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SUMMARY:PhD Defense\, Shradha Khanduja\, “Engineering next-generation ba
 cterial therapies for the treatment of solid tumors”
DTSTART;VALUE=DATE-TIME:20261001T150000Z
DTEND;VALUE=DATE-TIME:20261001T163000Z
UID:105073802610
DESCRIPTION:Committee Chair:  Neil ForbesABSTRACTMany biologic cancer the
 rapies do not effectively target tumors. When drugs are injected systemica
 lly\, they are quickly cleared from blood or are sequestered to other orga
 ns\, reducing the load in tumors and causing systemic toxicity. There curr
 ently exists no vehicle that can deliver any macromolecular therapy (DNA\,
  RNA\, or protein) selectively within tumors in a biomarker-independent ma
 nner. Here\, we present three critical classes of cancer therapies (DNA\, 
 protein\, and cytokine therapies) that have shown limited success in the c
 linic due to ineffective tumor targeting and systemic toxicity. We then sh
 ow how Salmonella was engineered to focus delivery of each of these therap
 eutic classes selectively into tumors and reduce disease burden without co
 mpromising safety. Engineered Salmonella is tumor-tropic and safe and grow
 s exponentially in tumors independently of any tumor receptor.To demonstra
 te DNA delivery\, we chose to deliver oncolytic parvoviruses (MVMp and H-1
 PV) into cancer cells. Oncolytic viruses (OVs) regress tumors by lysing ca
 ncer 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 recombin
 ation genes (recB\, sbcB\, sbcCD and recF) from the Salmonella genome. Wit
 hout these deletions\, we discovered that Salmonella cannot induce viral e
 xpression and replication. To create Virus delivering Salmonella (VDS)\, t
 he engineered Salmonella was transformed with the parvovirus plasmid and a
  plasmid containing the intracellular delivery system (PsseJ-lysE). In cul
 ture\, VDS delivered virus to multiple cancers\, including breast\, pancre
 atic\, liver\, and osteosarcoma. In mice\, VDS delivered functional virus 
 to mice with Hepa1-6 hepatomas\, and these viral particles reduced tumor v
 olume and increased survival compared to bacterial and viral-only controls
 . The delivery also generated anticancer immunity and suppressed tumor rec
 urrence.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-spec
 ific cytotoxicity. We stripped the receptor binding domain from PEA and de
 livered just the catalytic domain in the cytosol with engineered Salmonell
 a to solve this problem. The delivery resulted in tumor reduction in both 
 nude and syngeneic mouse models of pancreatic cancer and activated anti-tu
 mor immune response in the syngeneic model.By minimally modifying the Salm
 onella\, we transformed the strain from an intracellular into an extracell
 ular delivery vehicle of IFNγ. IFNγ\, when delivered systemically causes
  severe adverse effects due to non-specific targeting. Moreover\, IFNγ ha
 s a short half-life in serum\, limiting tumor accumulation. We engineered 
 the bacteria to lyse and release IFNγ extracellularly in the tumor microe
 nvironment. This delivery resulted in reduction in tumor volume in pancrea
 tic cancer and increased overall survival.By engineering Salmonella\, we c
 an deliver any therapy inside or outside the cell\, making this an attract
 ive tool for delivering drugs to solid tumors.
LOCATION:N410\, Life Science Laboratories
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