In a recent study published in an international magazine of Immunity, scientists at the University of Southampton have developed a new antibody that could hold the key to unlocking cancers’ defense against the body’s immune system. In the study, they engineered antibodies to target an immune receptor called 4-1BB, which can activate killer T-cells to find and destroy cancer cells.
As a target for immunotherapy, 4-1BB is present mainly on a population of T cells within the tumour called regulatory T cells, which switch off the killer T cells. Killer T cells also expressed 4-1BB, but to a lesser extent. The team found that in a pre-clinical tumour setting an anti-4-1BB antibody that deleted regulatory T cells caused regression of the tumour. However, because the type of antibody that is good at deleting regulatory T-cells is not as good at stimulating killer T-cells and vice versa, it is not possible to use a regular type of antibody to harness both therapeutic approaches.
The Southampton team also designed and engineered an antibody that can both delete regulatory T cells within the tumour and therefore remove the suppression they exert and activate the killer T cells at the same time. In laboratory studies, this dual-purpose antibody was highly effective in eradicating tumours. The study is the culmination of more than 10 years of research from Southampton scientists and their collaborators. They believe that this finding could lead to a new wave of cancer-fighting antibodies.
Aymen Al-Shamkhani, a member of the team, said that antibody immunotherapy has transformed patient outcomes in a number of cancers, but responses are frequently restricted to a minority of patients. This is a really very exciting breakthrough. Immune activating antibodies targeting immune receptors like 4-1BB have failed to translate successfully to the clinic but can help researchers understand how to target them successfully in cancer patients. By combining the two approaches of deleting regulatory T cells and activating killer T cells, researchers could potentially improve the way patients are treated in the clinic.
In addition, the research findings can be applied to both ovarian cancer and Squamous Cell Carcinoma. However, the Southampton team believe that they could be applicable to more cancers, following further research. A team member pointed out that this study is an important step towards improving immunotherapy. It helps us to understand why a type of treatment isn’t as successful in patients as hoped. But critically, it presents a potential solution as to how we can overcome these challenges to develop effective immunotherapy that works for more patients.
Sarah L. Buchan，Lang Dou，Marcus Remer, et al. Antibodies to Costimulatory Receptor 4-1BB Enhance Anti-tumor Immunity via T Regulatory Cell Depletion and Promotion of CD8 T Cell Effector Function, Immunity (2018). DOI: 10.1016/j.immuni.2018.09.014