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Innovative Light-Activated Immune Cells Target Solid Tumors
Recent advancements in immunotherapy highlight a promising direction in cancer treatment, particularly through the use of the body’s own immune system. Although therapies like CAR T-cell treatment have shown success with blood cancers, the battle against solid tumors has proven more challenging.
A multidisciplinary team from the Penn State College of Medicine has made significant strides in enhancing the effectiveness of immune cells in combating solid tumors. By engineering immune cells to respond to light, researchers have developed a method that allows these cells to penetrate and eliminate tumors grown in laboratory settings. They engineered a blue light-activated switch that modifies the structure and function of natural killer cells, which are crucial in fighting infections and tumors. When exposed to blue light, these modified cells can change shape, enabling them to infiltrate tumor spheroids—three-dimensional clusters of tumor cells—effectively destroying them.
This groundbreaking research, set to be published on October 25 in the Proceedings of the National Academy of Sciences, has also prompted the researchers to file a provisional patent application for their innovative technology.
“This technology stands apart in its approach,” noted Nikolay Dokholyan, senior author and G. Thomas Passananti Professor at Penn State College of Medicine. “Unlike CAR T-cell therapy, this method focuses on empowering immune cells to penetrate the tumor directly. I am not aware of any techniques that are similar to this.”
The Promise and Limitations of CAR T-Cell Therapy
CAR T-cell therapy has seen FDA approval since 2017, bringing hope to many patients suffering from blood cancers. The process involves extracting T-cells from a patient, engineering them to produce a receptor targeting a specific cancer protein, and reinfusing them to attack tumors. However, this therapy encounters significant obstacles when it comes to treating solid tumors, which account for about 90% of adult cancers and 40% of childhood cancers.
One key challenge is the tumor microenvironment, which creates a dense barrier of proteins and cells that complicates immune cell infiltration. Additionally, the variability among solid tumors makes it difficult for immune cells to consistently target the right protein. As noted by Dokholyan, enhancing the ability of these immune cells to bypass such defenses is essential for improving immunotherapy outcomes.
Innovative Engineering of Immune Cells
The research team’s approach involved computational modeling to design a modified version of the septin-7 protein, which maintains the cytoskeleton integrity in cells. By introducing a light-sensitive element to this protein, termed an “allosteric regulator,” they created a mechanism that does not interfere with the protein’s operation until activated by blue light.
Upon re-engineering natural killer cells with this modified septin-7, the presence of blue light triggered a transformation in the cells, allowing them to assume an elongated and more mobile shape. This morphological change enables them to navigate through tight spaces and infiltrate tumor spheroids effectively.
“These natural killer cells, which are about 10 micrometers in size, can be activated by blue light to change their shape and traverse openings as small as three micrometers,” explained Dokholyan. “This ability is critical for infiltrating tumors and attacking cancer cells from within.”
Preliminary Findings and Future Directions
The efficacy of these engineered immune cells was demonstrated through tests on tumor spheroids created from human breast and cervical cancer cells. Within a week, the modified cells successfully destroyed the tumor cells. In contrast, conventional natural killer cells struggled to penetrate the tumor mass, leading to continued tumor growth. Similar tests with mouse-derived immune cells against mouse melanoma tumor spheroids also validated the approach.
While these findings are promising, Dokholyan emphasizes the need for further research to assess the therapeutic potential of this technology. He also expresses interest in exploring additional activation mechanisms that could further influence protein functions and enhance cellular responses.
The research was supported by funding from the National Institutes of Health and the Passan Foundation, indicating strong institutional backing for these important advancements in cancer treatment.
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