title: Defining Effective Combinations of Immune Checkpoint Blockade and Oncolytic Virotherapy.
abstract: OBJECTIVE
  Recent data from randomized clinical trials with oncolytic viral therapies and with cancer immunotherapies have finally recapitulated the promise these platforms demonstrated in preclinical models. Perhaps the greatest advance with oncolytic virotherapy has been the appreciation of the importance of activation of the immune response in therapeutic activity. Meanwhile, the understanding that blockade of immune checkpoints (with antibodies that block the binding of PD1 to PDL1 or CTLA4 to B7-2) is critical for an effective antitumor immune response has revitalized the field of immunotherapy. The combination of immune activation using an oncolytic virus and blockade of immune checkpoints is therefore a logical next step.
  
  
  METHODS
  Here, we explore such combinations and demonstrate their potential to produce enhanced responses in mouse tumor models. Different combinations and regimens were explored in immunocompetent mouse models of renal and colorectal cancer. Bioluminescence imaging and immune assays were used to determine the mechanisms mediating synergistic or antagonistic combinations.
  
  
  RESULTS
  Interaction between immune checkpoint inhibitors and oncolytic virotherapy was found to be complex, with correct selection of viral strain, antibody, and timing of the combination being critical for synergistic effects. Indeed, some combinations produced antagonistic effects and loss of therapeutic activity. A period of oncolytic viral replication and directed targeting of the immune response against the tumor were required for the most beneficial effects, with CD8(+) and NK, but not CD4(+) cells mediating the effects.
  
  
  CONCLUSIONS
  These considerations will be critical in the design of the inevitable clinical translation of these combination approaches. Clin Cancer Res; 21(24); 5543-51. ©2015 AACR.See related commentary by Slaney and Darcy, p. 5417.
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Rojas
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Padma
authors.initials: P
authors.lastname: Sampath
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Weizhou
authors.initials: W
authors.lastname: Hou
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pennsylvania. ThorneSH@UPMC.edu.
authors.forename: Steve H
authors.initials: SH
authors.lastname: Thorne
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D007111:Immunity, Cellular; D056747:Immunomodulation / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors; D051379:Mice; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000175:diagnosis / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D014616:Vaccinia virus / Q000187:drug effects / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; D053645:Interleukin-2 Receptor alpha Subunit; D061026:Programmed Cell Death 1 Receptor