In The Pipeline: Crossing the Blood-Brain Barrier to Fight Tumors
Researchers have for the first time shown that an oncolytic virus, wild-type reovirus, infects and replicates in brain tumors following intravenous administration. Researchers gave the update on Reolysin, the proprietary formulation, at the American Society of Clinical Oncology annual meeting in Chicago.
Oncolytic viruses are known to preferentially replicate in, and kill cancerous cells. Wild-type reovirus is a proprietary isolate of reovirus type 3 Dearing, a double-stranded RNA human reovirus. In two trials using intralesional administration in gliomas and recurrent brain tumors, wild-type reovirus has been well tolerated, with early signs of efficacy. Recently, a trial in Leeds, UK (Adair et al. 2012 Sci Transl Med) has proven that intravenous wild-type reovirus accesses colorectal cancer liver metastases. Intravenous delivery to brain tumors would be easier, cheaper and more acceptable to patients than intralesional administration, according to the researchers.
However, no oncolytic virus had been shown to infect brain tumors following intravenous delivery. The study researchers sought to identify whether wild-type reovirus can cross the blood brain barrier and infect brain tumors following intravenous administration.
In their open-label, non-randomized, single center study of intravenous wild-type reovirus—administered to patients prior to planned surgery for recurrent high grade glioma or metastatic brain tumors—three patients have completed the study to date, including one glioblastoma multiforme, one grade 3 oligodendroglioma and one colorectal brain metastasis. Two of the three patients were taking high dose steroids while all three resected patient tumors contained wild-type reovirus RNA and protein. There was evidence for wild-type reovirus productive infection in two of the tumors. Grade 3-4 adverse reactions were neutropaenia in one patient and lymphopaenia in all three patients. In total, 12 patients will be treated with a single infusion of 1x1010TCID50of wild-type reovirus.
Here, Brad Thompson, PhD, President and CEO of Oncolytics, talks about the company’s study ((J Clin Oncol 32:5s, 2014 (suppl; abstr 3104).
The primary objective of your study is to determine the presence of wild-type reovirus in the resected tumors as assessed by immunohistochemistry, RNA in-situ hybridization and retrieval of infectious virions. What can you tell us about the method in question and your line of thinking behind approaching the cancer this way?
We have been searching for a method of treating primary and metastatic tumors in the brain without having to resort to surgical-assisted methods of drug delivery. This study’s primary objective was specifically designed to address the question: can IV-delivered virus cross the blood-brain barrier and infect these tumors? Now that this is known, we can design a traditional therapeutic study to demonstrate that Reolysin can be used to treat these tumors without a surgical delivery assist step.
Your abstract cites a completed trial in Leeds, UK (Adair et al. 2012 Sci Transl Med) that has proven that intravenous wild-type reovirus accesses colorectal cancer liver metastases. How significant of a finding was it to this approach and what effect did it have for your own research?
This finding was very significant in that approximately half of colorectal cancer patients have liver metastases. In order to treat this large patient group effectively, a new agent must be able to access the liver metastases, and Reolysin does just that. This study led to an ongoing randomized clinical study with Reolysin in colorectal cancer patients that includes many patients with metastatic liver disease.
What is the next approach for your company’s research?
We are seeking a therapy for patients with primary tumors or brain metastases that does not entail surgery as a drug delivery step, and reserves surgery for therapeutic use. Our next step is to look at pediatric patients, as children are in need of new, less-invasive options for brain cancers.