An international team of scientists reports that the clinical efficacy of checkpoint blockade, which is a novel approach to harnessing the immune response to treat cancer, might be dramatically improved if combined with oncolytic virotherapy, an investigational intervention that employs viruses to destroy tumors.
The researchers published their study (“Localized Oncolytic Virotherapy Overcomes Systemic Tumor Resistance to Immune Checkpoint Blockade Immunotherapy”) in Science Translational Medicine. The group evaluated a combination therapy in which the Newcastle disease virus (NDV), a bird virus not ordinarily harmful to humans, is injected directly into one of two melanoma tumors implanted in mice, followed by an antibody that boosts the immune response.
According to the researchers, the combination induced a potent and systemically effective antitumor immune response that destroyed the noninfected tumor as well. Even tumor types that have hitherto proved resistant to checkpoint blockade and other immunotherapeutic strategies were susceptible to this combined therapy.
“Combination therapy with localized NDV and systemic CTLA-4 blockade led to rejection of preestablished distant tumors and protection from tumor rechallenge in poorly immunogenic tumor models, irrespective of tumor cell line sensitivity to NDV-mediated lysis. Therapeutic effect was associated with marked distant tumor infiltration with activated CD8+ and CD4+ effector but not regulatory T cells, and was dependent on CD8+ cells, natural killer cells, and type I interferon,” wrote the investigators. “Our findings demonstrate that localized therapy with oncolytic NDV induces inflammatory immune infiltrates in distant tumors, making them susceptible to systemic therapy with immunomodulatory antibodies, which provides a strong rationale for investigation of such combination therapies in the clinic.”
“Many patients have benefited from cancer immunotherapies,” says Dmitriy Zamarin, M.D., Ph.D., a member of the Ludwig Cancer Center’s Collaborative Laboratory at Memorial Sloan-Kettering Cancer Center (MSK) and lead author of the study together with James Allison, Ph.D., of the MD Anderson Cancer Center in Houston, and Jedd Wolchok, M.D., Ph.D., director of the Ludwig Collaborative Laboratory at MSK. “But they have not been effective for all patients, or against all cancer types, since most cancers can potently suppress immune responses. We want to extend the benefits of immunotherapies to more patients and optimize their use against a larger variety of cancers.”
The team also found that NDV could be used to boost the effects of adoptive T-cell transfer, in which T cells are taken from patients, trained to recognize specific tumors and then reintroduced into their bodies. Adoptive transfer, too, has been hampered by the ability of tumors to suppress immune responses.
Pretreatment with NDV may similarly boost other immunotherapies, noted Dr. Zamarin, adding that NDV could also be engineered to package and express immune factors that might further boost desirable elements of the antitumor response.
The scientists are now working to expand production of NDV and devise protocols to evaluate their combination therapy in early-stage clinical trials.