High Dose of Intravenous Allogeneic Umbilical Cord-Derived Mesenchymal Stem Cells (CLV-100) Infusion Displays Better Immunomodulatory Effect among Healthy Volunteers: A Phase 1 Clinical Study

Abstract

Background. Mesenchymal stem cells (MSCs) express growth factors and other cytokines that stimulate repair and control the immune response. MSCs are also immunoprivileged with low risk of rejection. Umbilical cord-derived MSCs (UCMSCs) are particularly attractive as an off-the-shelf allogeneic treatment in emergency medical conditions. We aim to determine the safety and efficacy of intravenous allogeneic infusion of UCMSCs (CLV-100) by Cytopeutics® (Selangor, Malaysia) in healthy volunteers, and to determine the effective dose at which an immunomodulatory effect is observed. Methodology. Umbilical cord samples were collected after delivery of full-term, healthy babies with written consent from both parents. All 3 generations (newborn, parents, and grandparents) were screened for genetic mutations, infections, cancers, and other inherited diseases. Samples were transferred to a certified Good Manufacturing Practice laboratory for processing. Subjects were infused with either low dose (LD, 65 million cells) or high dose (HD, 130 million cells) of CLV-100 and followed up for 6 months. We measured cytokines using ELISA including anti-inflammatory cytokines interleukin 1 receptor antagonist (IL-1RA), interleukin 10 (IL-10), pro-/anti-inflammatory cytokine interleukin 6 (IL-6), and the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Results. 11 healthy subjects (LD, n = 5 ; HD, n = 6 ; mean age of 55 ± 13 years) were recruited. All subjects tolerated the CLV-100 infusion well with no adverse reaction throughout the study especially in vital parameters and routine blood tests. At 6 months, the HD group had significantly higher levels of anti-inflammatory markers IL1-RA ( 705 ± 160 vs. 306 ± 36 pg / mL ; p = 0.02 ) and IL-10 ( 321 ± 27 vs. 251 ± 28 pg / m L; p = 0.02 ); and lower levels of proinflammatory marker TNF-α ( 74 ± 23 vs. 115 ± 15 pg / mL ; p = 0.04 ) compared to LD group. Conclusion. Allogeneic UCMSCs CLV-100 infusion is safe and well-tolerated in low and high doses. Anti-inflammatory effect is observed with a high-dose infusion.

Mesenchymal Stem Cell Transplantation for the Treatment of Age-Related Musculoskeletal Frailty

“…In a phase II clinical study, Tompkins et al [ 144 ] discovered that the therapeutic effects are limited to 100 million cells dosage as there are no significant therapeutic differences between 100 million and 200 million cells in the tested parameters. Another recent clinical trial concluded that administration of 130 million cells is more effective than the lower dosage of 65 million cells in producing immunomodulatory effects in healthy patients [ 146 ]. Therefore, it is postulated that a specific range of cell number is needed to exert the therapeutic effects and administration of excessive cells does not provide additional benefits.…”

Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System

“…Additionally, Chin et al continued to observe an increased level of anti-inflammatory cytokine IL-1RA in subjects from baseline up until 6 months post-MSC transfusion. However, note that the subjects were healthy and middle-aged which may contribute to the relatively long effectiveness of the treatment [ 176 ]. A possible solution to the limitation of MSC therapy is to find ways to sustain the survival of transplanted MSCs and increase the cell homing to the target sites to prolong the therapeutic effects.…”

“…Nevertheless, there are no significant therapeutic differences between 100 million and 200 million cells in the other tested parameters which brought to the question on why the therapeutic effects are limited to 100 million even though the dosage was doubled [ 138 ]. Another recent clinical trial concluded that administration of 130 million cells is more effective than the lower dosage of 65 million cells in producing immunomodulatory effects in healthy patients [ 176 ]. Therefore, it is postulated that a specific range of cell number is needed to exert the therapeutic effects and administration of excessive cells does not provide additional benefits.…”

Therapeutic Effects of Genetically Modified Wharton’s Jelly Mesenchymal Stem Cells Expressing Erythropoietin on Breast Cancer-related Anemia in Mice Model

“…hWJMSCs have led to promising outcomes in preclinical and clinical studies due to their limited heterogeneity, ease of their isolation and culture, availability in several tissues, and ability to self-regenerate [18]. Also, compared to adult and fetal stem cells, hWJMSCs show a higher proliferation rate and minimum stimulation of immune and in ammatory systems [19]. So, they have newly emerged as an appropriate therapeutic vehicle for gene therapy and drug delivery.…”