Innovative immunotherapy harnesses natural killer T cells to combat solid tumors

In the fight against cancer, chimeric antigen receptor T cell (CAR-T) therapy has achieved notable success in treating blood cancers. However, it has been largely ineffective against solid tumors.

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

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 report that CAR-natural killer T cells (CAR-NKT) utilize a multimodal approach, combining direct tumor cell killing, reprogramming of the tumor microenvironment, and promotion of systemic immune responses, to create a more immunogenic environment in tumors.

Their findings are published in Nature Cancer.

Previous research has shown that CAR-T cells' limited ability to penetrate and function within solid tumors is primarily due to the physical barriers within tumors and the suppressive nature of the tumor microenvironment. Natural killer T cells possess innate-like properties that make them uniquely equipped to fight solid tumors. Specifically, they express a T cell receptor that recognizes 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 tumor microenvironment. These macrophages promote tumor 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 tumor microenvironment from a pro-tumor to an anti-tumor environment.

They also reported that CAR-NKT cells promoted epitope spreading-;a process by which the immune system recognizes 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 tumor 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 tumors and achieving long-term tumor 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 tumor 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

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