In the fight against cancer, chimaeric antigen receptor T cell (CAR-T) therapy has achieved notable success in treating blood cancers.

However, it has been largely ineffective against solid tumours.

Now, a newly published study by UNC Lineberger Comprehensive Cancer Centre researchers demonstrates that a different immunotherapy approach utilising natural killer T (NKT) cells produced significant antitumor activity in preclinical models of solid tumours.

Gianpietro Dotti, MD, professor of microbiology and immunology at UNC School of Medicine and co-leader of the UNC Lineberger immunology research programme, Xin Zhou, PhD, a postdoctoral fellow in the Dotti lab, and their colleagues report that CAR-natural killer T cells (CAR-NKT) utilise a multimodal approach, combining direct tumour cell killing, reprogramming of the tumour microenvironment, and promotion of systemic immune responses, to create a more immunogenic environment in tumours.

Their findings are published in Nature Cancer.

“CAR-T cells are very potent cells. However, the most surprising finding in our work is that these potent cells are strongly inhibited in tumour models that recapitulate the complexity of the tumour microenvironment,” said Dotti, the paper’s corresponding author.

“In particular, tumour-associated macrophages seem to have a potent inhibitory effect on CAR-T cells. CAR-NKT seem capable to avoid the inhibitory effects of macrophages since they can directly target them.”

Previous research has shown that CAR-T cells’ limited ability to penetrate and function within solid tumours is primarily due to the physical barriers within tumours and the suppressive nature of the tumour microenvironment.

Natural killer T cells possess innate-like properties that make them uniquely equipped to fight solid tumours.

Specifically, they express a T cell receptor that recognises glycolipid antigens presented by CD1d molecules.

Dotti, Zhou and their colleagues demonstrated that CAR-NKT cells effectively eliminated CD1d-expressing M2-like macrophages within the tumour microenvironment.

These macrophages promote tumour growth and suppress immune responses, making their removal a critical aspect of enhancing antitumor immunity.

By targeting these cells, CAR-NKT therapy effectively reprograms the tumour microenvironment from a pro-tumour to an anti-tumour environment.

They also reported that CAR-NKT cells promoted epitope spreading—a process by which the immune system recognises and attacks new targets—leading to the activation of T-cell responses.

“Our findings demonstrate that CAR-NKT cells not only effectively eliminate CD1d-expressing M2-like macrophages within the tumour microenvironment but also stimulate endogenous immune cells,” said Zhou, the paper’s first author.

“This dual function—overcoming suppressive immune cells and promoting sustained immune activity—represents a crucial advancement in improving CAR-based therapies for solid tumours and achieving long-term tumour control.”

The researchers also report that they were able to help CAR-NKT cells overcome therapeutic exhaustion, a known shortcoming of CAR-T therapies that have had extended exposure to tumour antigens.

Signs of exhaustion include co-expression of the immune checkpoint markers PD1 and TIM3, which dampens the immune cells’ effectiveness.

However, the researchers demonstrated that combining CAR-NKT cells with PD1 blockade—an immune checkpoint inhibitor commonly used in cancer treatment—significantly boosted their antitumor activity.

The researchers also reported that combining CAR-NKT cells with vaccination approaches, such as those using alpha-galactosylceramide-loaded dendritic cells, further enhanced the antitumor response.

Alpha-galactosylceramide is a known potent stimulator of NKT cells.

Looking ahead, Dotti said his team is focused on developing approaches to simplify the process for producing CAR-NKT cells.

“CAR-NKT cells have been already safely used in clinical trials. However, the manufacturing of CAR-NKT for clinical use is more complex than the manufacturing of CAR-T cells. We are working on simplifying the manufacturing of CAR-NKT.”

Source: University of North Carolina Health Care