From Mie University and Sysmex Corporation in Japan comes a new approach to improving the effectiveness of a promising cancer treatment. The study, led by Dr. Hiroyuki Hiratsuka, Dr. Yasushi Akahori, Dr. Shingo Maeta, Dr. Yuriko Egashira, and the late Dr. Hiroshi Shiku, offers fresh insights into how chimeric antigen receptors can become more sensitive to cancer targets. Published in the Journal of Biological Chemistry, this research could refine immunotherapy to tackle even hard-to-treat cancer cells.
Dr. Shiku’s team describes chimeric antigen receptors as custom-built molecules designed to help immune cells recognize and attack cancer cells. Immune cells, also known as T-cells, play a vital role in defending the body against infections and diseases. However, the scarcity of cancer-specific markers on tumors often limits how well these therapies work. “Our work focuses on overcoming these challenges by adjusting how chimeric antigen receptors bind to their targets,” explains Dr. Shiku. The research highlights the importance of fast binding rates—how quickly these receptors attach to their targets—in improving the ability of these immune cells to detect and kill cancer cells with few markers.
This study uses a system that targets a protein commonly found in certain tumors but rarely in healthy tissues. Proteins are essential molecules that perform a wide range of functions in the body, including serving as markers for cancer detection. Applying Sysmex’s antibody engineering technology, which allows the preparation of multiple CARs with different affinities, the researchers created six versions of chimeric antigen receptors, each with unique properties, and tested how well they identified and destroyed cancer cells. Immune cells equipped with receptors that bind more quickly showed significantly better performance, even in conditions where cancer markers were sparse, a long-standing hurdle in treatment.
Findings from the study reveal a strong connection between how well these receptors bind to their targets and their effectiveness in killing cancer cells. Binding refers to the process where receptors attach to specific markers on cells, allowing immune cells to recognize and attack harmful cells. Receptors with enhanced binding rates not only destroyed cancer cells faster but also avoided attacking healthy cells. “This strategy lets us take advantage of rapid binding while minimizing unwanted effects,” notes Dr. Hiratsuka.
The implications of this research extend far beyond the current findings. By fine-tuning the binding behavior of chimeric antigen receptors, scientists can better target cancer proteins displayed on the surfaces of cells. These proteins act like flags on the surface of cancer cells, helping the immune system identify them. This advance opens the door to treating cancers that were previously considered out of reach for these therapies.
Dr. Shiku and colleague’s experiments also underline the value of precision in designing these therapies. Precision in this context means tailoring treatments to work specifically against the unique characteristics of cancer cells. By combining lab results with advanced computer models, they gained a detailed understanding of how binding behavior influences the sensitivity of these engineered immune cells. “Our findings provide a roadmap for designing treatments that are both powerful and safe,” says Dr. Shiku.
Even with these advancements, the researchers emphasize the need for further studies to apply these discoveries in real-world medical settings. Real-world settings refer to practical environments such as hospitals and clinics where these therapies will be used. They plan to explore ways to adapt their findings to different types of cancer and to test the therapies in live organisms. “This research not only enhances our understanding of how these treatments work but also sets the stage for personalized approaches to cancer care,” adds Dr. Shiku.
This work from the Dr. Shiku’s team highlights the transformative potential of chimeric antigen receptor therapies in cancer treatment. By improving the precision and effectiveness of these customized immune cells, the study brings the medical community closer to achieving the full potential of immunotherapy in fighting cancer.
Journal Reference
Hiroyuki Hiratsuka, Yasushi Akahori, Shingo Maeta, Yuriko Egashira, Hiroshi Shiku. “Fast on-rates of chimeric antigen receptors enhance the sensitivity to peptide MHC via antigen rebinding.” Journal of Biological Chemistry, 2024. DOI: https://doi.org/10.1016/j.jbc.2024.107651
