title: Targeting localized immune suppression within the tumor through repeat cycles of immune cell-oncolytic virus combination therapy.
abstract: A major limitation to the use of immunotherapy in the treatment of cancer has been the localized immune suppressive environment within the tumor. Although there is evidence that tumor-selective (oncolytic) viruses may help to overcome this immune suppression, a primary limitation to their use has been limited systemic delivery potential, especially in the face of antiviral immunity. We recently demonstrated that tumor-trafficking immune cells can efficiently deliver oncolytic viral therapies to their tumor targets. These cells act as both a therapeutic agent and also a carrier vehicle for the oncolytic virus. Here, we demonstrate that such delivery is also possible in the face of pre-existing antiviral immunity, so overcoming the limited systemic delivery of naked, cell-free virus. It was also found that treatment of previously immunized mice or repeat treatments leading to immunization resulted in a switch from a primarily oncolytic to an immunotherapeutic mechanism of action. Furthermore, repeat cycles of treatment with combination immune cell-viral therapy resulted in increased tumor infiltration of effector T-cells and a general reduction in the levels of known immune suppressive lymphocyte populations. This therefore represents a novel and effective means to overcome localized immune suppression within the tumor microenvironment.
authors.affiliation: University of Pittsburgh Cancer Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15238, USA. thornesh@upmc.edu
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Thorne
authors.forename: Wenchun
authors.initials: W
authors.lastname: Liang
authors.forename: Padma
authors.initials: P
authors.lastname: Sampath
authors.forename: Tobi
authors.initials: T
authors.lastname: Schmidt
authors.forename: Rachel
authors.initials: R
authors.lastname: Sikorski
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Contag
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D055612:Cytokine-Induced Killer Cells / Q000276:immunology; D004285:Dogs; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods* / Q000451:nursing*