Tuong Thi Van Thuy1*, Dao Van Toan2 and Nguyen Duc Phuc3
Received: July 17, 2023; Published: August 01, 2023
*Corresponding author: Tuong Thi Van Thuy, Tuong Thi Van Thuy, Stem Cell Center, Phu San Ha Noi Hospital, Ha Noi, Vietnam
Mesenchymal stem cells (MSCs) were discovered in the 1970s with their unique properties of differentiation, immunomodulation, multiple secreting, and homing factors to injured organs. MSC-based therapies have emerged as a promising strategy for various diseases such as cancer, tissue regeneration, or immunologic/ inflammatory-related diseases. This study evaluated the clinical application of MSCs for cancer therapy in trials registered on ClinicalTrial.gov as of July 2022. The results showed 40 clinical trials used MSCs in various cancer conditions. 62% of trials used MSCs for therapeutic purposes to minimize the side effects of cancer treatment. Besides, 38% of trials were focused on using MSCs as a therapeutic agent to directly treat cancer. Most trials (38/40) are ongoing phase I/II, and 2 are entering phase III. 84% of trials used allogeneic MSCs compared with 13% using autologous sources, and 3% using both. 25/40 trials showed participants received a single dose of MSCs, while the most times were 12 times in a pancreatic cancer treatment trial. Conclusion: MSC-based therapy for cancer in clinical trials should be applied to  minimize the side effects of oncological treatments and  directly affect the tumor via selectively delivering anti-cancer payloads to tumor cells. Allogeneic MSCs are a priority selected in clinical cancer therapy.
Keywords: Mesenchymal Stem Cells; MSC-Based Therapy; Cancer Condition; Cancer Treatment; Clinical Trials
Mesenchymal stem cells (MSCs) were discovered quite early in the 1970s (Friedenstein, Chailakhjan ). But many years later, the characteristics, differentiation, and potential of mesenchymal stem cells and clinical applications are focused on research and evaluation (Horwitz, et al. ). Due to their unique properties of differentiation, immune-regulatory ability, secretion of many growth factors, and inhibition and migration to damaged tissues, MSCs are currently one of the most widely studied topics in experimental medicine (Stefańska, et al. ). Similar to damaged tissue, tumor tissue also secretes chemotactic substances that attract MSCs to migrate to the tumor site. When infiltrating the tumor, MSCs interact with tumor cells and the surrounding healthy tissue environment to directly and indirectly affect tumor formation and growth directly and indirectly (Aravindhan, et al. [2,6]). Moreover, the collection of MSCs can be done easily, with minimally invasive procedures, and rapid mass expansion through laboratory culture. Thus, it is interesting about the use of MSCs therapy is maximized for precise and personalized medicine. Thanks to the evidence for the efficacy of MSCs cell therapy in cancer treatment in the laboratory (in vitro) (Akimoto, et al. [1,7-8]) and experimental animal models (in vivo) (Scioli, et al. ); there have been numerous registered clinical trials, which are being performed in the field of oncology over the current decades. Therefore, we conducted a meta- analysis of clinical trials using MSCs in the treatment of various cancer conditions, registered on ClinicalTrials.gov with the goal of:
1. Determining the purpose of using MSCs therapy in the clinical
2. Evaluating relevant factors of MSCs therapy such as characteristics of MSCs, and usage of MSCs in the clinical trials.
Clinical trials that were registered on ClinicalTrials.gov were reported to use MSCs in the treatment of cancer in various conditions. This is a database of clinical studies performed worldwide. The US National Library of Medicine provides this resource.
Meta-analytical study. The defined search term is “cancer” in the Condition or Disease section and “mesenchymal stem cell” in the other terms as a therapeutic drug name. All clinical studies found that met the criteria for using MSCs in the treatment of cancer with various conditions as of July 2022 were included. Study data included clinical trial name, clinical trial number, country, the purpose of treatment, type of cancer, type of autologous/allogeneic MSCs, source of MSCs tissue, route of administration, therapeutic agent, the number of infusions, phase of the clinical trial, and sample size.
Initial search results with defined terms showed 64 studies registered on ClinicalTrials.gov up to July 2022. But only 40 studies were identified to use MSCs in various cancer conditions. Details of the clinical trials are shown in (Supplementary Table 1). There are 38 clinical trials in phase I and phase II, and only 2 trials in phase III (Figure 1). The characteristics of MSCs in clinical trials are shown in (Table 1 & Figure 2). There is a variety of MSC sources, including bone marrow (11/40), adipose tissue (5/40), umbilical cord tissue (4/40), and cord blood (4/40). In addition, there was one registered trial that used cord tissue-derived MSCs for allogeneic transplantation and bone marrow-derived MSCs for autologous transplantation. However, in 16/40 trials, the authors did not disclose what type of MSCs used for therapy (Figure 2A). 84% of trials used allogeneic MSCs compared with 13% using autologous mesenchymal stem cell sources, and 3% using both sources (Figure 2B). For the MSCs-based therapeutic purpose of reducing the side effects of cancer treatments, a single dose was applied more 28 times than multiple doses (95% CI 2.8- 283.0) (Table 1).
