Abstract CT027: Oncolytic virus DNX-2401 with a short course of temozolomide for glioblastoma at first recurrence: Clinical data and prognostic biomarkers

Abstract

Abstract DNX-2401 is a replication competent oncolytic adenovirus that has shown a potent antitumor effect in preclinical glioma models and a safe profile when administer as a single agent in glioma patients. Previously, our group showed that combination of DNX-2401 with temozolomide significantly increased the survival of mice bearing gliomas. Even though virotherapy is becoming a real therapeutic option still the precise mechanism of action, the interplay with the tumor microenvironment and biomarkers that predict response remain elusive. The main objective of this clinical trial was to investigate safety, OR, and OS following treatment with DNX-2401 and temozolomide. In addition, we aim to seek biomarkers that predict response to the virus. We included 31 glioma patients at first recurrence after prior surgery and standard treatment with radiotherapy, and temozolomide. Tumor resection or biopsy was performed to confirm recurrent disease. All patients received a single intraparenchymal injection of DNX-2401 (3x1010 vp) followed by 4 cycles of 150 mg/m2 temozolomide 2-4 weeks later. Ninety-four percent of patients completed all 4 planned cycles. The safety objective of the trial was achieved with no severe toxicities related to DNX-2401. Grade 3-4 adverse events were consistent with those associated with temozolomide (e.g., lymphopenia) or underlying disease. Several objective responses were observed with three patients alive 30, 19 and 27 months after treatment. The study is ongoing and results will be updated. Patients with higher titers of neutralizing antibodies prior to virus administration appeared to respond better to treatment. No differences were seen in the levels of serum cytokines amongst patients and treatment times. FGF2 is a growth factor that has been shown to increased cell susceptibility to virus infection and replication through inhibition of the interferon pathway. Interestingly, high expression of FGF2 in tumor samples was associated with significantly longer overall survival. FGF2 expression was inversely correlated with IFN-γ expression in the tumor and in exosomes isolated from liquid biopsies in the same patient. These data also suggest that patients with stronger innate responses did worse than those where the IFN pathway was downregulated. In summary, our data demonstrate that DNX-2401 in combination with temozolomide is well tolerated, can be safely administered and shows therapeutic activity. Moreover, FGF2 as a prognostic biomarker of DNX-2401 treatment response deserves further investigation. Citation Format: Marta M. Alonso, Marc García-Moure, Marisol Gonzalez-Huarriz, Miguel Marigil, Ruben Hernandez-Alcoceba, María Buñales, Sandra Hervás, Jaime Gallego, Candelaria Gomez-Manzano, Juan Fueyo, Frederick Lang, Joanna Peterkin, Ricardo Diez-Valle, Sonia Tejada. Oncolytic virus DNX-2401 with a short course of temozolomide for glioblastoma at first recurrence: Clinical data and prognostic biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT027. doi:10.1158/1538-7445.AM2017-CT027