Findings
A UCLA research team has identified the best design for a promising new type of immunotherapy that could be mass-produced to treat multiple solid tumors. The study focused on engineered invariant natural killer T cells, or NKT cells — powerful immune cells with a unique ability to infiltrate solid tumors — and systematically compared four targeting systems, called chimeric antigen receptors, or CARs, that direct these cells to attack cancer.
Background
CAR-T cell therapies have revolutionized treatment for certain blood cancers like leukemia and lymphoma, but these successes haven’t extended to solid tumors, which make up the vast majority of cancers. Solid tumors build dense protective barriers that block therapeutic cells from reaching the cancer and display varied targets that allow cancer cells to escape detection.
CAR-NKT cells offer key advantages for overcoming these obstacles. Unlike CAR-T cells, they can easily locate tumors and penetrate the tissue barriers that often keep other therapeutic cells out. They also directly kill cancer cells while also eliminating the immunosuppressive cells that shield tumors.
Despite this promise, a key question remained: Which CAR design would work best? The choice largely influences whether CAR-NKT cells launch a rapid but short-lived attack or maintain a sustained campaign, which is critical for battling solid tumors.
By directly comparing CAR designs in NKT cells, this study removes a major roadblock in advancing CAR-NKT cell therapies toward clinical application.
Method
The research team engineered human blood stem cells to produce specialized immune cells called NKT cells. They equipped these NKT cells with four different versions of a cancer-targeting system called CAR, programmed to target mesothelin, a protein found on ovarian, pancreatic, lung and breast cancers. Each CAR design featured various molecular “engines” to power the cells’ cancer-fighting abilities: CD28, 4-1BB, a combination of CD28 and 4-1BB, and NKG2D/2B4.
First, the team tested these engineered cells in the laboratory, pitting them against tumor cells from ovarian, pancreatic, lung and breast cancers, measuring how effectively they destroyed tumors, released cancer-fighting signals and stayed active over time.
Next, they evaluated which CAR design was most effective at treating mouse models of ovarian cancer, tracking tumor size, survival rates and where the engineered cells traveled in the body.
After these evaluations, the 4-1BB-containing CAR design emerged as superior, demonstrating the strongest anti-tumor activity and persistence.
Impact
This study marks the first systematic comparison of CAR designs for NKT cell therapy.
The results are particularly promising because these engineered cells combined powerful tumor-killing ability with long-term persistence, addressing two major obstacles that have limited CAR-T cell success against solid tumors.
Importantly, they showed none of the safety concerns researchers monitored for: they didn’t attack healthy tissues, trigger graft-versus-host disease, a dangerous condition in which donated immune cells attack healthy tissues, or grow uncontrollably.
Perhaps most transformative is this novel therapy’s off-the-shelf potential. Unlike current CAR-T cell therapies, which require collecting each patient’s immune cells, modifying them in specialized facilities and waiting weeks for their return, CAR-NKT cells can be mass-produced from donated blood stem cells, frozen and stored at hospitals for immediate use.
The team has demonstrated CAR-NKT cell therapy’s effectiveness against pancreatic cancer , triple-negative breast cancer and ovarian cancer in separate preclinical studies.
“By rigorously identifying the optimal CAR design for NKT cells, our findings provide a roadmap for advancing CAR-NKT cell therapies from the lab toward clinical trials,” said senior author Lili Yang , a professor of microbiology, immunology and molecular genetics and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and of the UCLA Health Jonsson Comprehensive Cancer Center .
Journal
The study was published in the journal Blood Immunology & Cellular Therapy .
Authors
Yanruide Li, Yichen Zhu, Tyler Halladay, Xinyuan Shen, Youcheng Yang , Zhe Li, Enbo Zhu, Yuning Chen, Jie Huang and Lili Yang.
Funding
The research was supported by 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, UCLA’s department of microbiology, immunology and molecular genetics, the UCLA Office of the Chancellor and the UCLA Goodman-Luskin Microbiome Center.
Blood Immunology & Cellular Therapy