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Committee Chair: Neil ForbesABSTRACTMany biologic cancer therapies do not effectively target tumors. When drugs are injected systemically, they are quickly cleared from blood or are sequestered to other organs, reducing the load in tumors and causing systemic toxicity. There currently exists no vehicle that can deliver any macromolecular therapy (DNA, RNA, or protein) selectively within tumors in a biomarker-independent manner. Here, we present three critical classes of cancer therapies (DNA, protein, and cytokine therapies) that have shown limited success in the clinic due to ineffective tumor targeting and systemic toxicity. We then show how Salmonella was engineered to focus delivery of each of these therapeutic classes selectively into tumors and reduce disease burden without compromising safety. Engineered Salmonella is tumor-tropic and safe and grows exponentially in tumors independently of any tumor receptor.To demonstrate DNA delivery, we chose to deliver oncolytic parvoviruses (MVMp and H-1PV) into cancer cells. Oncolytic viruses (OVs) regress tumors by lysing cancer cells and inducing antitumor immune responses that can clear hard-to-treat and late-stage cancers. However, when injected into the blood, OVs are cleared or sequestered before reaching tumors. Because the parvovirus plasmid is not stable in Salmonella, we deleted four homologous recombination genes (recB, sbcB, sbcCD and recF) from the Salmonella genome. Without these deletions, we discovered that Salmonella cannot induce viral expression and replication. To create Virus delivering Salmonella (VDS), the engineered Salmonella was transformed with the parvovirus plasmid and a plasmid containing the intracellular delivery system (PsseJ-lysE). In culture, VDS delivered virus to multiple cancers, including breast, pancreatic, liver, and osteosarcoma. In mice, VDS delivered functional virus to mice with Hepa1-6 hepatomas, and these viral particles reduced tumor volume and increased survival compared to bacterial and viral-only controls. The delivery also generated anticancer immunity and suppressed tumor recurrence.For protein delivery, we chose to deliver Pseudomonas Exotoxin A (PEA) into pancreatic cancer cells. Therapeutic forms of PEA when injected systemically are highly immunogenic, cause lymphopenia and have non-specific cytotoxicity. We stripped the receptor binding domain from PEA and delivered just the catalytic domain in the cytosol with engineered Salmonella to solve this problem. The delivery resulted in tumor reduction in both nude and syngeneic mouse models of pancreatic cancer and activated anti-tumor immune response in the syngeneic model.By minimally modifying the Salmonella, we transformed the strain from an intracellular into an extracellular delivery vehicle of IFNγ. IFNγ, when delivered systemically causes severe adverse effects due to non-specific targeting. Moreover, IFNγ has a short half-life in serum, limiting tumor accumulation. We engineered the bacteria to lyse and release IFNγ extracellularly in the tumor microenvironment. This delivery resulted in reduction in tumor volume in pancreatic cancer and increased overall survival.By engineering Salmonella, we can deliver any therapy inside or outside the cell, making this an attractive tool for delivering drugs to solid tumors.
📍 N410, Life Science Laboratories