title: Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Coupled with Enzymatic Depletion of Tumor Hyaluronan Induces Complete Regression of Aggressive Pancreatic Tumors.
abstract: Bacterial-based therapies are emerging as effective cancer treatments and hold promise for refractory neoplasms, such as pancreatic ductal adenocarcinoma (PDAC), which has not shown significant improvement in therapy for more than 25 years. Using a novel combination of shIDO-ST, a Salmonella-based therapy targeting the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO), with an enzyme, PEGPH20, which depletes extracellular matrix hyaluronan, we observed extended survival with frequent total regression of autochthonous and orthotopic PDAC tumors. This observation was associated with migration and accumulation of activated polymorphonuclear neutrophils (PMN) from spleens into tumors, which was not seen using a scrambled control (shScr-ST). Purified splenic PMNs from PEGPH20/shIDO-ST-treated mice exhibited significant IDO knockdown and were able to kill tumor targets ex vivo through mechanisms involving FasL and serine proteases. In addition, CD8(+) T cells were observed to contribute to late control of pancreatic tumors. Collectively, our data demonstrate that entry of shIDO-ST and PMNs into otherwise impermeable desmoplastic tumors is facilitated by PEGPH20-mediated HA removal, further highlighting an important component of effective treatment for PDAC.
authors.affiliation: Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, California. emanuel@coh.org ddiamond@coh.org.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Manuel
authors.affiliation: Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, California.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Apuzzo
authors.affiliation: Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, California.
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Lampa
authors.affiliation: Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, California.
authors.forename: Teodora I
authors.initials: TI
authors.lastname: Kaltcheva
authors.affiliation: Halozyme Therapeutics, Inc., San Diego, California.
authors.forename: Curtis B
authors.initials: CB
authors.lastname: Thompson
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.affiliation: Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Vincent
authors.initials: V
authors.lastname: Chung
authors.affiliation: Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, California. emanuel@coh.org ddiamond@coh.org.
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015815:Cell Adhesion Molecules / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D055785:Gene Knockdown Techniques / Q000379:methods; D015316:Genetic Therapy / Q000379:methods; D006820:Hyaluronic Acid / Q000172:deficiency* / Q000378:metabolism; D006821:Hyaluronoglucosaminidase / Q000627:therapeutic use*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy / Q000379:methods; D009368:Neoplasm Transplantation; D009504:Neutrophils / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011994:Recombinant Proteins / Q000627:therapeutic use
chemical_list: D019496:Cancer Vaccines; D015815:Cell Adhesion Molecules; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011994:Recombinant Proteins; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; C066852:hyaluronidase PH-20