Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial

Abstract

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2–20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1–69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7–13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05–0.87). A total of 56.2% (95% CI 41.1–70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

Immunosurveillance in clinical cancer management

“…133 Durvalumab has been shown to improve overall survival in patients with NSCLC who were previously treated with chemotherapy plus RT as induction therapy compared with placebo, 134 suggesting that RT can also induce immunological benefits that can be amplified with ICIs (at least in some tumors). Accumulating evidence from early phase clinical trials suggests that ICDinducing oncolytic viruses may also represent promising combinatorial partners for ICIs in patients with melanoma and glioblastoma, 135,136 but results from larger studies are awaited. In summary, various ICD-inducing strategies appear to cooperate with ICIs toward superior disease control in patients with a wide range of tumors.…”

Efficacy of tumour-treating fields therapy in recurrent glioblastoma: A narrative review of current evidence

“…Numerous pioneering therapies, including imatinib, axitinib, personalized peptide immunization, nivolumab with or without ipilimumab, pembrolizumab, enzastaurin, and afatinib, have been the subject of scrutiny for glioblastoma treatment. [42][43][44] However, the evidence substantiating their efficacy remains insufficient, particularly in recurrent Glioblastoma, failing to demonstrate substantial therapeutic benefits. Therefore, the necessity of further research into these therapies may warrant critical examination.…”

“…This striking phenomenon consistently emerges in various GBM cell lines upon exposure to TTFields. [44] The DNA sensors, such as cGAS and AIM2, can detect the clusters of cytosolic micronuclei generated by TTFields. These DNA sensors activate their corresponding inflammasomes, cGAS/STING and AIM2/caspase 1, upon recruitment to these clusters.…”

“…[50] The mechanism of action of TTFields therapy is rooted in two fundamental principles: dipole alignment and dielectrophoresis. [44,51] The principle of dipole alignment capitalizes on the existence of negatively and positively charged proteins within cells that orient towards the oppositely charged electrodes when exposed to an electric field. Additionally, the concept of dielectrophoresis operates on the movement of molecules towards regions of heightened electric field intensity when subjected to electric current.…”

Promises of oncolytic viral therapy for adult and children with brain glioma

“…The demonstrated ability of OVs to reshape the brain-tumor microenvironment have awaken interest in combinational strategies with other immunotherapies such as immune checkpoint inhibitors [33]. In this context, a multicenter phase I/II study evaluated the combination of intratumoral DNX-2401 followed by intravenous anti-PD1 antibody Pembrolizumab in patients with recurrent GBM [35 ▪ ]. Primary endpoint of safety was met, and notable survival benefit was observed in selected patients with durable responses, with median OS of 12.5 months.…”