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Combination therapies present a compelling therapeutic regimen against the immunosuppressive and heterogeneous microenvironment of solid tumors. However, incorporating separate therapeutic modalities in regimen designs can be encumbered by complex logistical, manufacturing, and pharmacokinetic considerations. Herein, we demonstrate a single-vector combinational anticancer therapy using a lpp gene knock-out leaky probiotic for simultaneous secretion of immunotherapeutic and oncolytic effector molecules. Through fusion protein design and vector optimization, a Nissle1917 (EcN) bacteria vector is engineered to secrete Neo-2/15 cytokine functionalized anti-PDL1 nanobody (aPDL1-Neo2/15) and anti-mesothelin-functionalized hemolysin E (HlyE-aMSLN). The multifunctional leaky probiotic enables synchronous immune activation and tumor-targeted cytolytic activity for effective tumor suppression, elevation of tumor immune cell infiltration, and establishment of anticancer immunological memory. lpp gene knock-out is further shown to improve probiotic tolerability and intravenous applicability, offering a therapeutically viable approach for combination regimen development. 

Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica
Doctoral Dissertation