Safety and efficacy of the tumor-selective adenovirus enadenotucirev, in combination with nivolumab, in patients with advanced/metastatic epithelial cancer: A phase i clinical trial (SPICE)

Marwan Fakih, Wael Harb, Daruka Mahadevan, Hani Babiker, Jordan Berlin, Tom Lillie, David Krige, Jo Carter, Chris Cox, Minesh Patel, Lola Parfitt, Mark Powell, Lee Rosen

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Background Novel combination therapies to overcome anti-PD-1 resistance are required. Enadenotucirev, a tumor-selective blood stable adenoviral vector, has demonstrated a manageable safety profile and ability to increase tumor immune-cell infiltration in phase I studies in solid tumors. Methods We conducted a phase I multicenter study of intravenous enadenotucirev plus nivolumab in patients with advanced/metastatic epithelial cancer not responding to standard therapy. Co-primary objectives were safety/tolerability and maximum tolerated dose and/or maximum feasible dose (MTD/MFD) of enadenotucirev plus nivolumab. Additional endpoints included response rate, cytokine responses, and anti-tumor immune responses. Results Overall, 51 heavily pre-treated patients were treated, 45/51 (88%) of whom had colorectal cancer (35/35 patients with information available were microsatellite instability-low/microsatellite stable) and 6/51 (12%) had squamous cell carcinoma of the head and neck. The MTD/MFD of enadenotucirev plus nivolumab was not reached, with the highest dose level tested (1×10 12 vp day 1; 6×10 12 vp days 3 and 5) shown to be tolerable. Overall, 31/51 (61%) patients experienced a grade 3-4 treatment-emergent adverse event (TEAE), most frequently anemia (12%), infusion-related reaction (8%), hyponatremia (6%), and large intestinal obstruction (6%). Seven (14%) patients experienced serious TEAEs related to enadenotucirev; the only serious TEAE related to enadenotucirev occurring in >1 patient was infusion-related reaction (n=2). Among the 47 patients included in efficacy analyses, median progression-free survival was 1.6 months, objective response rate was 2% (one partial response for 10 months), and 45% of patients achieved stable disease. Median overall survival was 16.0 months; 69% of patients were alive at 12 months. Persistent increases in Th1 and related cytokines (IFNγ, IL-12p70, IL-17A) were seen from ∼day 15 in two patients, one of whom had a partial response. Among the 14 patients with matching pre-tumor and post-tumor biopsies, 12 had an increase in intra-tumoral CD8 + T-cell infiltration and 7 had increased markers of CD8 T-cell cytolytic activity. Conclusions Intravenously dosed enadenotucirev plus nivolumab demonstrated manageable tolerability, an encouraging overall survival and induced immune cell infiltration and activation in patients with advanced/metastatic epithelial cancer. Studies of next-generation variants of enadenotucirev (T-SIGn vectors) designed to further re-program the tumor microenvironment by expressing immune-enhancer transgenes are ongoing. Trial registration number NCT02636036.

Original languageEnglish (US)
Article numbere006561
JournalJournal for ImmunoTherapy of Cancer
Issue number4
StatePublished - Apr 24 2023
Externally publishedYes


  • clinical trials as topic
  • immunotherapy
  • oncolytic viruses
  • therapies, investigational

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Immunology and Allergy
  • Pharmacology
  • Immunology


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