New CAR-NKT cell therapy targets endometrial cancer on two fronts
Approach showed strong anticancer activity in preclinical models
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Researchers have developed a new cell therapy that aims to treat endometrial cancer by targeting cancer cells while also depleting immune cells that help protect the tumor.
The therapy showed strong anticancer activity in multiple laboratory models, and researchers are now preparing applications to regulatory authorities to begin testing the approach in people.
The study, “Stem cell engineering for the generation of allogeneic CAR-directed natural killer T cells targeting endometrial carcinoma,” was published in Experimental Hematology & Oncology.
Endometrial cancer remains difficult to treat long term
Endometrial cancer, marked by the uncontrolled growth of cells in the lining of the uterus, is one of the most common forms of gynecological cancer. While treatments are available, they often are not sufficient to control the disease over the long term.
“Across all forms of endometrial cancer, recurrence remains one of the greatest challenges — and it’s especially frequent and devastating in aggressive subtypes,” Sanaz Memarzadeh, MD, PhD, co-author of the study at the University of California Los Angeles (UCLA), said in a university news story. “Patients often discover the cancer has returned after undergoing a combination of surgery, chemotherapy and radiation, so it’s crucial that we devise and test new therapeutic strategies that can help save women’s lives.”
To identify new strategies, Memarzadeh and colleagues analyzed tumor tissue samples from six patients. They found that endometrial cancer cells often express high levels of the protein mesothelin, suggesting it could be a useful therapeutic target.
The researchers also found that the tumor cells themselves are often surrounded by anti-inflammatory cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). These cells normally help regulate immune responses, but in cancer they can suppress anti-tumor immunity, effectively helping tumors evade immune attack.
These surrounding immune cells tended to express high levels of the protein marker CD1d, which can be recognized by a specific type of immune cell known as natural killer T-cells (NKTs).
Engineered CAR-NKT cells designed to target cancer on 2 fronts
Based on these findings, the researchers proposed that NKTs engineered to target the tumor-associated protein mesothelin may be able to attack endometrial cancer on multiple fronts — by directly targeting tumor cells while also depleting immune cells that help protect the tumor, making it easier for the immune system to mount an anti-tumor response.
“This cancer is remarkably good at escaping treatment, but it can’t escape multiple attack pathways at once,” said Lili Yang, PhD, study co-author at UCLA. “By the time it adapts to one threat, our therapy has already hit it from another angle.”
The researchers generated NKT cells, which naturally recognize CD1d, and engineered them with chimeric antigen receptors (CARs) targeting mesothelin. CARs are lab-made proteins that direct immune cells to attack specific targets. Traditional CAR-based therapies typically use a patient’s own immune cells, which are collected, engineered, and returned — a process that can be time-consuming and costly. Here, the team developed a method to generate CAR-equipped NKTs from donated blood stem cells, allowing the cells to be cryopreserved (frozen and stored) and used when needed.
“The idea is to pre-make the product, cryopreserve it and have it ready to go as soon as the patient needs the therapy,” Yang said.
Preclinical testing shows strong anticancer activity
The researchers tested their CAR-NKT therapy across multiple laboratory models of endometrial cancer, where it consistently demonstrated strong anticancer activity without raising any notable safety concerns. This preclinical work “lays a strong foundation for future translational and clinical efforts aimed at bringing CAR-NKT cell therapy to patients with [endometrial cancer] and potentially other hard-to-treat malignancies,” the researchers wrote. The team is now working to advance the approach toward early clinical testing.
Because mesothelin is also expressed in other cancer types, this CAR-NKT approach may have applications beyond endometrial cancer.
“This is a platform technology,” said Yanruide (Charlie) Li, PhD, study co-author at UCLA. “The goal is one product that doesn’t require patient-by-patient customization.”
