Summary

Stem cells have become pivotal players in the evolving landscape of gene and cell therapy for cancer treatment, holding immense potential to address the intricacies of this disease. Various stem cells, including hematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs), and mesenchymal stromal/stem cells (MSCs) have been used in cell therapy with promising results. These versatile cells can be harnessed to deliver therapeutic genes, offering a targeted and precise approach to combat tumours. Moreover, stem cells exhibit unique properties, including the ability to modulate the immune system, making them valuable assets in enhancing the body’s natural defences against cancer.

Among various stem cell types, MSCs stand out as particularly promising candidates. Engineerable and capable of homing to tumour sites, MSCs offer a dual advantage by delivering therapeutic payloads and fostering an immune response against cancer cells. The integration of MSCs into gene and cell therapy strategies holds the potential to reshape cancer treatment paradigms, offering novel and personalised solutions for patients.

Get an update on the upcoming trends and advances in using MSCs for cancer therapy through this series of Stem Cell Express.

1. Harnessing the Potential of iPSCs-Derived MSCs

MSCs utilised in current clinical trials are primarily sourced from adipose tissues, umbilical cords, or bone marrows through invasive procedures. The constrained expansion capability of MSCs necessitates repetitive isolation procedures to meet the demands of cell therapy, coupled with the high costs associated with in vitro expansion, limiting their clinical accessibility and widespread adoption. Traditional methods, marked by limited proliferative potential and donor-to-donor variability, result in inconsistent clinical trial outcomes.

The identification of an appropriate donor source or exploration of alternative methodologies for MSC production is crucial to address the existing bottleneck hindering large-scale MSC production.

iPSCs represent a revolutionary advancement in regenerative medicine, offering the potential to generate various cell types for therapeutic purposes. iPSCs possess high self-renewal capacity, proliferation, and differentiation abilities to mesoderm, endoderm, and ectoderm, bypassing ethical concerns associated with embryonic stem cells (ESCs). Among the various cell lineages that iPSCs can generate, MSCs emerge as a particularly valuable cell population.

The advantage of using iPSC-derived MSCs lies in overcoming limitations associated with harvesting MSCs from adult tissues, including invasive procedures and limited cell yield. iPSC-derived MSCs can be generated in large quantities, providing a consistent and expandable cell source. Furthermore, these cells can potentially address issues related to donor variability and age-related changes, delivering a more standardised and reliable cellular product. The pluripotent origin of iPSCs enhances their scalability and reproducibility for therapeutic applications. Notably, iPSC-derived MSCs closely resemble tissue-derived MSCs in morphology, immunophenotype, and three-lineage differentiation capacity, while exhibiting stronger regeneration ability in animal disease models.

In 2017, Cynata Therapeutics conducted the world’s first formal phase 1 trial (no. NCT02923375) of an allogeneic iPSC-derived cell product (CYP-001) in adults with steroid-resistant (SR) acute graft-versus-host disease (aGVHD). The trial demonstrates that, within a limited number of subjects with SR-aGVHD, CYP-001 is safe and tolerable. Although further trials with larger sample sizes are necessary to confirm efficacy, the aGvHD response observed is encouraging, paving the way for utilising iPSC-derived MSCs in the treatment of various diseases. In summary, the promising results of the trial indicate that iPSC-derived MSCs not only demonstrate safety and tolerability in treating steroid-resistant acute graft-versus-host disease (SR-aGVHD) but also open new horizons for their application in cancer therapy. With their potential for large-scale production of stable and sustainable ‘off-the-shelf’ products, iPSC-derived MSCs stand as a versatile and encouraging resource for addressing the complex challenges in both immunological disorders and cancer treatment.

2. MSC-EVs: Pioneering Cell-Free Therapy with Promise for Cancer Treatment

In recent years, extracellular vesicles (EVs) derived from MSCs have emerged as a promising platform for drug delivery, capitalising on their inherent biocompatibility and targeted delivery capabilities, setting them apart from artificial nanocarriers like liposomes. It is suggested that many of the paracrine functions of MSCs, including the release of growth factors, cytokines, chemokines, and EVs, contribute to their therapeutic effects.

EVs can be categorised based on size—exosomes (30–150 nm), microvesicles (150–500 nm), and apoptotic bodies (800–500 nm). MSC-derived EVs mirror the biological potential of MSCs, offering a safer alternative to MSC cell therapy, which may be susceptible to genetic or phenotypic changes and aggregation in the lung microvasculature.

MSC-EVs, for these reasons, present an intriguing option for achieving cell-free therapy, particularly notable for their potential in cancer treatment. Beyond their intrinsic and target-specific homing capabilities, MSC-EVs safeguard biological cargo, including miRNAs and mRNAs, from degradation in vivo. Additionally, MSC-EVs exhibit lower immunogenicity compared to MSCs and can be genetically modified to enhance tissue targeting efficiency, serving as effective carriers for anti-cancer drugs and biologics, thereby overcoming drug resistance in cancer therapy.

Clinical trials exploring MSC-EVs span diverse indications such as COVID-19, diabetes, Alzheimer’s disease, and notably, cancer therapy. A phase I trial (NCT03608631) targeting the KRAS G12D mutation in pancreatic cancer is currently underway. KRAS G12D, a common mutation in pancreatic cancer, is the focus of therapies aiming to address this mutation specifically. Researchers are evaluating the safety and suitable dosage of MSC-EVs carrying KrasG12D siRNA in patients with metastatic pancreatic cancer.

