Infecting just one tumor with a virus could boost the systemic effectiveness of cancer immunotherapy

March 5, 2014

A Ludwig Cancer Research study suggests that the clinical efficacy of checkpoint blockade, a powerful new strategy to harness the immune response to treat cancers, might be dramatically improved if combined with oncolytic virotherapy, an investigational intervention that employs viruses to destroy tumors.

Published today in the journal Science Translational Medicine, the study 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 essentially releases the brakes on the . The researchers report that the combination induced a potent and systemically effective anti- immune response that destroyed the non-infected tumor as well. Even tumor types that have hitherto proved resistant to checkpoint blockade and other immunotherapeutic strategies were susceptible to this combined therapy.

"Many patients have benefited from cancer immunotherapies," says Dmitriy Zamarin, a member of Ludwig's Collaborative Laboratory at Memorial Sloan Kettering Cancer Center (MSK) and lead author of the study together with James Allison of the MD Anderson Cancer Center in Houston, and Jedd Wolchok, 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."

Zamarin and his colleagues found that an inflammatory immune response induced in the tumor by NDV primarily accounts for the efficacy of the therapy. The checkpoint blockade antibody used in this study binds CTLA-4, a molecule found on that acts like a brake (or "checkpoint") on the immune response. A version of this antibody is already used for cancer therapy, and it has proved potent in a clinical trial evaluating its combination with another immunotherapy as well.

The researchers noticed that when NDV was injected into a tumor implanted in mice, cancer-killing immune cells flooded into that tumor. "But we also found, to our surprise, that a similar infiltration of activated immune cells occurred in a distant tumor, one in which the virus was never detected," says Zamarin.

The researchers show that NDV infection alerts T cells of the immune system to the presence of cancer cells, which otherwise suppress and attack. Subsequent injection of the anti-CTLA-4 antibody dials up the incipient anti-tumor response so dramatically that it overcomes the tumor's immune suppression and destroys both NDV-exposed tumors and unexposed tumors. And the effect appears to be durable. When the same tumors are reintroduced into treated animals, they are swiftly eliminated.

Combining the two therapeutic strategies, Zamarin explains, overcomes the limitations of each. Oncolytic virotherapy has long been hindered by the immune system's tendency to disable systemically introduced viruses long before they can target tumors. The current study circumvented this problem by injecting NDV directly into the tumor.

Checkpoint blockade, meanwhile, has failed against tumors that suppress immune detection and attack. The researchers found that NDV prompted the cells of such tumors to betray themselves to the immune system when they informed it about the virus. As a consequence, the strategy even made colorectal and prostate tumors that were resistant to immunotherapy susceptible to checkpoint blockade.

The team also found that NDV could be used to boost the effects of an investigational immunotherapy known as 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. Additionally, Zamarin notes, NDV could be engineered to package and express immune factors that might further boost desirable elements of the anti-tumor response. The researchers are now working to expand production of NDV and devise protocols to evaluate their combination therapy in early stage clinical trials.

Explore further: Researchers find promising results with local hyperthermia of tumors

More information: "Localized Oncolytic Virotherapy Overcomes Systemic Tumor Resistance to Immune Checkpoint Blockade Immunotherapy," by D. Zamarin et al. Science Translational Medicine, 2014.

Related Stories

Researchers find promising results with local hyperthermia of tumors

March 4, 2014
A combination of iron-oxide nanoparticles and an alternating magnetic field, which together generate heat, have activated an immune system response to tumors in mice according to an accepted manuscript by Dartmouth-Hitchcock ...

Cancer vaccine could use immune system to fight tumors

February 27, 2014
Cincinnati Cancer Center (CCC) and UC Cancer Institute researchers have found that a vaccine, targeting tumors that produce a certain protein and receptor responsible for communication between cells and the body's immune ...

Investigational drug may increase survival for some patients with advanced melanoma

March 4, 2014
An experimental drug aimed at restoring the immune system's ability to spot and attack cancer halted cancer progression or shrank tumors in patients with advanced melanoma, according to a multisite, early-phase clinical trial ...

Mouse model exposes a new type of T cell to target melanoma

October 24, 2012
Cancers arise in the body all the time. Most are nipped in the bud by the immune response, not least by its T cells, which detect telltale molecular markers—or antigens—on cancer cells and destroy them before they grow ...

Researchers discover how cancer 'invisibility cloak' works

October 28, 2013
Researchers at National Jewish Health have discovered how a lipid secreted by cancer tumors prevents the immune system from mounting an immune response against it. When lysophosphatidic acid (LPA) binds to killer T cells, ...

Marker may predict response to ipilimumab in advanced melanoma

February 4, 2014
Among patients with advanced melanoma, presence of higher levels of the protein vascular endothelial growth factor (VEGF) in blood was associated with poor response to treatment with the immunotherapy ipilimumab, according ...

Recommended for you

Study reveals new mechanism used by cancer cells to disarm attacking immune cells

November 20, 2017
A new study by researchers at The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute (OSUCCC - James) identifies a substance released by pancreatic cancer cells that protects ...

Clinical trial suggests new cell therapy for relapsed leukemia patients

November 20, 2017
A significant proportion of children and young adults with treatment-resistant B-cell leukemia who participated in a small study achieved remission with the help of a new form of gene therapy, according to researchers at ...

Cell-weighing method could help doctors choose cancer drugs

November 20, 2017
Doctors have many drugs available to treat multiple myeloma, a type of blood cancer. However, there is no way to predict, by genetic markers or other means, how a patient will respond to a particular drug. This can lead to ...

Lung cancer triggers pulmonary hypertension

November 17, 2017
Shortness of breath and respiratory distress often increase the suffering of advanced-stage lung cancer patients. These symptoms can be triggered by pulmonary hypertension, as scientists at the Max Planck Institute for Heart ...

Researchers discover an Achilles heel in a lethal leukemia

November 16, 2017
Researchers have discovered how a linkage between two proteins in acute myeloid leukemia enables cancer cells to resist chemotherapy and showed that disrupting the linkage could render the cells vulnerable to treatment. St. ...

Computer program finds new uses for old drugs

November 16, 2017
Researchers at the Case Comprehensive Cancer Center at Case Western Reserve University School of Medicine have developed a computer program to find new indications for old drugs. The computer program, called DrugPredict, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.