Preliminary results from the CAPTIVE / KEYNOTE-192 study (NCT02798406) dose escalation study evaluating a single intratumoral injection of DNX-2401 (tasadenoturev; DNAtrix) followed by standard dosing with pembrolizumab (Keytruda?; Merck Sharp & Dohme Corp/MSD) every three weeks to determine the optimal dose, safety, and efficacy in patients with recurrent glioblastoma, demonstrate that combination of the two agents is well tolerated and associated with promising survival.[1]*
Glioblastoma and gliosarcoma are the most common and aggressive forms of malignant brain tumor in adults and can be resistant to conventional therapies. The purpose of the? CAPTIVE / KEYNOTE-192 study is to evaluate how well a recurrent glioblastoma or gliosarcoma tumor responds to one injection of DNX-2401, a genetically modified oncolytic adenovirus, when delivered directly into the tumor followed by intravenous administration of the immune checkpoint inhibitor pembrolizumab.
The results from the multicenter phase II study were presented at the Annual Meeting of the Society for Neuro-Oncology (SNO), being held in New Orleans, Louisiana from November 15 – 18, 2018.
Oncolytic virus: Mechanism of Action
Oncolytic viruses have long been viewed as a potential tools to directly kill cancer cells. But a growing body of research suggests that some oncolytic viruses may work?at least in part?by triggering an immune response in the body against the cancer.
DNX-2401 is an investigational oncolytic immunotherapy.? The agent is a modified common cold virus that selectively targets and kills cancer cells. In clinical trials, DNX-2401 has demonstrated robust efficacy and safety.
DNX-2401 works by setting off a chain reaction of tumor cell killing by selectively replicating within cancer cells (but not normal cells), causing tumor destruction and further spread of the oncolytic virus to adjacent tumor cells.
This process then triggers an immune response directed against the tumor. Previous studies demonstrated that DNX-2401 was well tolerated, provided clinical benefit, and extended survival for patients with recurrent glioblastoma.
Mechanism of Action: DNX-2401 (Tasadenoturev) is based on engineering stable genetic changes to adenovirus genomes to ensure safety and to enhance anti-tumor efficacy. Two stable genetic changes cause DNX-2401 to replicate selectively in retinoblastoma (Rb) pathway deficient cells and infect cells that express certain RGD-binding integrins more efficiently. Because virtually all tumor cells are defective in Rb function and already in the cell cycle, DNX-2401 replicates in and kills these tumor cells selectively and efficiently.Remarkable results
“I am excited by the early results of the trial. We have had some very remarkable responses. If I had not done the case myself, I would not have believed the complete response we have seen in one of our patients,” said Gelareh Zadeh, MD, Associate Professor at the Department of Surgery University of Toronto, and presenting author for the CAPTIVE / KEYNOTE-192 study.
“There are limited treatment options for patients with this devastating disease, and we are encouraged by the initial data showing safety and disease control with the combination of DNX-2401 and pembrolizumab,” added Frank Tufaro, PhD, CEO of DNAtrix.
“We are pleased that enrollment is nearly complete and we are looking forward to maturation of the survival data.”
DNAtrix collaborators also presented additional results from studies of DNX-2401 (a.k.a. Delta-24-RGD) and murine DNX-2440 (a.k.a. Delta-24-RGDOX), an oncolytic adenovirus expressing the immune modulator OX40 ligand.
Reference
[1] Combination Adenovirus + Pembrolizumab to Trigger Immune Virus Effects (CAPTIVE) – NCT02798406
*Experimental Dose: DNX-2401 + pembrolizumab
Intratumoral dose (1.0 mL) of DNX-2401 followed 7-9 days later by intravenous pembrolizumab, 200 mg, given every three weeks through 105 weeks (2 yrs.) or until progressive disease or unacceptable toxicity.[1]
Last Editorial Review: November 18, 2018
Featured Image: New Orleans, Louisiana, USA at Crescent City Connection Bridge over the Mississippi River. Courtesy: ? 2010 ? 2018 Fotolia. Used with permission. Mechanism of Action: DNX-2401 (Tasadenoturev) is based on engineering stable genetic changes to adenovirus genomes to ensure safety and to enhance anti-tumor efficacy. Two stable genetic changes cause DNX-2401 to replicate selectively in retinoblastoma (Rb) pathway deficient cells and infect cells that express certain RGD-binding integrins more efficiently. Because virtually all tumor cells are defective in Rb function and already in the cell cycle, DNX-2401 replicates in and kills these tumor cells selectively and efficiently. Courtesy: ? 2010 ? 2018 DNAtrix. Used with permission.
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