CAR-NKT Cells Show Promise in Overcoming Solid Tumor Barriers

Chimeric antigen receptor T-cell therapy (CAR-T) has shown significant promise in treating blood malignancies in the fight against cancer. Nevertheless, its efficacy against solid tumors has been mainly lacking.

Researchers at UNC Lineberger Comprehensive Cancer Center recently published a study showing that a distinct immunotherapy strategy employing natural killer T (NKT) cells had notable anticancer efficacy in preclinical models of solid tumors.

CAR-natural killer T-cells (CAR-NKT) use a multimodal approach combining direct tumor cell killing, reprogramming the tumor microenvironment, and promoting systemic immune responses to create a more immunogenic tumor environment.

This information is reported by Gianpietro Dotti, MD, Professor of Microbiology and Immunology at UNC School of Medicine and Co-leader of the UNC Lineberger immunology research program, Xin Zhou, PhD, a Postdoctoral Fellow in the Dotti lab, and their colleagues.

The research was published in the journal 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 tumor models that recapitulate the complexity of the tumor microenvironment. In particular, tumor-associated macrophages seem to have a potent inhibitory effect on CAR-T cells. CAR-NKT seem capable of avoiding the inhibitory effects of macrophages since they can directly target them.”

Gianpietro Dotti, Professor and Study Corresponding Author, University of North Carolina

Previous studies have demonstrated that physical barriers inside tumors and the tumor microenvironment's suppressive properties are the main causes of CAR-T cells' restricted capacity to enter and operate inside solid tumors.

Due to their innate characteristics, natural killer T-cells are especially suited to combat solid tumors. They express a T-cell receptor specifically designed to identify glycolipid antigens presented by CD1d molecules.

Dotti, Zhou, and associates showed that CD1d-expressing M2-like macrophages in the tumor microenvironment were successfully eradicated by CAR-NKT cells. These macrophages promote tumor growth and decrease immune responses, making their elimination vital to improving antitumor immunity.

By focusing on these cells, CAR-NKT therapy efficiently reprogrammes the tumor microenvironment from a pro-tumor to an anti-tumor state.

They revealed that CAR-NKT cells stimulated T-cell responses by promoting epitope dissemination, the immune system's method of identifying and attacking novel targets.

Our findings demonstrate that CAR-NKT cells not only effectively eliminate CD1d-expressing M2-like macrophages within the tumor microenvironment but also stimulate endogenous immune cells. This dual function overcoming suppressive immune cells and promoting sustained immune activity represents a crucial advancement in improving CAR-based therapies for solid tumors and achieving long-term tumor control.”

Xin Zhou, Postdoctoral Fellow and Study First Author, University of North Carolina

The researchers also state that they successfully assisted CAR-NKT cells in overcoming therapeutic exhaustion, a recognized drawback of CAR-T treatments after prolonged exposure to tumor antigens.

Co-expression of the immune checkpoint markers TIM3 and PD1, which reduces the efficacy of immune cells, is a sign of fatigue. However, the researchers also showed that CAR-NKT cells' anticancer activity increased when combined with PD1 inhibition. This immune checkpoint inhibitor is frequently used to treat cancer.

The researchers also found that the antitumor response was further improved when CAR-NKT cells were combined with vaccination strategies, such as those that used dendritic cells loaded with alpha-galactosylceramide, a well-known, strong NKT cell stimulant.

Considering the future, Dotti’s group is working on methods to make the production of CAR-NKT cells easier.

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.”

Gianpietro Dotti, Professor and Study Corresponding Author, University of North Carolina