This study describes an innovative strategy to improve the anti-tumor activity of T cells, key players of the immune system with the ability to detect and kill cancer cells.
Due to their increased metabolism, tumors accumulate numerous metabolites that influence their growth and modulate immune cells. One potential therapeutic intervention is to tune the concentrations of these metabolites in favor of an effective anti-tumor response. However, methods to locally control metabolite concentrations in tumors are challenging.
Certain non-pathogenic bacterial strains colonize tumors and are able to survive and thrive in the necrotic core. In collaboration with Synlogic, Cambridge (USA), the group of Roger Geiger used a synthetic biology approach to develop an engineered probioticEscherichia colistrain that continuously converts ammonia, a metabolic waste product that accumulates in tumors, to L-arginine. L-arginine is an immunomodulatory metabolite that enhances anti-tumor functions of T cells.
The engineered bacteria colonize tumors, increase intratumoral L-arginine, enhance T cell activity, and synergize with PD-L1 blocking antibodies. Thus, engineered microbial therapies enable metabolic modulation of tumors leading to enhanced efficacy of immunotherapies.
This bacteria-based therapy is suitable for the development of human therapeutics. The non-pathogenic bacteria have an intrinsic “kill-switch” as they are susceptible to antibiotics and possess desirable engineerability, safety and manufacturability features. Intratumoral injections of probiotic bacteria were previously found safe in clinical studies.
Canale F. P., Basso C., Antonini, G., Perotti, M., Li, N., Sokolovska, A., Neumann, J., James, M. J., Geiger, S., Jin, W., Theurillat, J. P., West, K. A., Leventhal, D. S., Lora, J. M., Sallusto F. & Roger Geiger
A dedicatedNews & Viewsis availablehere. doi: 10.1038/d41586-021-02639-8
Left: Tumor growth curves of mice that received different therapeutic treatments. Right: Survival curves of mice.