Abstract
In a phase I trial, DNX-2401 is safe and achieves durable responses in patients with recurrent glioma.
Major finding: In a phase I trial, DNX-2401 is safe and achieves durable responses in patients with recurrent glioma.
Mechanism: DNX-2401 induces direct lysis of tumor cells and promotes tumor immune cell infiltration.
Impact: Oncolytic virotherapy with DNX-2401 may achieve durable responses in a subset of patients with glioma.
Despite standard treatment with surgery, radiochemotherapy, and adjuvant chemotherapy, glioblastomas have a poor survival rate and generally recur. Oncolytic adenoviruses have emerged as a potential therapeutic modality, and in preclinical studies the tumor-selective oncolytic adenovirus DNX-2401 induced tumor regression via direct oncolysis of tumor cells and by inducing an antitumor immune response. Lang and colleagues evaluated the safety and efficacy of DNX-2401 in a phase I dose-escalation study enrolling 37 patients with recurrent malignant glioma in two groups. Group A (25 patients), the treatment-only group, received a single intratumoral injection of DNX-2401, and group B (12 patients), the treat-resect-treat group, received intratumoral DNX-2401 followed 14 days later by tumor resection. DNX-2401 was well tolerated; no dose-limiting toxicities occurred, and no study drug-related grade 3+ adverse events occurred. Immunostaining of tumors from group B patients revealed that 55% (6/11) tumors had continued oncolytic adenovirus replication 14 days after treatment with DNX-2401, indicative of direct lysis of tumor cells. Further, post-treatment tumor sites exhibited inflammation, necrosis, and immune cell infiltration including CD8+ and T-BET+ T cells. In group A, tumor reductions were observed in 72% (18/25) of patients. The median overall survival was 9.5 months. In group A, three patients achieved complete and durable responses and two patients experienced sustained stable disease, and these patients (20%) survived for more than 3 years after treatment. Taken together, these findings reveal that DNX-2401 is safe and has antitumor activity in patients with glioma. Further, DNX2401 exhibited robust viral replication and direct killing of tumor cells in addition to producing an antitumor immune response, supporting further clinical investigation of DNX-2401.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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