The purpose of MSCs-Based Cancer Therapy in a Clinical Trial
The results showed that out of 40 trials, 25 evaluated the potential of MSCs to ameliorate the adverse events that occurred in conventional anticancer therapies, such as hemorrhagic cystitis due to radiation therapy (NCT02814864), xerostomia following radiotherapy (NCT03874572), anthracyclines-induced cardiomyopathy (NCT02509156), cisplatin-induced acute renal failure (NCT01275612), radiation-induced xerostomia (NCT03874572), erectile dysfunction after treatment for prostate cancer (NCT01089387) or radiation-induced hemorrhagic cystitis (NCT02814864). In addition, 15 studies mentioned the possibility of using MSCs as “carriers” of therapeutic agents that directly act on killing cancer cells. The antineoplastic agents for transferring into MSCs may be the cytokines INFβ (NCT0253047), TNF-related apoptosis ligand (MSCTRAIL) (NCT03298763), or the oncolytic adenovirus ICOVIR5 (CELYVIR) (NCT05047276). Notably, in the NCT01844661 trial using CELYVIR to treat metastatic solid tumors or refractory tumors in children and adults, initial results have been published. Two adult patients with neuroblastoma showed a stable condition, and one of the patients continued treatment for another 6 weeks. The authors concluded that multiple doses of CELYVIR had good safety and beneficial anti-tumor effects (Ruano, et al. ). Interestingly, the authors noted that the disease condition in one pediatric patient after 3 years of treatment with CELYVIR was completely improved (García-Castro, et al. ). Thus, two clear goals of MSCS therapy in cancer treatment have been identified. There are to reduce the side effects of traditional cancer treatments and to directly affect the tumor cell through its ability of anti-cancer payloads to tumor cells.
The Characteristics of Clinical Trials Using MSCs-Based Therapy on Cancer
Most of these trials (38/40) are phase I and phase II, which are in the process of evaluating mainly the safety, appropriate dose, and initial effectiveness of MSC application on cancerous patients. In parallel, there were 2 trials (NCT03106662, NCT00851162) in phase III registered on ClinicalTrials.gov to help evaluate the clinical effectiveness of this new method on a broader scale. The predominant use of allogeneic MSCs in clinical trials compared with autologous MSCs. Furthermore, there was no association between the goals of MSCs therapy in cancer treatment and the autologous or allogenic transplantation of MSCs. This demonstrates the acceptance of scientists and clinicians about the ability to safely tolerate allogeneic MSCs as well as the convenience and ease of providing stem cell sources for this therapeutic activity. Diversification of MSCs sources, especially MSCs from tissue sources that are considered waste medical products such as adipose tissue, umbilical cord blood, and the umbilical cord is considered a new trend in modern medicine when banks of common stem cell banks are increasingly expanding the scope of sample source (Harris ). Regarding how to use MSCs, all trials mentioned the used dose, how many times infusions were, and the route to insert MSCs into the patients. The lowest dose of MSCs was 5 x 105 cells/ kg (NCT02530047, NCT04758533) and the highest dose was 8 x 108 cells/kg (NCT03106662). 25/40 trials included a single dose of MSCs transplantation, while the most times of stem cell infusions were 12 times in a pancreatic cancer trial (NCT04087889). The authors tend to use low and repeated doses (doses below 106 cells/kg), and doses were repeated weekly. Besides, the authors often use high doses as a single dose. Interestingly, it can be observed that, with clinical trials using MSCs therapy for direct tumor treatment, MSCs are more likely to be selected for transplantation in more than 1 dose.
Meanwhile, for the purpose of preventing complications, MSCs therapy is usually applied in a single dose more than multi doses (OR=28, 95% CI: 2.8 – 293.0). Next, the route used to bring MSCs into the body includes 2 groups. The first administration route includes the ways to insert MSCs into the body through the vascular route; the most common was still the intravenous route. In addition, the intra- arterial route was also mentioned (NCT03896568). The second group is to deliver MSCs directly to the target tissue site such as direct injection into the tumor (NCT02079324, NCT04657315) or seeding MSCs into biological materials (scaffold) and then grafting into the patient’s body at the tumor site where the tumor has been removed. On the other hand, depending on the cause, some other routes were also mentioned, such as intraperitoneal injection for ovarian cancer (NCT02530047). Although initial results are still in the follow-up phase, the potential of MSCs in cancer treatment has been recognized. The next challenge for scientists and clinicians is to explore the interactions between MSCs and cancer cells to eliminate or control cancer cells. Clinical trials need to be carried out at later phases so that application and effect would be evaluated comprehensively on an enormous area. It hopes that many publications on MSC-based therapy in the field of cancer treatment will be reported soon. Besides patients with cancer will approach an effective and safe therapeutic product that improves survival and quality of patient life.
The use of MSCs in cancer treatment is being tested as a combination treatment for 2 purposes: 1) participating in attenuating the systemic effects of traditional cancer treatments in patients, and 2) participating as a therapeutic agent to directly attack cancerous cells via its ability of anti-cancer payloads to the tumor location. in the synergistic enhancement of tumor-killing efficiency in cancer patients and undergoing and finishing cancer therapies. The trend of using allogeneic MSCs is dominant; this brings up the MSCs- provided convenience for treatment as well as the initially recognized safety of this type of stem cells.
This work is supported by the Vietnam Association of Japan Alumni (VAJA) and Toshiba International Foundation (TIFO).