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New discovery on how body attacks cancer

Proteins found in cancer linked to immune response that target tumors

A team of researchers based at University College in London have shed light on a link between cancer neoantigens and the immune response to cancer. The discovery could influence the nature of future cancer immunotherapy treatments and predict their efficacy on an individual basis, University Microbiology Prof. Victor Engelhard said.

Neoantigens are cell-surface proteins produced by genetic mutations unique to an individual patient’s cancer cells and are recognizable by human immune cells known as T-cells.

Engelhard, who is also co-director for the immunotherapy department at the University Cancer Center, conducts research on T-cell-mediated immunity to cancer, in the hopes of eventually developing a vaccine for patients already battling the disease.

Engelhard breaks down modern cancer immunotherapy techniques into two categories — adoptive T-cell therapy and checkpoint blockade inhibition therapy.

In adoptive T-cell therapy, T-cells from the tumor are genetically modified to recognize a known neoantigen and then re-introduced to the patient’s body.

Checkpoint blockade inhibition therapy, the focus of this research, is a little more complex.

Tumors produce a ligand for the T-cell receptor that “up-regulates” inhibitory molecules on the surface of the T-cell that cause the T-cell to shut down. Checkpoint blockade inhibition therapy disrupts the binding of the tumor-produced ligand by introducing an antibody, allowing for normal T-cell function.

“[Checkpoint blockade inhibition therapy] has been very, very effective in a small number of cancers,” Engelhard said. “Melanoma is one, non-small-cell lung cancer is another, which is the major focus of the work these folks are doing.”

Engelhard said the research highlights two important principles that positively affect patient survival — a high mutational burden and antigen expression across a high percentage of the tumor cells.

“Their observation, which is very clear, is that the immune response seems to be primarily directed against the antigens that are expressed in all or most cancer cells and cancer sites in an individual patient,” Engelhard said.

While he is skeptical of the study’s applicability to other cancer types, since most cancers besides melanoma and adenocarcinoma have comparatively low mutational burdens, Engelhard sees potential for the research to help predict when and what kind of immunotherapy is right for a cancer patient.

“When you ask about implications for immunotherapy, it gives us insight into another mechanism of the cancer cell evading the immune response,” he said. “It gives us insight into why checkpoint blockade inhibitor therapy might not work. It also suggests of course that adoptive T-cell therapy wouldn’t work in those cases either.”

Immunology Prof. David Kittlesen said that clinical applications for the research will take time and extensive testing.

“Current hurdles include the time required for identifying the relevant targets as well as the expense of what would quite likely be a personalized vaccine,” he said in an email statement.

Kittlesen notes that the study addresses a major challenge of immunotherapy targeting — finding an antigen target widespread enough for T-cells to effectively combat the cancer.

“As a result of genetic instability and proliferation, the millions of cancer cells within a single patient’s tumor are not all the same, and if the target recognized by the immune system is present on only some of the cells others will escape being destroyed,” Kittlesen said.

A related treatment method, the combination of radiation or chemotherapy with immunotherapy in an effort to increase mutational load and antigen presentation, was not shown to increase patient survival, according to Engelhard.

In addition to contributing to scientific knowledge about the overall efficacy of immunotherapy treatments in the context of neoantigen genetics and abundance, the study provides numerous avenues for future biological and clinical research.

“This is a really beautiful study,” Engelhard said.

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