He earned his MSc and PhD degrees from the Faculty of Medicine at the University of Toronto and has extensive writing experience in the pharmaceutical industry.
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Autoimmune diseases affect millions of people worldwide. Current treatment options often involve broad-spectrum immunosuppression, which effectively reduces inflammation but can cause undesirable side effects like increased susceptibility to infections.
In a recent study, immunologist Saad Kenderian and his team at the Mayo Clinic reported a more targeted approach by developing chimeric antigen receptor-engineered mesenchymal stromal cells (CAR-MSC) (1). This approach repurposes CAR technology in MSC and shows promise as a future therapeutic for autoimmune diseases.
MSC are a subject of growing interest in autoimmune disease management. These versatile cells, residing in various tissues including bone marrow, fat, and umbilical cord blood, can differentiate into specialized cells such as bone cells, cartilage cells, and fat cells. Additionally, MSC possess immunomodulatory properties: They dampen inflammation and promote immune tolerance, a state where the immune system coexists with self-antigens (2).
“MSC have immune suppressive properties. ... What we've learned from the clinical trials of MSC therapy is that it’s safe,” said Kenderian. “So early on, we thought that we can use what we've learned from CAR technology and engineer CAR-MSC to make them better and more effective in what they're supposed to do.”
Despite these promising characteristics, the therapeutic efficacy of MSC in autoimmune contexts has remained limited. This is partly due to their inability to effectively target specific sites of inflammation and their struggle to stay active in the face of the aggressive immune response characteristic of autoimmune conditions.
“By using CAR technology, we're able to improve MSC and make them more immune suppressive and more effective in suppressing immune-mediated diseases,” said Kenderian. “There were several hurdles that we had to overcome. How do you engineer the MSC so that they still are stem cells, and what signal is going to drive the function that we want?”
By using CAR technology, we're able to improve MSC and make them more immune suppressive and more effective in suppressing immune-mediated diseases.
- Saad Kenderian, Mayo Clinic
CAR are engineered receptors designed to recognize specific antigens on cells. Kenderian and his team harnessed this technology to engineer MSC to express CAR specific for E-cadherin (EcCAR-MSC), a marker associated with autoimmune diseases. These EcCAR-MSC combine the immunosuppressive properties of MSC with the targeting ability of CAR, potentially creating a robust and targeted therapeutic tool.
To evaluate the efficacy of the engineered EcCAR-MSC, the researchers used a mouse model of graft-versus-host disease (GvHD). This serious autoimmune complication, where the transplanted donor immune cells attack the recipient's body, can occur during stem cell therapy. They observed that EcCAR-MSC administration in GvHD mice improved survival, reduced GvHD clinical symptom scores, and increased T cell suppression compared to GvHD mice that received unmodified MSC only. Further analysis of gene expression on EcCAR-MSC demonstrated an upregulation of T cell-inhibitory receptors, anti-inflammatory cytokines, and activation of immunosuppressive gene pathways. The group showed that the EcCAR-MSC administration also displayed more efficient trafficking to target tissues. This nonclinical data suggested that EcCAR-MSC promoted overall immune tolerance in GvHD — one of the significant limitations of traditional MSC therapy.
Mohamad Mohty, an immunologist at Saint-Antoine Hospital who was not part of this study, commented, “This paper proved very attractive because MSC are a very heterogeneous, not well-defined cell population. By engineering it using CAR and the E-cadherin target, maybe we have an insight into immunotherapy. Here, we have a perfect start because the construction of the CAR-MSC and technology is robust.”
Kenderian added, “[The CAR-MSC technology] is opening up collaboration with tissue engineers and companies interested in some form of this approach with other cell engineering strategies. It opens up the field of engineering MSC.”
References
- Sirpilla, O. et al. Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression. Nat Biomed Eng 8, 443–460 (2024).
- Song, N., Scholtemeijer, M. & Shah, K. Mesenchymal Stem Cell Immunomodulation: Mechanisms and Therapeutic potential.Trends Pharmacol Sci 41, 653–664 (2020).
