CAR T-Cell Therapy Shows Promise for Gut Repair & Aging | CSHL News

For many, the simple act of eating becomes less comfortable with age. A growing body of research suggests that a key factor isn’t necessarily *what* we eat, but how well our intestines can process it. Damage to the intestinal epithelium – the single-layer lining crucial for digestion and gut health – is a common consequence of aging, and can be exacerbated by cancer treatments like radiation. But a new approach, pioneered by scientists at Cold Spring Harbor Laboratory (CSHL), offers a potential pathway to rejuvenate aging guts and improve intestinal repair, leveraging the power of immunotherapy.

The intestinal epithelium typically renews itself every three to five days, a remarkable feat of cellular regeneration. However, this process can leisurely or even halt with age or after exposure to radiation, leading to inflammation and conditions like leaky gut syndrome. Researchers are now exploring whether CAR T-cell therapy, a type of immunotherapy already used to treat certain cancers, can effectively “jump-start” this repair process.

Targeting Senescent Cells: A New Approach to Gut Health

The work at CSHL builds on earlier investigations into cellular senescence, led by Assistant Professor Corina Amor Vegas. Senescent cells are those that have stopped dividing but haven’t died, accumulating with age and contributing to a range of age-related conditions, including diabetes and dementia. Amor Vegas’s team previously engineered CAR T-cells – chimeric antigen receptor T-cells – designed to selectively eliminate these lingering senescent cells in mice, resulting in improved metabolic health.

The current study, in collaboration with Assistant Professor Semir Beyaz and graduate student Onur Eskiocak, investigated whether removing senescent cells could restore the intestine’s ability to heal. They delivered CAR T-cells directly to the intestines of both young and old mice. The results, according to Amor Vegas, were significant. “In both cases, we see really significant improvements,” she stated. “They’re able to absorb nutrients better. They have much less inflammation. When irritated or injured, their epithelial lining is able to regenerate and heal much faster.”

Protecting Against Radiation-Induced Gut Damage

Radiation therapy, particularly for cancers affecting the pelvic or abdominal regions, often causes significant damage to the intestinal epithelium. This can lead to severe gastrointestinal side effects and long-term gut dysfunction. The CSHL team modeled this scenario by exposing mice to radiation. Mice treated with CAR T-cells demonstrated markedly improved recovery compared to those without the therapy. Importantly, a single dose of CAR T-cell treatment provided benefits lasting for at least a year.

This finding is particularly encouraging given the prevalence of radiation-induced gut damage in cancer patients. The researchers likewise observed that the anti-uPAR CAR T-cells promoted regeneration in human intestinal and colorectal cells in laboratory settings, suggesting the potential for translation to human therapies.

Understanding the Mechanism: uPAR and Cellular Senescence

The CAR T-cells used in the study target a surface marker called uPAR (urokinase plasminogen activator receptor), which is highly expressed on senescent cells. By eliminating these cells, the therapy appears to create space for healthy cells to proliferate and repair the damaged intestinal lining. While the precise biological mechanisms are still under investigation, the findings strongly suggest a therapeutic role for targeting senescent cells in gut health.

Further research, published in Nature, highlights the role of mRNA N4-acetylcytidine (ac4C) modification and the enzyme N-acetyltransferase 10 (NAT10) in regulating colon epithelial cell senescence. Knocking down NAT10 alleviated senescence in both cell cultures and aged mice, suggesting a potential target for rejuvenating the intestinal lining. This research also identified a link between NAT10 and the DYRK1A protein, which appears to drive colon epithelial senescence when stabilized by NAT10. Elevated levels of both NAT10 and DYRK1A were found in tissues from elderly patients with ulcerative colitis, correlating with disease severity.

What This Means for Aging and Cancer Patients

The implications of this research are far-reaching. For aging individuals experiencing digestive issues, this approach could offer a way to restore gut function and improve nutrient absorption. For cancer patients undergoing radiation therapy, it could mitigate the debilitating side effects of gut damage and accelerate recovery. However, it’s crucial to emphasize that this research is still in its early stages. The studies have primarily been conducted in mice, and further research is needed to determine the safety and efficacy of CAR T-cell therapy in humans.

The researchers acknowledge that more work is needed to fully understand the long-term effects of CAR T-cell therapy on the gut microbiome and immune system. The potential for off-target effects – where the CAR T-cells attack healthy cells – also needs to be carefully evaluated.

Next Steps: From Lab to Clinic

The CSHL team is currently focused on preparing for potential clinical trials to assess the safety and efficacy of this approach in humans. Beyaz emphasizes that this is “one good step toward a long journey in understanding how You can better heal the elderly.” The researchers are also exploring ways to optimize the CAR T-cell therapy, such as improving targeting specificity and reducing the risk of off-target effects. Further investigation into the role of NAT10 and DYRK1A in intestinal aging could also lead to the development of new therapeutic strategies. The team plans to continue monitoring the mice treated with CAR T-cells to assess the durability of the treatment effects and identify any potential long-term complications.