Engineered gamma-delta T cells could fight treatment resistant bowel cancer
Engineered gamma-delta T cells with enhanced survival and specific bowel cancer targeting capabilities have shown promising results in organoid studies.
Researchers at University College London (UCL; UK) have made a significant advancement in cancer treatment by modifying a rare type of immune cell to effectively target bowel cancer cells that typically resist standard treatments.
Bowel cancer is extremely deadly, claiming over 900,000 lives annually worldwide. The main challenge lies in how this cancer behaves and responds to treatment. Current chemotherapy primarily works by attacking rapidly dividing cells, but many bowel cancer cells grow slowly, which allows them to evade this standard treatment approach. These slow-growing cancer cells can survive chemotherapy and return later, often becoming more aggressive than before. The surviving cells pose a significant threat of cancer recurrence, making bowel cancer particularly difficult to treat effectively.
The UCL team focused on a special type of immune cell called gamma-delta T cells (γδT cells), which are much rarer than other types of immune cell but have unique properties that make them promising for cancer treatment. Unlike more common T cell types that need specific warning signals to identify threats, γδT cells can directly sense when cells are stressed or behaving abnormally. This natural ability to detect problematic cells makes them particularly suited for cancer detection. Additionally, these cells can be transferred between people, meaning healthy donors could provide cells for cancer patients, which is a significant advantage over other immune cell therapies that require using the patient’s own cells. Previous research had already shown that these cells could kill bone cancer cells, providing a foundation for this new study.
The researchers enhanced these γδT cells through a two-step process designed to make them more effective against bowel cancer. First, they extracted γδT cells from seven healthy volunteers and used a lentivirus to insert a gene that produces stIL-15 protein. This protein acts like a survival boost, helping the cells live longer and multiply faster than their natural counterparts. In the second step, they added a B7-H3 antibody to some of the enhanced cells. This antibody works like a targeting system, helping the immune cells recognize and attach specifically to bowel cancer cells that display the B7-H3 protein on their surface.
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The team conducted extensive testing using tumor organoids grown from bowel cancer patient cells. The researchers tested over 1000 different experimental conditions to thoroughly understand how the engineered cells interact with bowel cancer cells.
The results revealed several important findings. While regular γδT cells died quickly when exposed to cancer, the engineered versions survived much longer and remained active. However, the researchers discovered that when engineered cells used only one attack method called AIC (Antibody-Independent Cytotoxicity), the cancer cells could “rewire” the immune cells, essentially tricking them into becoming less effective at fighting the cancer.
The breakthrough came when they tested the supercharged cells that had been enhanced with B7-H3 antibodies. These cells could use two attack methods simultaneously: AIC (Antibody-Independent Cytotoxicity) and ADCC (Antibody-Dependent Cellular Cytotoxicity). This dual approach prevented cancer cells from disabling the immune response and successfully killed even the slow-growing, chemotherapy-resistant cancer cells that had previously been difficult to treat.
This research represents a potential paradigm shift in bowel cancer treatment because it specifically addresses the slow-growing cancer cells that evade chemotherapy. The dual-attack mechanism stops cancer from turning the tables on the immune system, which has been a major challenge in cancer immunotherapy. The approach could help patients whose cancer has returned or doesn’t respond to standard treatments, offering new hope for those facing the most difficult cases. Because the treatment uses donor cells rather than requiring each patient’s own immune cells, it could be more widely applicable and easier to implement in clinical settings.