Triple-negative breast cancer (TNBC) remains one of the most aggressive forms of the disease, characterized by the absence of three common targets that guide other breast cancer therapies. Researchers at the University of California, Los Angeles (UCLA) have developed a novel immunotherapy that may shift the standard of care for TNBC. In a study published in the Journal of Hematology & Oncology, the team describes a CAR-NKT cell therapy designed to assault tumors from multiple angles while dismantling their protective microenvironment.
According to senior author Lili Yang, a professor of microbiology, immunology and molecular genetics and a member of the UCLA Broad Center for Regenerative Medicine and Stem Cell Research, the therapy represents a significant step toward a treatment that is not only more effective but also more accessible. “Patients with TNBC have waited too long for better options. To have a therapy showing superior cancer-fighting capability and nearing clinical testing is incredibly exciting,” Yang stated.
The therapy employs engineered immune cells known as CAR-NKT cells, which can be mass-produced from donated blood stem cells and stored for immediate use. This off-the-shelf model contrasts with current personalized cell therapies, offering potential reductions in both cost and wait times—important considerations for patients facing aggressive disease.
Mechanisms Behind the CAR-NKT Strategy
CAR-T cell therapies have transformed some hematologic cancers by turning a patient’s own immune cells into targeted anti-tumor agents. Yet, solid tumors such as TNBC present unique barriers, including robust defense mechanisms and rapid evolution to evade treatment. The UCLA approach leverages invariant natural killer T (NKT) cells, a potent immune subset, engineered with a chimeric antigen receptor (CAR) that targets mesothelin, a protein linked to more aggressive TNBC.
Researchers found that this CAR-NKT system operates through three complementary mechanisms:
- Direct targeting of mesothelin to exploit its association with invasion and metastasis.
- Activation of natural killer receptors that recognize more than 20 molecular markers, reducing the likelihood of tumor escape through single-marker loss.
- Engagement of the cells’ native T cell receptor to alter the tumor microenvironment by removing immunosuppressive cells.
First author Yanruide (Charlie) Li described the approach as “like attacking a fortress from every direction at once,” noting that the cancer’s adaptive capacity is overwhelmed when multiple targets are engaged simultaneously. In tests using tumor samples from patients with late-stage metastatic breast cancer, the CAR-NKT cells demonstrated robust tumor cell kill across all samples and eliminated immunosuppressive cells that tumors typically recruit.
Towards Broad Accessibility and Expanded Applications
A key aspect of the therapy is its potential to overcome practical barriers that have limited cell-based cancer treatments. Conventional autologous cell therapies require harvesting a patient’s immune cells, transporting them to specialized facilities for genetic modification, and re-administering a personalized product—a process that can incur substantial cost and delay. Yang’s team proposes a scalable model in which NKT cells are produced from donated stem cells and can be distributed widely, potentially reducing the cost per dose to about $5,000 and enabling rapid deployment.
Beyond TNBC, the therapy’s target—mesothelin—is also highly expressed in ovarian, pancreatic and lung cancers. This raises the possibility that a single CAR-NKT product could address multiple tumor types that remain challenging to treat with existing immunotherapies. Yang described the platform as having broad potential and emphasized ongoing efforts to advance preclinical work toward clinical testing.
With preclinical work completed for both TNBC and ovarian cancer, the UCLA team plans to submit regulatory applications to the U.S. Food and Drug Administration to initiate clinical trials. Yang remarked, “We’ve walked 99 steps to get here. We’re missing just one final step to begin testing and demonstrate what this promising therapy can really do for patients.”
Contributing authors include Xinyuan Shen, Yichen Zhu, Zhe Li, Ryan Hon, Yanxin Tian, Jie Huang, Annabel Zhao, Nathan Ma, Catherine Zhang, David Lin, Karine Sargsyan and Yuan Yuan. The research received support from the California Institute for Regenerative Medicine, the Department of Defense, the UCLA Broad Stem Cell Research Center, the Wendy Ablon Trust, the Parker Institute for Cancer Immunotherapy, and UCLA’s microbiology, immunology and molecular genetics department, among others.
Further information is available from the UCLA Health Jonsson Comprehensive Cancer Center and related UCLA centers involved in the work.
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