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, ; HD, ; mean age of 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 ( vs. ; ) and IL-10 ( vs. L; ); and lower levels of proinflammatory marker TNF-α ( vs. ; ) 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 cells (MSCs) are multipotent fibroblast-like cells that reside in various tissues of the human body. MSCs have the capacity to regenerate and replicate as well as to differentiate into various specialized cells and tissues in the body, including chondrocytes, adipocytes, osteocytes, and neuron-like cells [1–3]. The self-renewal and multilineage potentials of MSCs in providing new cells for tissue repair by replacing the damaged cells suggest its therapeutic potentials in tissue regeneration [2, 4–8].
Several studies have reported that the mechanism of MSCs in repairing tissue damage is associated to their immunomodulatory properties rather than its capacity for differentiation [9, 10]. One of MSCs’ vital biological function, the immunomodulation, provides MSCs with the ability to migrate and adhere to any injury or inflammation sites found in the body and thereby interact with various immune cells such as T cells, B cells, natural killer cells, dendritic cells, neutrophils, and macrophages before evoking effective immune responses to ameliorate the intense inflammatory reaction of the injured site via direct cell-cell contact mechanism and/or the release of soluble inducible factors [11–13].
MSCs can be isolated from various tissues including bone marrow, peripheral blood, adipose tissue, cord blood, and umbilical cord. Recent studies have shown that MSCs derived from human umbilical cord (UCMSCs) possess several advantages compared to MSCs isolated from other tissues, including high-proliferation and self-renewal capacity and multilineage differentiation capability. Umbilical cord is considered as a medical waste, and the collection of UC-MSCs is noninvasive which eliminates any ethical concern from its collection. [14, 15]. In addition, UCMSCs possess low immunogenicity allowing them to be utilized in allogeneic transplantation without any rejection and thereby providing a new approach for the treatment of autoimmune diseases .
Consequently, UCMSCs have been developed as an “off-the-shelf” cell therapy for a variety of diseases especially in autoimmune diseases. Clinical studies in graft-versus-host disease (aGVHD) have demonstrated that UCMSCs dramatically improved the patients’ conditions with no adverse effects and no evidence of cancer recurrence throughout the trial period ([17, 18]). Moreover, UCMSCs treatment in active systemic lupus erythematosus (SLE) resulted in amelioration of the disease activity, serologic changes, and stabilization of proinflammatory cytokines in the patients .
The production of UCMSCs cells products from manufacturing methods must be tested for its safety prior to be used as therapeutic agents in cell therapy (). Therefore, this Phase 1 clinical study was conducted to establish a new UCMSCs cell line (CLV-100) by assessing the safety and efficacy of intravenous allogeneic infusion of our manufactured UCMSCs (CLV-100) among healthy volunteers. This study also sought to compare the immunomodulatory effect of different dosage of CLV-100 between high-dose and low-dose infusion in healthy volunteers based on several clinical assessments and measurements of changes in systemic biomarkers. The findings of this study will act as a guideline and benchmark for future CLV-100 clinical research.
2. Materials and Methods
2.1. Study Design
This is an open-label nonrandomized Phase 1 study assessing the safety and efficacy of CLV-100 infusion among 11 healthy subjects recruited at NSCMH Medical Centre in Seremban, Malaysia. The subjects were divided into 2 groups; low-dose group received 65 million cells (equivalent to about 1 million cells per kg body weight) (LD, ), while high dose group received 130 million cells (equivalent to about 2 million cells per kg body weight) (HD, ) of allogeneic infusion of CLV-100. This study was approved by the Medical Research and Ethics Committee (MREC) Ministry of Health Malaysia (NMRR-13-1152-17400) and monitored by independent Data Safety and Monitoring Board (DSMB). All subjects provided written informed consent before participating in the study. The inclusion and exclusion criteria were listed in Table 1.
Key inclusion criteria
(i) Men and women aged 40 years and older
(ii) Subjects with normoglycemia
(iii) Subjects with normotension
(iv) Subjects with normal fasting lipid profile
(v) Subject must understand patient information sheet and signed informed consent form
Key exclusion criteria
(i) Subject who has enrolled in another investigational drug trial or innovative therapeutics product-related trial or has completed the aforesaid within 3 months
(ii) Subject with history of current or past use (within 1 year) of alcohol, smoking, or drug abuse
(iii) Pregnant or nursing women
(iv) Subject with known documented drug allergies
(v) Subject who is required of the following medicines on a regular basis: anti-histamine, steroid, antibiotic, anti-inflammatory, immunosuppressant, and pain killer medications
(vi) Subject who is currently on any hormone replacement or hormone suppressive therapy for any indication
(vii) Subject with any acute or chronic infections or communicable diseases including hepatitis B, hepatitis C, or HIV
(viii) Subject with any active or past history of neoplasia and primary hematological disease
(ix) Subject with any renal impairment indicated by serum creatinine ≥120 μmol or creatinine clearance <60 mL/min
(x) Subject with any cardiovascular disease including documented coronary disease of more than 50% stenosis, angina, myocardial infarction, heart failure, stroke, transient ischemic attack, and/or peripheral artery disease
(xi) Subject with any diabetes mellitus
(xii) Subject with any liver impairment indicated by serum aspartate transaminase and alanine transaminase greater than 1.5 times upper limit normal
(xiii) Subject with any chronic pulmonary or airways disease
(xiv) Subject with any current or past history of mental illness or cognitive impairment.