DNX-2401, an Oncolytic Virus, for the Treatment of Newly Diagnosed Diffuse Intrinsic Pontine Gliomas: A Case Report

Abstract

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive glial brain tumors that primarily affect children, for which there is no curative treatment. Median overall survival is only one year. Currently, the scientific focus is on expanding the knowledge base of the molecular biology of DIPG, and identifying effective therapies. Oncolytic adenovirus DNX-2401 is a replication-competent, genetically modified virus capable of infecting and killing glioma cells, and stimulating an anti-tumor immune response. Clinical trials evaluating intratumoral DNX-2401 in adults with recurrent glioblastoma have demonstrated that the virus has a favorable safety profile and can prolong survival. Subsequently, these results have encouraged the transition of this biologically active therapy from adults into the pediatric population. To this aim, we have designed a clinical Phase I trial for newly diagnosed pediatric DIPG to investigate the feasibility, safety, and preliminary efficacy of delivering DNX-2401 into tumors within the pons following biopsy. This case report presents a pediatric patient enrolled in this ongoing Phase I trial for children and adolescents with newly diagnosed DIPG. The case involves an 8-year-old female patient with radiologically diagnosed DIPG who underwent stereotactic tumor biopsy immediately followed by intratumoral DNX-2401 in the same biopsy track. Because there were no safety concerns or new neurological deficits, the patient was discharged 3 days after the procedures. To our knowledge, this is the first report of intratumoral DNX-2401 for a patient with DIPG in a clinical trial. We plan to demonstrate that intratumoral delivery of an oncolytic virus following tumor biopsy for pediatric patients with DIPG is a novel and feasible approach and that DNX-2401 represents an innovative treatment for the disease.

Therapeutic efficacy of an immune stimulatory gene therapy strategy in a mouse model of high grade brainstem glioma

“…Our results are consistent with other pre-clinical studies that report the brainstem can tolerate adenoviral mediated immunotherapy (65,66). Results from a clinical trial (NCT03178032) utilizing adenoviral vector delivery of an oncolytic virus into the pons of DIPG patients will also shed light on the feasibility and toxicity of intratumoral adenoviral delivery into the brainstem (67).…”

Overcoming the limitations of locally administered oncolytic virotherapy

“…Notably, oAd, which is currently being marketed as Oncorine, was the first oncolytic virus to be approved for clinical use [6]. In support, numerous reports have demonstrated that locally administered oAds can induce potent antitumor effect in preclinical and clinical studies [7][8][9][10][11][12][13]. However, there are several notable limitations in clinical trials that restrict the therapeutic efficacy of oAds.…”

Pharmacologic inhibition of lysine specific demethylase-1 (LSD1) as a therapeutic and immune-sensitization strategy in diffuse intrinsic pontine glioma (DIPG)

“…Other promising clinically-actionable drug candidates in DIPG could also be combined with NK cell therapy, such as the DRD2-antagonist ONC201 which has been shown to recruit NK cells into tumors 41 , and has clinical trial data in adult gliomas 42 and recently began a trial in pediatric K27M+ tumors (NCT03416530). Oncolytic viruses targeting DIPG have also begun clinical trials 43 and NK cells have been shown to be involved in the immune response to lysed tumor cells in the brain 44 . We did not yet test synergy of NK cells with standard-of-care radiotherapy or chemotherapy in our models, which is warranted based on pre-clinical 45,46 and clinical trial 47 data of adult gliomas.…”