While MSC-EVs show promise as a novel cell-free therapeutic tool for clinical cancer treatment, challenges persist. Standardised protocols for the isolation and characterisation of heterogeneous MSC-EVs are imperative. Safety and efficacy concerns arise due to documented tumour-promoting properties, internalisation by other cells, and clearance by macrophages. The low yield of natural MSC-EVs and their limited efficacy in drug delivery underscores the need for further preclinical and clinical studies to propel MSC-EVs therapy into widespread clinical applications.

3. CRISPR/Cas9-Mediated Gene Editing Enhances the Therapeutic Potential of MSCs

Although MSCs have garnered widespread attention for their inherent advantages and beneficial properties, the application of MSCs in their intact form presents certain limitations. MSCs may not efficiently navigate to specific target tissues or tumours, restricting their ability to deliver therapeutic agents precisely to the site of action. Additionally, these cells may exhibit a limited duration of persistence in the body after administration, necessitating repeated doses for sustained therapeutic effects. Concerns also arise about the potential for MSCs, when administered intact, to differentiate into unintended cell types or display unpredictable behaviour in vivo, emphasising the need for precise control over their actions.

To overcome these challenges, various methods are recommended to enhance MSC efficiency through genetic modification. Several techniques, including viral vectors (lentiviral vectors/adenoviral vectors), plasmid transfection, electroporation, transposon, nanoparticle-mediated delivery, and the revolutionary CRISPR/Cas9 technology, are employed for this purpose.

Among these methodologies, CRISPR/Cas9 stands out as a highly effective gene-editing tool widely embraced in the scientific community. Its first clinical application approval in the U.K. for treating sickle-cell disease and transfusion-dependent beta-thalassemia (TDT) has paved the way for addressing a spectrum of diseases. In cancer treatment, CRISPR/Cas9 is gaining prominence for genetically engineering immune cells, particularly T-cells, to bolster their effectiveness in combating tumours.

One of the distinctive features of CRISPR/Cas9 is its ability to simultaneously target multiple gene sequences, making it a more cost-effective option compared to other gene-editing technologies. The applications of CRISPR/Cas9-edited MSCs are diverse, including preserving MSC stemness, reducing MSC senescence and apoptosis, and enhancing MSC survival and immunomodulatory properties. Each of these modifications is strategically aimed at elevating the therapeutic efficiency of MSCs. The results of CRISPR/Cas9 engineering on MSCs studies are summarised in Figure 3, highlighting the transformative potential of this gene-editing tool in advancing the therapeutic capabilities of MSCs.

References

Abdal Dayem A, Lee SB, Kim K, Lim KM, Jeon TI, Seok J, Cho AS. Production of Mesenchymal Stem Cells Through Stem Cell Reprogramming. Int J Mol Sci. 2019 Apr 18;20(8):1922. doi: 10.3390/ijms20081922. PMID: 31003536; PMCID: PMC6514654.

Bloor AJC, Patel A, Griffin JE, et al. Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study. Nat Med. 2020;26(11):1720-1725. doi:10.1038/s41591-020-1050-x

Dalmizrak A, Dalmizrak O. Mesenchymal stem cell-derived exosomes as new tools for delivery of miRNAs in the treatment of cancer. Front Bioeng Biotechnol. 2022;10:956563. Published 2022 Sep 26. doi:10.3389/fbioe.2022.956563

Golchin A, Shams F, Karami F. Advancing Mesenchymal Stem Cell Therapy with CRISPR/Cas9 for Clinical Trial Studies. Adv Exp Med Biol. 2020;1247:89-100. doi:10.1007/5584_2019_459

Hazrati A, Malekpour K, Soudi S, Hashemi SM. CRISPR/Cas9-engineered mesenchymal stromal/stem cells and their extracellular vesicles: A new approach to overcoming cell therapy limitations. Biomed Pharmacother. 2022;156:113943. doi:10.1016/j.biopha.2022.113943

Lotfy A, AboQuella NM, Wang H. Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials. Stem Cell Res Ther. 2023;14(1):66. Published 2023 Apr 7. doi:10.1186/s13287-023-03287-7

Phelps J, Sanati-Nezhad A, Ungrin M, Duncan NA, Sen A. Bioprocessing of Mesenchymal Stem Cells and Their Derivatives: Toward Cell-Free Therapeutics. Stem Cells Int. 2018;2018:9415367. Published 2018 Sep 12. doi:10.1155/2018/9415367

Sanmartin MC, Borzone FR, Giorello MB, Yannarelli G, Chasseing NA. Mesenchymal Stromal Cell-Derived Extracellular Vesicles as Biological Carriers for Drug Delivery in Cancer Therapy. Front Bioeng Biotechnol. 2022;10:882545. Published 2022 Apr 14. doi:10.3389/fbioe.2022.882545

Shan C, Liang Y, Wang K, Li P. Mesenchymal Stem Cell-Derived Extracellular Vesicles in Cancer Therapy Resistance: from Biology to Clinical Opportunity. Int J Biol Sci. 2024;20(1):347-366. Published 2024 Jan 1. doi:10.7150/ijbs.88500

Zhang J, Chen M, Liao J, et al. Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Hold Lower Heterogeneity and Great Promise in Biological Research and Clinical Applications. Front Cell Dev Biol. 2021;9:716907. Published 2021 Sep 30. doi:10.3389/fcell.2021.716907