In the battle against cancer, chimeric antigen receptor (CAR) T cell therapy has shown considerable effectiveness in treating blood cancers, but it struggles to target solid tumors. A recent study reveals that an alternative immunotherapy using natural killer T (NKT) cells has demonstrated remarkable antitumor effects in early experimental models of solid tumors.
In the struggle against cancer, CAR-T therapy has shown significant effectiveness in combating blood cancers. Nevertheless, it has proven largely ineffective against solid tumors.
Researchers from the UNC Lineberger Comprehensive Cancer Center have recently published findings indicating that using NKT cells as a different immunotherapy approach resulted in strong antitumor activity in preclinical models involving solid tumors.
Gianpietro Dotti, MD, a professor of microbiology and immunology at UNC School of Medicine and co-leader of the UNC Lineberger immunology research program, along with postdoctoral fellow Xin Zhou, PhD, and their team, have discovered that CAR-natural killer T cells (CAR-NKT) employ a multifaceted strategy that includes direct tumor cell destruction, modifying the tumor environment, and enhancing overall immune responses to foster a more immune-friendly atmosphere in tumors.
The results of their research are detailed in Nature Cancer.
“While CAR-T cells are incredibly powerful, our most unexpected discovery is how significantly these cells are inhibited in tumor models reflecting the complexities of the tumor microenvironment,” remarked Dotti, the corresponding author of the paper. “In particular, macrophages associated with tumors appear to have a strong suppressive impact on CAR-T cells. However, CAR-NKT cells can evade this suppression because they directly attack these macrophages.”
Prior studies have indicated that CAR-T cells encounter obstacles in solid tumors mainly due to both physical barriers and the suppressive qualities of the tumor environment. Natural killer T cells, possessing characteristics that mimic innate immune cells, are particularly well-suited for combating solid tumors. They have a T cell receptor that targets glycolipid antigens presented by CD1d molecules.
Dotti, Zhou, and their team have shown that CAR-NKT cells can successfully target and eliminate CD1d-expressing M2-like macrophages in the tumor microenvironment. These macrophages are known to facilitate tumor growth and hinder immune responses, making their elimination essential for an effective antitumor response. By focusing on these cells, CAR-NKT therapy transitions the tumor microenvironment from supporting tumor development to fostering an anti-tumor activity.
Additionally, they found that CAR-NKT cells induced epitope spreading, a mechanism where the immune system begins to recognize and attack new targets, thereby activating T-cell responses.
“Our research illustrates that CAR-NKT cells not only effectively remove CD1d-expressing M2-like macrophages from the tumor microenvironment but also encourage the activity of intrinsic immune cells,” stated Zhou, the primary author of the paper. “This combined effect—counteracting suppressive immune cells and generating sustained immune activity—marks a significant improvement in developing CAR-based therapies for solid tumors and achieving long-term control over tumors.”
The researchers also noted that they helped CAR-NKT cells to overcome therapeutic exhaustion, a common drawback faced by CAR-T therapies after prolonged exposure to tumor antigens. Indicators of exhaustion include the co-expression of immune checkpoint markers such as PD1 and TIM3, which reduce the effectiveness of immune cells. However, their study showed that pairing CAR-NKT cells with PD1 blockade—a frequently used immune checkpoint inhibitor in cancer therapy—substantially enhanced their antitumor effectiveness.
Furthermore, the researchers reported that combining CAR-NKT cells with vaccination methods, like using alpha-galactosylceramide-loaded dendritic cells, further improved the antitumor response. Alpha-galactosylceramide is recognized as a strong activator of NKT cells.
Looking to the future, Dotti mentioned that the team is concentrating on streamlining the production process for CAR-NKT cells. “While CAR-NKT cells have been safely administered in clinical trials, manufacturing them for clinical application is more intricate than for CAR-T cells. We are dedicated to simplifying the production of CAR-NKT cells.”
