolate mofetil. Initial 11 patients enrolled to the study received hUC-MSC concurrently with the intravenous methylprednisolone and CYP induction therapy, and for the 12th to 18th patients enrolled, the hUC-MSC were administered together with the intravenous methylprednisolone only and intravenous CYP was delayed to 4 weeks later. In result, similar proportion of patients on hUC-MSC and placebo achieved complete remission. Improvements in serum albumin, complement, renal function, SLEDAI and BILAG scores were similar in both groups. The trial was abandoned after 18 patients were enrolled when it had become obvious it would not demonstrate a positive treatment effect. They concluded that hUC-MSC has no apparent additional effect

**146**

be reduced 50–90%.

enrolled to the clinical trials. In addition, although there are plenty of MSC trial reports that shows evidence for MSCs efficacy in SLE, randomized prospective controlled trials using MSCs are still missing.

In addition, the tissue source of donor MSCs shows remarkable variability, while some investigators believe in the superior anti-inflammatory effects of audiogenic MSCs other disagree and suggest umbilical cord MSCs immune modulatory efficacies. Since future MSC clinical trials and MSC therapies will be dependent on the availability of the donor tissue, technologic advancement to optimize the MSCs that can be easily obtained such as adipogenic tissue or peripheral blood must be prioritized.

Most MSC products used in clinical trials still lack a clear product definition, how they are selected, and application protocols. It is possible that the dose, route and frequency of the cell product protocol used in a clinical trial may not be universally applicable. Furthermore, due to the ever-thriving knowledge about MSCs functions we are yet to establish clear outcome criteria for testing MSC efficacy and safety.

Most MSC clinical trials have the inclusion criteria to enroll patients with severe disease activity and criteria of failure of currently available treatments. Therefore, there might be already irreversible and secondary tissue damage and MSCs may not be able to reverse this outcome when used in the late phase of the organ damage. If MSCs can be given in an earlier stage of disease their efficacy might be a lot better.

In summary, as you would see from the list of clinical trials and their outcomes (**Table 1**) discussed in this chapter the investigators that take roles in MSC clinical trials are not only struggling with the source of MSCs and optimization of efficacy they are also facing very complex regulatory issues. The variable sources of stem cells, cumbersome manufacturing processes are further complicating design of clinical trials. Further studies assessing the efficacy of MSC treatments needs to be performed.
