PHASE I THERAPEUTIC AWARD: A NOVEL ENGINEERED BACTERIAL ANTICANCER IMMUNOTHERAPY FOR MERKEL CELL CARCINOMA

Tranquility Biodesign is developing an innovative approach for immunomodulating the tumor microenvironment (TME) through engineered bacterial anticancer therapeutics. Merkel Cell Carcinoma (MCC) is a rare skin cancer with few therapeutic options. Immunomodulation of TME can improve responses to current therapies by re-activating suppressed immune cell activity. Tranquility intends to combine an attenuated strain of Brucella melitensis, Bm∆vjbR, with a genetically engineered biosynthetic cluster that includes the enzyme toluene ortho-monooxygenase (Bm∆vjbR-TOM). This allows conversion of tryptophan to hydroxyindole (HI), a potent immunomodulatory compound. Preliminary data has shown that treatment of tumor cells with HI promotes tumor suppressive immunomodulatory effects including activation of pro-inflammatory macrophages, cytotoxic CD8+ T-cells, and promotion of tumor-suppressive CD4+ T-cell differentiation. Importantly, Bm∆vjbR has also been tested for safety in immunosufficient and immunodeficient mice, as well as non-human primates and pregnant goats and sheep. In each of these systems, the bacterium displayed exceptional safety profiles. To validate the potential of Bm∆vjbR-TOM for the development of a bacterial anticancer therapeutic, the Bm∆vjbR strain will first be engineered to express the TOM enzyme through genomic integration, and TOM enzymatic activity will be validated through chromogenic assays. Then, the anticancer efficacy of the resultant strain will be characterized against MCC tumor growth in immune-competent as well as humanized NOD/SCID mouse models. Upon completion of this proposal, proof of concept for Bm∆vjbR-TOM as a new potential candidate for anticancer therapeutic development will be demonstrated.