Summary

Currently, most MSC-based treatments aim to alleviate the adverse effects of traditional cancer therapies and directly target cancer cells. While many clinical trials are in early phases, preliminary results underscore the potential of MSCs in cancer treatment. Further research and translational studies are warranted to fully understand and harness their therapeutic potential.

Mesenchymal stem cells (MSCs) are multipotent cells capable of self-renewal, commonly found in bone marrow, umbilical cord, adipose tissue, and peripheral blood. Due to their regenerative potential, immune modulation capabilities, and ability to home to inflamed or injured tissues, MSCs hold promise for therapeutic applications in humans.

By searching the Clinical Trials data, there are 1,626 stem cell–related clinical trials registered on http://www.clinicaltrials.gov, using the search term “Mesenchymal stem cells”. While many focused on cardiovascular diseases, autoimmune diseases, orthopedic conditions, and various other ailments, a subset examined MSCs as a therapeutic option for cancer treatment.

However, the number of clinical trials investigating MSC-based therapies for cancer remains limited (refer to Table 1). Preliminary findings suggest that most trials are in the early phases (Phase 1 or 2), predominantly employing bone marrow-derived MSCs, with some utilising adipose tissue-derived or cord blood-derived MSCs. Some studies did not specify the MSC source. Allogeneic MSCs are more commonly used than autologous ones.

Table 1: Selected MSCs-based clinical trials for cancer therapy.

MSCs serve two primary purposes in cancer therapy: first, to mitigate adverse effects of standard cancer treatments, and second, to directly target cancer cells. While many studies focus on native MSC infusion or transplantation, the potential pro-tumour effects of unmodified MSCs raise concerns about their efficacy. Consequently, some trials explore engineered MSCs to enhance homing capabilities and serve as carriers for therapeutic agents like cytokines or oncolytic viruses, delivering anti-tumour agents directly to cancer cells.

MSCs Alleviating Treatment-Induced Conditions

A plethora of MSC-based therapies aim to mitigate the adverse effects linked with conventional anticancer treatments. These include anthracycline-induced cardiomyopathy, radiation-induced hyposalivation and xerostomia, radical prostatectomy-induced erectile dysfunction, and chemotherapy-induced myelosuppression. Moreover, MSCs are under investigation for the treatment of Graft-versus-Host Disease (GvHD) after hematopoietic stem cell transplantation (HSCT) for hematologic malignancies.

Genetically Engineered MSCs and Oncolytic Virus

Certain studies delve into the utilisation of MSCs as carriers of therapeutic agents for direct cancer cell eradication. These therapeutic approaches encompass MSCs expressing INF-β (NCT02530047), MSCs secreting TRAIL (NCT03298763), and MSCs carrying a suicide gene, cytosine deaminase (NCT04657315). In a clinical trial (NCT05113342) conducted by Cartesian Therapeutics, they evaluated Descartes-25, a groundbreaking allogeneic RNA cell therapy, for multiple myeloma. Descartes-25 is engineered to deliver two complementary antitumour proteins directly to the tumour: a novel three-arm bispecific antibody that binds B-cell Maturation Antigen (BCMA) with femtomolar avidity and the potent antitumour cytokine interleukin-12 (IL-12). Descartes-25 cells are further engineered with a membrane-bound homing protein that directs MSCs to the tumour microenvironment for local delivery of their antitumour cargo. This represents a targeted combination therapy utilising MSCs therapy and RNA therapy to target the cancer cells.

NCT01844661 marks the initiation of the first-in-man, first-in-child trial using Celyvir, an autologous MSC carrying an oncolytic adenovirus to treat metastatic solid tumours or refractory tumours in children and adults. This is also one of the few clinical trials with published data. In this phase I/Ib study, bone marrow-derived MSCs infected with ICOVIR5, an oncolytic adenovirus, were well tolerated in patients with relapsed/refractory pediatric solid tumours. Additionally, two out of nine patients with neuroblastoma who received the treatment showed disease stabilisation, with one continuing treatment for up to 6 additional weeks. The authors concluded that multiple doses of CELYVIR showed good safety and warrant further evaluation in the phase 2 setting.

Other groups also explore the potential of combining MSCs with oncolytic viruses for glioblastoma (ClinicalTrials.gov: NCT03896568; M.D. Anderson Cancer Center). This represents a phase 1 trial utilising allogeneic bone marrow-derived MSCs loaded with oncolytic adenovirus DNX-2401 administered via intra-arterial injection in patients with recurrent glioblastoma. Another endeavour is a phase I/II trial employing adipose tissue-derived MSCs infected with oncolytic measles virus encoding thyroidal sodium iodide symporter (MV-NIS) to treat patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer (ClinicalTrials.gov: NCT02068794; Mayo Clinic). 

MSCs Combined with Chemo-or Radio-Therapies

Furthermore, combining MSC-based anticancer therapies with traditional chemo- or radio-therapies presents an attractive option that could potentially enhance the efficacy of current strategies. One such clinical trial combines radiotherapy with bone marrow-derived MSCs infected with oncolytic virus, ICOVIR-5 (NCT04758533). Another study (NCT03298763) combines chemotherapy with MSC expressing TRAIL to evaluate its anti-tumour activity in metastatic Non-small cell lung cancer (NSCLC) patients in a Phase I/II clinical trial.

MSCs-derived exosome

The exploration of MSC-derived exosomes stands at the forefront of current research in cell-free therapies. For cancer treatment, an active Phase I clinical trial aims to evaluate the therapeutic efficacy of iExosomes in pancreatic cancer featuring the KrasG12D mutation. iExosomes, isolated from MSCs are loaded with siRNA targeting KrasG12D, thus selectively inhibiting its activity within patients. The MSC-derived exosome platform holds significant promise for enhancing the anticancer effects of conventional therapies.