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E - Disease Models and Clinical Applications -> Cancer – Oncolytic Viruses

Virotherapy for Diffuse Intrinsic Pontine Glioma: Results from a Phase I Clinical Trial with DNX-2401

Type: Oral Abstract Session

Presentation Details
Session Title: Late-Breaking Abstracts I
Location: Salon H
Start Time: 5/17/2022 8:00
End Time: 5/17/2022 8:15

Pediatric high-risk brain tumors remain the leading cause of cancer-related death in children. For the last 30 years, numerous treatment approaches for the most aggressive types of pediatric brain tumors have failed to improve survival, leaving the 5-year survival rate at approximately 0%. Diffuse intrinsic pontine glioma (DIPG) is the most aggressive pediatric brain tumor. Median overall survival (OS) with radiation therapy (RT) is approximately 10-11 months and survival at 2 years is <10%. Thus, it is clear that new therapeutic strategies are needed to more effectively treat these tumors. Oncolytic viruses designed to selectively replicate in and destroy tumor cells represent a promising therapeutic strategy that could improve the outcome of this malignancy. A Phase 1, single-center study was conducted to evaluate the oncolytic adenovirus, DNX-2401 (tasadenoturev), followed by RT in patients with DIPG. Newly-diagnosed patients 1-18 years old received a tumor biopsy followed by intratumoral injection of DNX-2401 via cannula and conventional RT 1-3 weeks later. Subjects were enrolled (n=12) from December 2017 to January 2020 and had a median age of 9 (range 3-18) and Lansky/Karnofsky performance scores of 90-100 (n=4; 33%) or 70-80 (n=8; 67%). Genetic assessment was completed for 11 subjects (92%) and histone H3 mutations were identified in 10 subjects, including H3.3 (n=8), H3.2 (n=1), and H3.1 (n=1); 1 subject was H3 wildtype (n=1). p53 mutations were identified in 5 of 11 subjects. DNX-2401 was administered in a dose-escalation manner (1e10 vp (n=4) or 5e10 vp (n=8)), followed by RT (11 of 12; 92%). No dose-limiting toxicities were observed and the treatment regimen was well-tolerated. The most commonly reported AEs (> 5 subjects), regardless of study drug relationship, include asthenia, headache, vomiting, pyrexia, and neurological deterioration. Three SAEs were reported, including grade 3 abdominal pain, grade 3 lymphopenia, and grade 3 clinical deterioration. Tumor reductions were reported for 9 subjects (75%), including 2 confirmed (17%) and 2 unconfirmed (17%) partial responses per RAPNO criteria. As of the data cutoff, median OS is 17.8 months, and OS-24 is 25%, with follow-up ongoing for 3 subjects (33.5, 31.4, 19.6 months). Median OS for subjects with an H3.3 mutation (n=8) is 21.2 months. The immune cell composition of the biopsies was assessed using multiplexed quantitative immunofluorescence. T cells were barely detectable in these tumors, while macrophages were abundant. We detected increased clonal T cell diversity following treatment with the virus in peripheral blood lymphocytes when paired pre- and post-treatment samples from the trial were compared Additionally, we measure pre- and post-treatment neutralizing antibodies and their relationship with survival. DNX-2401 followed by RT can be safely administered to pediatric patients with newly diagnosed DIPG. These encouraging data support the translation of oncolytic viruses for high-risk pediatric brian tumors.

Marc Garcia-Moure1, Jaime Gallego Perez-Larraya1, Ana Patiño-Garcia1, Sara Labiano1, Jasper van der Lugt2, Jessica Dobbs3, Joan Robbins4, Ricardo Diez-Valle5, Fred F. Lang6, Candelaria Gomez-Manzano7, Juan Fueyo7, Sonia Tejada-Solis5, Marta M. Alonso1

1Pediatrics, University Hospital of Navarra, Pamplona, Spain,2Pediatrics, Princess Maxima, Utrech, Netherlands,3DNATrix, SanDiego, CA,4DNatrix, SanDiego, CA,5Neurosurgery, Fundación Jimenez Díaz, Madrid, Spain,6Neurosurgery, MD Anderson Cancer Center, Houston, TX,7NeuroOncology, MD Anderson Cancer Center, Houston, TX
  M.M. Alonso: 1; Commercial Interest i.e. Company X; DNatrix. 1; What was received? i.e. Honorarium; grant. 1; For what role? i.e. Speaker; research.

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