title: Repurposing Sunitinib with Oncolytic Reovirus as a Novel Immunotherapeutic Strategy for Renal Cell Carcinoma.
abstract: OBJECTIVE
  In addition to their direct cytopathic effects, oncolytic viruses are capable of priming antitumor immune responses. However, strategies to enhance the immunotherapeutic potential of these agents are lacking. Here, we investigated the ability of the multi-tyrosine kinase inhibitor and first-line metastatic renal cell carcinoma (RCC) agent, sunitinib, to augment the antitumor immune response generated by oncolytic reovirus.
  
  
  METHODS
  In vitro, oncolysis and chemokine production were assessed in a panel of human and murine RCC cell lines after exposure to reovirus, sunitinib, or their combination. In vivo, the RENCA syngeneic murine model of RCC was employed to determine therapeutic and tumor-specific immune responses after treatment with reovirus (intratumoral), sunitinib, or their combination. Parallel investigations employing the KLN205 syngeneic murine model of lung squamous cell carcinoma (NSCLC) were conducted for further validation.
  
  
  RESULTS
  Reovirus-mediated oncolysis and chemokine production was observed following RCC infection. Reovirus monotherapy reduced tumor burden and was capable of generating a systemic adaptive antitumor immune response evidenced by increased numbers of tumor-specific CD8+IFNγ-producing cells. Coadministration of sunitinib with reovirus further reduced tumor burden resulting in improved survival, decreased accumulation of immune suppressor cells, and the establishment of protective immunity upon tumor rechallenge. Similar results were observed for KLN205 tumor-bearing mice, highlighting the potential broad applicability of this approach.
  
  
  CONCLUSIONS
  The ability to repurpose sunitinib for augmentation of reovirus' immunotherapeutic efficacy positions this novel combination therapy as an attractive strategy ready for clinical testing against a range of histologies, including RCC and NSCLC. Clin Cancer Res; 22(23); 5839-50. ©2016 AACR.
authors.affiliation: Department of Oncology, University of Calgary, Calgary, Alberta, Canada.|Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Lawson
authors.affiliation: Department of Oncology, University of Calgary, Calgary, Alberta, Canada.|Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Mostafa
authors.affiliation: Department of Oncology, University of Calgary, Calgary, Alberta, Canada.|Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Zhong Qiao
authors.initials: ZQ
authors.lastname: Shi
authors.affiliation: Department of Oncology, University of Calgary, Calgary, Alberta, Canada.|Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Spurrell
authors.affiliation: Department of Oncology, University of Calgary, Calgary, Alberta, Canada.|Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Wenqian
authors.initials: W
authors.lastname: Chen
authors.affiliation: Southern Alberta Institute of Urology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Kawakami
authors.affiliation: Department of Oncology, University of Calgary, Calgary, Alberta, Canada.|Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Kathy
authors.initials: K
authors.lastname: Gratton
authors.affiliation: Department of Oncology, University of Calgary, Calgary, Alberta, Canada.|Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Satbir
authors.initials: S
authors.lastname: Thakur
authors.affiliation: Department of Oncology, University of Calgary, Calgary, Alberta, Canada. Don.morris@ahs.ca.|Tom Baker Cancer Centre, Calgary, Alberta, Canada.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Morris
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000628:therapy* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000276:immunology*; D011758:Pyrroles / Q000494:pharmacology*; D012087:Reoviridae / Q000276:immunology*; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib