Immunity to a Frequent Virus May Assist Deal with Tumors

Today, many people who receive cancer diagnoses have more treatment options than in the past. However, for some cancers, like pancreatic cancer, surgery and chemotherapy remain the only available therapies.

Tatiana Hurtado de Mendoza, a cancer biologist at the University of California, San Diego, was motivated to explore better options to cancer treatments. “I’ve had a lot of cancer in the family, and my grandmother and my mom they all refuse any type of traditional chemotherapy or radiotherapy. So, I’ve always been very keen on finding immunotherapy approaches that would not involve any cytotoxic agents.”

While cancer immunotherapies have been breakthrough options for targeting and killing tumors more specifically than chemotherapy, for example, these treatments have their own limitations. They rely upon the expression of unique tumor antigens, struggle to overcome immunosuppressive tumor microenvironments, and remain costly.

To address the obstacles of cost and lack of specific tumor antigens in some cancers, Hurtado de Mendoza explored using a tumor-targeting peptide to direct antigens to tumor sites after systemic delivery.^1,2 Other researchers have explored leveraging individuals’ existing immunity against previous infections to fight tumors. For example, immunologist David Masopust at the University of Minnesota and his group demonstrated that injecting viral peptides into tumors in mice previously infected with the same virus activated T cells that migrated to and killed the tumor.³

When Hurtado de Mendoza saw this approach, she reached out to virologist Chris Benedict at La Jolla Institute for Immunology to combine her tumor-targeting peptide platform with antiviral immunity. In a study published in Journal for ImmunoTherapy of Cancer, she, Benedict, and their teams showed that systemic administration of peptides from a common virus activates T cells that provide antitumor immunity.⁴

“If we could turn this into a therapy, it can help so many people, and it’s such a low cost to produce. And it can just work across different mutations [and] different tumor types,” Hurtado de Mendoza said.

She and her team focused on cytomegalovirus (CMV) because approximately 80 percent of the global population has immunity to this virus, meaning that if the researchers found that targeting it makes a good cancer treatment, the therapy could potentially work for most people.^5,6

To develop antiviral immunity in a model system in their study, the researchers infected wildtype mice with a murine CMV strain. Two to three months after infection and after immune memory had developed with no detectable viral replication, the team implanted pancreatic cancer cells into the same organ in the mice. A little over a week later, they systemically administered their tumor-targeting peptide and peptides from CMV that either CD4⁺ or CD8⁺ T cells could recognize.

The team saw that this regimen increased apoptosis in the tumor and increased the amount of CMV-specific T cells in the tumor microenvironment compared to mice that had not been infected but received these peptides. This strategy decreased the tumor size and extended the animals’ survival.

Hurtado de Mendoza said that these findings were exciting. But, she added, “The funny story, actually, is that when we were doing our controls of not using the targeting peptide and just using the CMV antigens alone, it worked just as well.” After seeing this, the team continued their study using just the CMV peptides by themselves to simplify the experimental design.

Using flow cytometry, the researchers saw more CD4⁺ and CD8⁺ T cells specific for a CMV peptide go to both the liver and the tumors; only those T cells in the tumors caused significant apoptosis. The team also showed that CMV peptide therapy increased the population of T cells, macrophages, and dendritic cells in the tumor microenvironment based on single-cell RNA sequencing. This coincided with a decrease in expression of genes related to cancer functions, like angiogenesis, and an increase in immune processes, like antigen presentation.

Although excited about their promising results, the team was curious about the mechanism underlying this tumor localization. Since CMV remains in cells in a latent form, they considered that tumor immunosuppression may allow the virus to reactivate, but they didn’t find viral DNA in the tumor. The researchers also considered the possibility that an unknown tumor antigen could possess molecular mimicry with a CMV protein, leading to the T cell homing to these cancerous cells. In an experiment comparing CMV peptides to control peptides, though, they did not see a significant difference in the T cell recruitment to the tumor.

In addition to exploring the mechanism behind this tumor T cell localization further, the group is also studying the accumulation of these immune cells in the liver and why the response in this site is different from that of the tumor. “We still have a lot of pretty cool unanswered questions to explore,” Hurtado de Mendoza said.

Since this treatment approach doesn’t rely on tumor mutations, Hurtado de Mendoza said, “The beauty of this therapy is that it has a very broad applicability across a different range of tumor types.” Because of this, the researchers are also testing this treatment strategy in breast cancer models. “One of the big advantages is that this is just peptides, so the cost of producing these types of therapies is really low and less complicated,” Hurtado de Mendoza said.

While Masopust, who wasn’t involved with the study, agreed that the systemic delivery of viral peptides to activate antitumor immunity is easier and more attractive in a clinical setting than intratumoral delivery, he said that this approach also carries its own risks that researchers will have to explore further before translating it into human trials. He also pointed out that, while the study showed proof of principle for the systemic approach, none of the tumors were fully eliminated. “Even though tumor clearance is hard, I think the field has moved to a state where you’re really looking for cures,” Masopust said.

But he added, “That doesn’t mean that there shouldn’t be interest [and] excitement here.” For example, he said that exploring synergy with other immunotherapies or different viruses to target could be ways to improve tumor elimination.

Overall, Masopust said, “It’s great in that it supports the overall principle of leveraging antiviral cell immunity for immunotherapy.”

Disclosure of conflict of interest: Hurtado de Mendoza and her collaborator, Chris Benedict, are inventors on a patent application for the use of human CMV peptides for therapy.

Disclosure of conflict of interest: David Masopust is the inventor of a patent for the use of viral peptides for tumor immunotherapy