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Best Practices in Immunotherapy – June/July 2017 Vol 8

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2017 ASCO-SITC Clinical Immuno-Oncology Symposium

Oncolytic Virotherapy: A New Cornerstone for Immuno-Oncology

When administered by intratumoral injection, oncolytic viruses have been shown to enhance the body’s immune response and be effective in combination with checkpoint antibodies. According to data presented at the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium, however, a single intravenous dose of an oncolytic virus can be highly effective in disseminated cancer as well.

“A new cornerstone for immuno-oncology is emerging,” said Stephen J. Russell, MD, PhD, Director of Molecular Medicine at Mayo Clinic, Rochester, MN. “Virus-mediated tumor destruction, which is associated with inflammatory in situ killing, boosts the immune response to tumor antigens. Virotherapy may thus be an ideal antigen-agnostic approach to enhance the potency of checkpoint inhibitor antibodies.”

“It’s certainly much easier than defining all those unique tumor neoantigens and creating a vaccine based on that information,” Dr Russell added.

After intratumoral injection, oncolytic viruses spread at sites of tumor growth, cause tumor cell death, and in the course of killing tumor cells, amplify the specific antitumor immune response. Although the survival advantage didn’t quite reach statistical significance, Dr Russell reported, a phase 3 registration trial in advanced melanoma has shown a durable response rate in patients randomized to talimogene laherparepvec (T-VEC), a genetically modified herpesvirus approved by the FDA in 2015.

Furthermore, studies combining T-VEC with either ipilimumab or pembrolizumab have demonstrated promising efficacy with minimal evidence of increased toxicity.

“The big question, however, is whether these viruses can be given intravenously,” said Dr Russell. “We wanted to see whether oncolytic viruses could reach target tumor sites from the bloodstream and then boost the immune response to tumor neoantigens.”

Engineered Measles Virus Can Eliminate Disseminated Cancer

After attenuating the measles virus and encoding a transgene to enhance immune system recruitment, Dr Russell and colleagues initiated several clinical trials using the virus intravenously. However, Dr Russell focused on a single case from a single myeloma trial to illustrate the therapy’s “extraordinary potential.”

“After a single intravenous dose of measles virus, tumor markers returned to normal range, bone marrow normalized, and PET-CT resolved,” said Dr Russell, referring to a 49-year-old woman with Bence Jones myeloma who had become refractory to all available myeloma therapies.

“Prior to virotherapy, the patient was relapsing fairly rapidly after a second stem cell transplant, with diffuse marrow infiltration and multiple plasma cytomas, including one on her forehead,” Dr Russell continued. “Importantly, she was measles seronegative, so the virus could reach the tumor when given intravenously.”

As Dr Russell reported, 3.5 years later the patient remains in complete remission and off all therapy. Although the patient experienced 2 focal relapses, which would typically be harbingers of systemic relapse, she was fully controlled by local radiotherapy, “suggesting some kind of abscopal effect,” he added.

According to Dr Russell, the result in this patient was the first demonstration that a systemically administered oncolytic can eliminate disseminated cancer.

“There was rapid debulking followed by longer-term immune control,” he observed. “Immune data showed very strong T-cell responses against NY-ESO, WT-1, and a number of neoantigen targets that presented on her myeloma cells.”

Intravenous Virotherapy Boosts Immune Response

Additional studies in a number of mouse tumor models have also demonstrated “very impressive efficacy” for intravenous virus administration. A single dose of vesicular stomatitis virus (VSV), a rhabdovirus that causes a blistering disease in cattle, causes complete eradication of large tumors and long-term immune control.

“If we deplete T cells from these animals, we lose that long-term immune control,” said Dr Russell, who noted that cured mice are resistant to tumor rechallenge, “which is expected from immune-mediated activity.”

To test the virotherapy in combination with a checkpoint inhibitor antibody, the researchers moved to an acute myeloid leukemia (AML) model. The mice are treated with PD-L1, the virus, or a combination of virus and PD-L1.

“Survival curves indicate that combination is considerably more effective than either treatment alone,” said Dr Russell. “And if we do cell depletion studies, we lose that efficacy by depleting natural killer cells or CD8+ T cells.”

Finally, analysis with the ELISpot assay demonstrated that animals treated with VSV get a robust T-cell response against the virus, which is not the case with PD-L1 treatment alone, said Dr Russell. Moreover, this T-cell response is amplified by coadministering the anti–PD-L1 antibody. Although the tumor-specific T-cell response was smaller, responses were observed with both PD-L1 and virus alone.

“The virus clearly has the ability to stimulate an immune response against the tumor antigen, and when combined with anti–PD-L1 therapy, there is an increased response against the tumor antigen,” he concluded.

Based on these findings, Dr Russell and colleagues are initiating a phase 1 clinical trial in multiple myeloma, lymphoma, and AML, and another in endometrial cancer at Mayo Clinic.

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