Oncolytic Virus Shows Early Promise in Glioma

Frederick F. Lang, MD

The oncolytic virus Delta-24-RGD can infect, replicate, and kill glioma cells in patients, according to phase I research presented at the 2014 Society for Neuro-Oncology (SNO) Annual Meeting in Miami.

Delta-24-RGD is a novel replication-competent, tumor-selective, oncolytic adenovirus that has enhanced infectivity, according to lead author Frederick F. Lang, MD, who presented the data. After preclinical studies demonstrated promising results, researchers began a first-in-human phase I study to assess the virus’s capacity to replicate in human gliomas.

Study objectives included a focus on the maximum-tolerated dose of Delta-24-RGD administered directly into the tumor or via the post resection catheter, determine local and systemic toxicity of the virus after intracranial injection, and determine the biological effects at the molecular level with the examination of post-treatment tumor specimens.

“We wanted to show it could do what it was meant to do at a biological level,” said Lang, who is a professor and director of clinical research in the Department of Neurosurgery at The University of Texas MD Anderson Cancer Center.

The study assigned 37 patients with recurrent high-grade gliomas to two arms. Arm A (n = 25) received one intratumoral injection of Delta-24-RGD into biopsy-proven recurrent glioma. The biological endpoint cohort, arm B (n = 12), had an initial intratumoral injection via an implanted catheter and then 14 days later via en bloc tumor/catheter resection, which was done to obtain posttreatment specimens. There was then a subsequent injection in arm B of Delta-24-RGD into the postresection cavity.

One requirement of the study’s eligibility criteria was that each patient’s glioma type was limited to glioblastoma, gliosarcoma, anaplastic gliomas, anaplastic infiltrating glioma, mixed anaplastic glioma, and anaplastic ependymoma. All patients had to have unequivocal evidence of tumor recurrence or progression via MRI within 15 days before the baseline procedure. Patients had to have failed prior surgical resection, biopsy, chemotherapy, or radiation. Physician investigators had to agree that the injection would not deliver Delta-24-RGD into the ventricular system. Additionally, patients may or may not have had previous chemotherapy.

Researchers escalated the dose in eight cohorts. The maximum tolerated dose was 3 x 10¹⁰ vp.

Median overall survival was 11 months. Three patients (12%) had complete responses, which Lang said was a particularly noteworthy result. These patients are still alive and have no evidence of disease 3.2, 2, and 1.75 years after treatment. A review of serial MRIs showed increased enhancement before tumor regression, which was consistent with inflammatory-mediated responses. These three responders had 10- to 1000-fold increases in interleukin 12p70, the latter of which induces Th1 responses and cell-mediated immunity.

In a symptomatic patient in group A, histological analysis of a resected tumor identified macrophages and CD8 inflammatory-mediated responses during the period of increased MRI enhancement.

As noted, the biological specimens showed that the virus is capable of infecting, replicating in, and killing glioma cells in patients, the researchers concluded. “Viral-induced and anti-tumor immunity likely plays a role in the antiglioma effect,” said Lang, noting that researchers came to this conclusion based on imaging and correlative histological and cytokine studies.

Delta-24-RGD had a “favorable toxicity profile,” according to Lang et al.

Future research will include what may be unique about the immune system of the three patients who responded to the virus, Lang said. Researchers also want to see what can be applied to others based on the findings from those responders. “Can we make patients who didn’t respond look like the 12% who did in some way? This is a great area of research we need to work on,” he said.

Lang FF, Conrad C, Gomez-Manzano C, et al. Phase I clinical trial of oncolytic virus Delta-24-RGD (DNX-2401) with biological endpoints: implications for viro-immunotherapy. Presented at: 19th Annual Meeting of the Society for Neuro-Oncology; November 13-16, 2014; Miami, FL. Abstract NT-18.

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