title: Phase I study with ONCOS-102 for the treatment of solid tumors - an evaluation of clinical response and exploratory analyses of immune markers.
abstract: BACKGROUND
  We conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined.
  
  
  METHODS
  The study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNγ) enzyme linked immunospot assay (ELISPOT).
  
  
  RESULTS
  No dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated TH1 cells and TH1 type immune profile were observed in the post-treatment biopsies of these two patients.
  
  
  CONCLUSIONS
  ONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors.
  
  
  BACKGROUND
  NCT01598129. Registered 19/04/2012.
authors.affiliation: Oncos Therapeutics, Helsinki, Finland.
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authors.affiliation: Oncos Therapeutics, Helsinki, Finland.
authors.forename: Sari
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authors.affiliation: Cancer Gene Therapy Group, Hartman Institute, University of Helsinki, Helsinki, Finland ; Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
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authors.affiliation: Docrates Cancer Center, Helsinki, Finland.
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authors.affiliation: Docrates Cancer Center, Helsinki, Finland ; The University of Texas MD Anderson Cancer Center, Houston, TX USA.
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authors.affiliation: Docrates Cancer Center, Helsinki, Finland.
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authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
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authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
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authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
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authors.affiliation: Pathology, Research Programs Unit and HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
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authors.affiliation: Hämatologie-Onkologie, Krankenhaus Nordwest, Frankfurt, Germany.
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authors.affiliation: Hämatologie-Onkologie, Krankenhaus Nordwest, Frankfurt, Germany.
authors.forename: Julia
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authors.affiliation: Hämatologie-Onkologie, Krankenhaus Nordwest, Frankfurt, Germany.
authors.forename: Claudia
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authors.affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
authors.forename: Matti
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authors.affiliation: Oncos Therapeutics, Helsinki, Finland.
authors.forename: Charlotta
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authors.affiliation: Oncos Therapeutics, Helsinki, Finland.
authors.forename: Mikael
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authors.affiliation: Oncos Therapeutics, Helsinki, Finland.
authors.forename: Elina
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authors.lastname: Haavisto
authors.affiliation: Oncos Therapeutics, Helsinki, Finland.
authors.forename: Tiina
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authors.lastname: Hakonen
authors.affiliation: Oncos Therapeutics, Helsinki, Finland.
authors.forename: Raita
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authors.affiliation: Oncos Therapeutics, Helsinki, Finland.
authors.forename: Magnus
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authors.affiliation: Medix Biochemica, Helsinki, Finland.
authors.forename: Juuso
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authors.lastname: Juhila
authors.affiliation: Oncos Therapeutics, Helsinki, Finland.
authors.forename: Petri
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authors.lastname: Priha
authors.affiliation: Oncos Therapeutics, Helsinki, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Suoranta
authors.affiliation: Merck Sharp & Dohme, Espoo, Finland.
authors.forename: Lotta
authors.initials: L
authors.lastname: Vassilev
authors.affiliation: Oncos Therapeutics, Helsinki, Finland.
authors.forename: Antti
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authors.lastname: Vuolanto
authors.affiliation: Docrates Cancer Center, Helsinki, Finland.
authors.forename: Timo
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authors.lastname: Joensuu
keywords: Anti-tumor immunity; Cytotoxic CD8+ T cell; Immunotherapy; Intratumoral; Oncolytic adenovirus; in situ vaccine