Cytomegalovirus Immunity Shows Promise in Pancreatic Cancer Therapy | UC San Diego Research

Researchers have demonstrated a promising preclinical immunotherapy approach that harnesses the body’s existing immune response to cytomegalovirus (CMV) to slow the growth of pancreatic tumors in mice. The collaborative study, conducted by scientists at the University of California San Diego and the La Jolla Institute of Immunology, offers a potential “off-the-shelf” treatment strategy for a cancer notoriously resistant to conventional therapies. Pancreatic cancer is often diagnosed at a late stage and has a poor prognosis, making new treatment avenues critically important.

Understanding the Challenge: Why Pancreatic Cancer Resists Treatment

Pancreatic cancer presents a formidable challenge in oncology. Despite accounting for a relatively small percentage of all cancer diagnoses, it is responsible for a disproportionately high number of cancer-related deaths. This is largely due to its aggressive nature, late detection, and limited responsiveness to many standard cancer treatments. Unlike some other cancers, pancreatic tumors often have a low mutational burden – meaning they don’t present many obvious targets for the immune system – and create an immunosuppressive environment that actively hinders immune responses. Standard immunotherapies, which have revolutionized treatment for cancers like melanoma and lung cancer, have largely failed to deliver the same benefits for pancreatic cancer patients.

Leveraging Pre-Existing Immunity to CMV

The UC San Diego team, working with CMV experts at the La Jolla Institute of Immunology, took a novel approach. Instead of attempting to identify unique mutations within individual tumors, they focused on exploiting a pre-existing immune response common in many people: immunity to cytomegalovirus. CMV is a widespread herpesvirus that typically causes mild or no symptoms in healthy individuals, but it establishes a long-lasting immune memory. The researchers hypothesized that this robust, pre-existing immunity could be redirected to target cancer cells.

“We were thrilled to see such a strong response in our preclinical studies,” said Dr. Tatiana Hurtado de Mendoza, assistant professor of surgery at UC San Diego School of Medicine. “By delivering small pieces of viral proteins – cytomegalovirus peptides – to pancreatic tumors, we were able to redirect the virus-specific T cells against the cancer cells.” This strategy aims to turn an immunologically “cold” tumor – one that the immune system struggles to recognize – into a target that can be effectively attacked.

How the Therapy Works: Redirecting T Cells

The therapy involved systemic injection of CMV-derived peptides, which are short fragments of viral proteins. In mice previously infected with CMV, these peptides reactivated memory T cells that recognized the virus. When these peptides accumulated within the tumor environment, the reactivated T cells infiltrated the tumor and began attacking cancer cells. This process effectively repurposed the immune system’s existing antiviral defenses to fight cancer. UC San Diego Health Sciences details this process further.

Dr. Remi Marrocco, a postdoctoral fellow at La Jolla Institute of Immunology, explained the significance of this approach: “Some tumors have plenty of mutations and all of those mutations make these tumors easy for the immune system to see and target. Pancreatic cancer has fewer mutations and a lot of immunosuppressive cells that inhibit immune responses against the tumor. It is a ‘cold’ tumor.”

The Role of CMV-Specific T Cells

The researchers highlighted the abundance and activity of CMV-specific memory T cells, making them an attractive population to recruit for cancer immunotherapy. Dr. Christopher Benedict, associate professor at La Jolla Institute of Immunology, noted, “We find more memory T cells that recognize cytomegalovirus than probably recognize any other known virus or bacteria at this point. These cells make up literally 10 per cent or more of our memory T cells, which is a huge number.” This large pool of pre-existing immunity offers a significant advantage in the fight against cancer.

Preclinical Results: Significant Tumor Growth Delay and Increased Survival

The preclinical results were encouraging. In mice with prior CMV infection, treatment with CMV peptides significantly delayed tumor growth and increased survival. Specifically, treated animals lived an average of 42 days, compared to 25 days for control animals – a 70% increase in survival. Published findings in the Journal for ImmunoTherapy of Cancer detail the experimental methodology and results.

Importantly, the therapy demonstrated minimal toxicity at the tested dose. The immune response appeared to concentrate within the tumors, with no detectable damage to other organs during treatment. Gene expression analysis of the tumors also revealed changes suggesting increased susceptibility to immune attack.

Expanding the Approach to Other Cancers

The research team is now exploring the potential of this approach in other difficult-to-treat solid tumors, including triple-negative breast cancer. They have received funding from a Curebound Discovery Award to support this work. To further refine the strategy for pancreatic cancer, they are using humanized mouse models that combine patient tumor tissue with blood-derived immune components to more accurately replicate human CMV immunity. They are also characterizing a panel of human CMV peptides identified by the Benedict and Sette laboratories at La Jolla Institute of Immunology, aiming to optimize immune activation based on individual genetic backgrounds.

“This approach has the potential to be tumor-agnostic, meaning it could be effective against a range of cancer types, including breast cancer, lung cancer and others,” said Dr. Hurtado de Mendoza. The La Jolla Institute for Immunology is actively researching the underlying mechanisms of CMV infection and vaccine strategies.

What Comes Next: Towards Clinical Evaluation

The researchers are focused on preparing the pancreatic cancer strategy for clinical evaluation. This involves refining the peptide selection process and conducting further studies in humanized mouse models to ensure safety and efficacy. If subsequent studies confirm similar results in human systems, this approach could offer a valuable addition to existing immunotherapy strategies, particularly for cancers that remain resistant to checkpoint inhibitors and other immune-based treatments. For pancreatic cancer, where treatment options are limited and prognosis remains poor, this represents a potentially significant step forward.