DUBLIN – Further information on the first death of a cancer patient undergoing oncolytic viral therapy with a vesicular stomatitis virus (VSV) strain engineered to express human interferon-β (IFN-β) has emerged.

The trial, which was sponsored by the Mayo Clinic, in Scottsdale, Ariz., was placed on clinical hold following the death in February of one patient during a phase I trial in patients with primary or metastatic liver cancer. (See BioWorld Today, June 26, 2015.)

The principal investigator on the study, Mitesh Borad, of the Mayo Clinic, presented his findings to the Recombinant DNA Advisory Committee of the NIH on June 9. He also reported on the trial at the 9th International Meeting on Oncolytic Virus Therapeutics, in Boston last month.

The patient, a 67-year-old white male with refractory metastatic colon cancer, was the second of two patients to receive the highest dose at the midpoint of a dose-escalation study – 1.8 x 107 viral particles. "The first patient did not experience a DLT (dose-related toxicity)," he told members of the committee, via conference call. The patient who did had received five prior drug therapies, as well as radioembolization, or the delivery of radioactive particles via catheter.

On day two and day three after intratumoral injection of VSV-IFN-β, the patient experienced dyspnea, chills, chest pain, pleural effusions and a drop in blood oxygen. It was not clear if those were treatment-related effects as he had previously exhibited similar symptoms, Borad said. The patient received fluid drainage and antibiotic therapy, following by steroid therapy on day three, which led to improvement in his symptoms.

"At day five, we started noticing that his liver enzymes started trending up, and this trend continued through day eight," Borad said. "By day eight, unfortunately, his clinical course also started to decline. He became encephalopathic. His ammonia was elevated. Later that day, he was also noted to have a witnessed tonic-clonic [or grand-mal] seizure." He received anti-epileptic therapy. By day 10 he was unable to speak. At that point, he received anti-viral ribavirin therapy. "His clinical course continued to deteriorate," Borad said. He became hypotensive and developed tachycardia and required pressor support to maintain blood pressure and cardiac function. "These events eventually led to the development of hepatorenal syndrome," Borad said.

'TOXICITIES WERE POSSIBLE'

On day 13, at the family's request, aggressive treatment was withdrawn – "unfortunately, said Borad – and the patient died that evening.

Questioned by committee member Laurie Zoloth, a bioethicist based in Northwestern University, in Evanston, Ill., on his use of the word "unfortunately," Borad replied that oncolytic viral therapy should be considered like CAR T-cell therapy. "There may be in some patients a very torrid period, where they get toxicity, but if they can pull through, they may well be the same patients who also demonstrate an anti-tumor response."

The informed consent discussion with the patient had focused more on the possibility of a cytokine storm than an apparently toxic level of viral replication. "The patient was clearly aware, with the type of treatment we were giving, that toxicities were a possibility, but the severity and nature of those toxicities sometimes only come in light in a real fashion when [one is] faced with them," Borad said.

The patient had a robust antibody response to the virus, and there was no apparent evidence of cytokine-release syndrome. Although profiling has not been fully completed, the patient's cytokine profile was similar to those of other patients. It has not yet been possible to determine the extent of immune cell infiltration into the tumor.

"We don't have in place a good assay for VSV-specific immune responses," Stephen Russell, of the Mayo Clinic, in Rochester, Minn., who developed the VSV-IFN-β construct, told the committee.

Peak serum concentration of IFN-b was 8.8 nanograms per milliliter, which was reached on day eight. That's about 20 times higher than the levels reported in a recent pharmacokinetic study on peginterferon-beta1a levels in healthy and renally impaired subjects, conducted by scientists at Cambridge, Mass.-based Biogen Inc. and colleagues. The paper, "Pharmacokinetics, Pharmacodynamics, and Safety of Peginterferon Beta-Ia in Subjects with Normal or Impaired Renal Function," appeared in the February 2015 issue of the Journal of Clinical Pharmacology.

Extensive replication of the virus was evident, in both normal and tumor tissues. "In all of these tissue specimens, we found significant elevations of viral genomes, up to tens of millions of copies to hundreds of millions of copies," Borad said. "Notably, there is a difference between the tumor areas and the normal areas of several logs. Clearly there is some differential in the ability of the normal tissues and the tumor tissues to be affected by the virus."

A viral recovery assay indicated two mutational differences between the viral genomes recovered from normal tissue and those recovered from cancerous tissue. Further experiments are now under way to determine the functional significance, if any, of these changes. Investigators also detected evidence of cellular lysis, which may be possibly linked to tumor lysis syndrome, a potentially fatal complication of cancer therapy resulting from the large-scale release of intracellular ions and other metabolites.

The study had recruited 14 of a planned 48 patients, when the patient death occurred. Twelve had received treatment, of whom one exhibited a partial response and two others had stable disease for more than four months. Borad said the study investigators plan to resume treatment at lower doses.

Deaths due to modern oncolytic viral therapy are rare. One of the most salient features of Thousand Oaks, Calif.-based Amgen's talimogene laherparepvec (T-Vec), which is in line to receive FDA approval by Oct. 27, is its safety, even when administered in combination with other agents. However, the very features that make VSV a potentially attractive cancer therapy – its rapid replication rate and its rarity in humans – may make it more dangerous for some advanced cancer patients with a high tumor burden. Newcastle disease virus, an avian virus, has also been linked with a patient's death: that of a 55-year-old man with renal carcinoma and lung metastases. He had received a single dose of PV701, a strain in development at Pro-Virus Inc., of Gaithersburg, Md., and died of respiratory failure.

The Medimmune arm of London-based Astrazeneca plc licensed the IFN-β program from Rochester-based Omnis Pharma Inc., in January.