NSF-SNSF: Programmable and dynamically-responsive bacterial therapeutics for cancer immunotherapy

Living cells can act as programmable and dynamically-responsive therapeutics to treat cancer. Although engineered human T cells have been effective for cancer therapy, they are almost prohibitively expensive. In contrast, bacterial cells can be manufactured at low cost and therefore hold promise as broadly applicable therapeutics.

To enable effective live-cell bacterial therapeutics, this project will develop a unique biosensing system to detect specific tumor antigens and respond with potent therapeutic effectors. In parallel, the proposed research will improve safety by engineering bacteria to make them more effective against tumors at lower doses.

Living bacteria therapies have been proposed as an alternative approach to treat tumors by sensing their environments and delivering localized anti-tumor payloads. Bacteria can be manufactured at low cost compared to human cell therapies and therefore hold promise as broadly applicable therapeutics. To address two major outstanding challenges for bacterial immunotherapy, this project will develop new bacterial sensing platforms with specificity for disease tissue and engineer bacteria with improved tumor colonization.

Ideally, bacteria would target protein antigens displayed on cancer cells, but engineered extracellular protein sensing is currently not possible. This project will develop a unique sensing system in E. coli bacteria to recognize extracellular cancer antigens and respond with a toxic, immunostimulatory payload. Effects on tumor growth will be evaluated in a mouse tumor model.

In parallel, bacteria with improved tumor colonization will be engineered by displaying extracellular factors that evade the host complement system. This approach will allow systemic bacterial delivery at low doses to avoid widespread inflammation, which is important because most tumors are not accessible to direct intratumoral injection. Successful completion of the project will produce improved bacterial live-cell therapeutics with synthetic signaling systems that allow autonomous responses in vivo, and with improved tumor colonization for safe, systemic delivery.

This collaborative U.S.-Swiss project is supported by the U.S. National Science Foundation (NSF) and the Swiss National Science Foundation (SNSF), where NSF funds the U.S. investigator and SNSF funds the partners in Switzerland.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.