title: Inhibitory Receptors Induced by VSV Viroimmunotherapy Are Not Necessarily Targets for Improving Treatment Efficacy.
abstract: Systemic viroimmunotherapy activates endogenous innate and adaptive immune responses against both viral and tumor antigens. We have shown that therapy with vesicular stomatitis virus (VSV) engineered to express a tumor-associated antigen activates antigen-specific adoptively transferred T cells (adoptive cell therapy, ACT) in vivo to generate effective therapy. The overall goal of this study was to phenotypically characterize the immune response to VSV+ACT therapy and use the information gained to rationally improve combination therapy. We observed rapid expansion of blood CD8+effector cells acutely following VSV therapy with markedly high expression of the immune checkpoint molecules PD-1 and TIM-3. Using these data, we tested a treatment schedule incorporating mAb immune checkpoint inhibitors with VSV+ACT treatment. Unlike clinical scenarios, we delivered therapy at early time points following tumor establishment and treatment. Our goal was to potentiate the immune response generated by VSV therapy to achieve durable control of metastatic disease. Despite the high frequency of endogenous PD-1+TIM-3+CD8+T cells following virus administration, antibody blockade did not improve survival. These findings provide highly significant information about response kinetics to viroimmunotherapy and juxtapose the clinical use of checkpoint inhibitors against chronically dysfunctional T cells and the acute T cell response to oncolytic viruses.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA; Medical Scientist Training Program, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Shim
authors.affiliation: Targeted Therapy Laboratory, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JJ, UK.
authors.forename: Shane
authors.initials: S
authors.lastname: Zaidi
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Kottke
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Evgin
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Karishma R
authors.initials: KR
authors.lastname: Rajani
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA; Medical Scientist Training Program, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Schuelke
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Driscoll
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Huff
authors.affiliation: Department of Ophthalmology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jose S
authors.initials: JS
authors.lastname: Pulido
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: vile.richard@mayo.edu.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Vile
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors / Q000235:genetics*; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007156:Immunologic Memory; D007167:Immunotherapy; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D009026:Mortality; D009362:Neoplasm Metastasis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D016896:Treatment Outcome; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D061026:Programmed Cell Death 1 Receptor
keywords: checkpoint inhibitors; oncolytic virotherapy; tumor therapy