Mesenchymal stromal cells in human immunodeficiency virus-infected patients with discordant immune response: Early results of a phase I/II clinical trial

Abstract

Between 15% and 30% of HIV-infected subjects fail to increase their CD4 + T-cell counts despite continuous viral suppression (immunological nonresponders [INRs]). These subjects have a higher morbidity and mortality rate, but there are no effective treatments to reverse this situation so far. This study used data from an interrupted phase I/II clinical trial to evaluate safety and immune recovery after INRs were given four infusions, at baseline and at weeks 4, 8, and 20, with human allogeneic mesenchymal stromal cells from adipose tissue (Ad-MSCs). Based on the study design, the first 5 out of 15 INRs recruited received unblinded Ad-MSC infusions. They had a median CD4 + nadir count of 16/μL (range, 2-180) and CD4 + count of 253 cells per microliter (171-412) at baseline after 109 (54-237) months on antiretroviral treatment and 69 (52-91) months of continuous undetectable plasma HIV-RNA. After a year of follow-up, an independent committee recommended the suspension of the study because no increase of CD4 + T-cell counts or CD4 + /CD8 + ratios was observed. There were also no significant changes in the phenotype of different immunological lymphocyte subsets, percentages of natural killer cells, regulatory T cells, and dendritic cells, the inflammatory parameters analyzed, and cellular associated HIV-DNA in peripheral blood mononuclear cells. Furthermore, three subjects suffered venous thrombosis events directly related to the Ad-MSC infusions in the arms where the infusions were performed. Although the current study is based on a small sample of participants, the findings suggest that allogeneic Ad-MSC infusions are not effective to improve immune recovery in INR patients or to reduce immune activation or inflammation. ClinicalTrials.gov identifier: NCT0229004.

Mesenchymal stem cell-based treatments for COVID-19: status and future perspectives for clinical applications

“…Based on their results, intravenous infusions of UC-MSCs were found to be safe and well tolerated during the one-month follow-up period. Clinical studies have shown that MSCs have a good therapeutic effect, but some studies have reported that allogeneic AD-MSC infusions are ineffective at improving immune recovery or reducing immune activation and inflammation in patients with an immune response [ 44 ]. Our study found that a small number of patients still had adverse events greater than grade 3 at the one-month follow-up period after post-menstrual blood-derived MSC transplantation [ 181 ].…”

“…Mesenchymal stem cells (MSCs) have the capacity to self-renew and differentiate, and MSC-based therapies have received much attention in both basic medicine and clinical research [42][43][44][45]. MSCs can be acquired from most human tissues, including but not limited to, bone marrow (BM), adipose tissue (AD), umbilical cord (UC), Wharton's jelly (WJ), peripheral blood, menstrual blood, placenta, endometrium, amniotic membrane, amniotic fluid, fetal, dental pulp, urine, liver, lung, spleen, intestine, muscle, and synovium [46][47][48][49][50].…”

Multipotent Stromal Cells and Viral Interaction: Current Implications for Therapy

“…al showed that UC-MSC therapy can increase the number of circulating naive and central memory CD4 + T-cells and restore HIV-specific IFN-γ and IL-2 production, evidence of systemic immune reactivation post-treatment and did not lead to increased viral loads [ 88 ]. However, in a early phase clinical trial for NIR, MSC infusions were found to not effectly improve immune recovery or reduce immune overactivation [ 89 ]. Supplemental in vivo research is needed to elucidate the effects of MSCs in reactivation of HIV-1 in host microenvironment.…”

Extinguish the Fire: Anti-inflammatory Strategies for Over Immune Activation in Chronic HIV-1 Infection

“…In addition to the anti-inflammatory agents, many other therapeutic strategies envisioned to correct immune activation are currently being examined in different studies and more candidates will show up as long as the virus is not eradicated. For example, human mesenchymal stem cell therapy has been carried out in long-term treated immunological non-responders in some early phase studies, yet the efficacy thereof to reduce immune activation and improve immune reconstitution remains controversial due to the sizes of different studies and more individualized approach in such studies [40,41] . The obstacles that we have encountered in HIV-1 cure and functional cure had demonstrated our knowledge limitation of the immunopathogenesis of HIV-1 infection.…”