Combinatorial leaky probiotic for anticancer immunopotentiation and tumor eradication.

Area of Science:

• Biotechnology
• Immunotherapy
• Microbiology

Background:

• Solid tumors possess immunosuppressive and heterogeneous microenvironments, challenging conventional combination therapies.
• Integrating multiple therapeutic agents often involves complex logistical, manufacturing, and pharmacokinetic hurdles.

Purpose of the Study:

• To develop a single-vector combinational therapy for solid tumors using a genetically modified probiotic.
• To engineer a probiotic vector for simultaneous secretion of immunotherapeutic and oncolytic molecules.

Main Methods:

• Engineered a Nissle1917 (EcN) bacteria vector with an lpp gene knockout.
• Designed fusion proteins for secretion of Neoleukin-2/15 (Neo-2/15) cytokine-functionalized anti-PDL1 nanobody (aPDL1-Neo2/15) and anti-mesothelin-functionalized hemolysin E (HlyE-aMSLN).

Main Results:

• Achieved synchronous immune activation and tumor-targeted cytolytic activity.
• Demonstrated effective tumor suppression, increased tumor immune cell infiltration, and established anticancer immunological memory.
• Showcased improved probiotic tolerability and intravenous applicability via lpp gene knockout.

Conclusions:

• The engineered multifunctional probiotic offers a viable approach for developing combination cancer regimens.
• This single-vector system simplifies combination therapy logistics while enhancing therapeutic efficacy against solid tumors.