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 tumours.

The study focused on engineered invariant natural killer T cells, or NKT cells — powerful immune cells with a unique ability to infiltrate solid tumours — and systematically compared four targeting systems, called chimaeric antigen receptors, or CARs, that direct these cells to attack cancer.

Background

CAR-T cell therapies have revolutionised treatment for certain blood cancers like leukaemia and lymphoma, but these successes haven’t extended to solid tumours, which make up the vast majority of cancers.

Solid tumours 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 tumours 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 tumours.

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 tumours.

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 specialised 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 tumour cells from ovarian, pancreatic, lung and breast cancers, measuring how effectively they destroyed tumours, 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 tumour size, survival rates and where the engineered cells travelled in the body.

After these evaluations, the 4-1BB-containing CAR design emerged as superior, demonstrating the strongest anti-tumour 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 tumour-killing ability with long-term persistence, addressing two major obstacles that have limited CAR-T cell success against solid tumours.

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 specialised 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 Centre of Regenerative Medicine and Stem Cell Research at UCLA and of the UCLA Health Jonsson Comprehensive Cancer Centre.

Journal

The study was published in the journal Blood Immunology & Cellular Therapy.

Source: University of California - Los Angeles Health Sciences