Proposed cancer treatment aims to harness 'sentinels' of immune system

Researchers use $2.4 million grant for dendritic cell immunotherapy; will study hybrid drug delivery vehicle that breaks through intracellular traffic jams

By the University at Buffalo

They patrol inside our skin and other soft tissue. Their job: Alert the immune system to toxic invaders so it can mount an attack.

But these sentries – known as dendritic cells – often fail to warn of cancer’s arrival. Why? Scientists surmise that, because cancer develops within the body, immune system cells do not view the disease as a hostile intruder.

To overcome this misperception, scientists are developing an immunotherapeutic workaround.

It involves training dendritic cells to engulf snippets of genetic information – in this case, key proteins found on patients’ cancer cells. These proteins provide dendritic cells with a target – in lieu of the unrecognized cancer cells – so they can alert and mobilize the immune system to fight cancer.

Emerging research suggests this approach – combined with other treatments – can help combat numerous forms of cancer. But it’s not equally effective; for example, patients whose cancer is spreading often do not respond very well to it.

Scientists at the University at Buffalo and Roswell Park Comprehensive Cancer Center earlier this year received a five-year, $2.4 million grant from the National Cancer Institute to address these limitations.

They are studying a drug delivery system for the lab-created protein targets. The system could ultimately enable the body’s cancer-fighting agents to break through intracellular traffic jams and produce stronger immune responses.

Blaine Pfeifer, Ph.D., professor of chemical and biological engineering in the UB School of Engineering and Applied Sciences, is one of the grant’s principal investigators. He and colleagues previously designed the delivery system, which combines a bacterial core and a synthetic polymer coating.

“We conjoin these two vehicles, creating a hybrid that is designed to efficiently deliver cargo – for this scenario, the target proteins – to key locations within the dendritic cells, which ultimately trigger an immune response,” Pfeifer said.

Jason Muhitch, Ph.D., assistant professor of oncology in the department of immunology at Roswell Park, is the grant’s other principal investigator.

“Dendritic cells act as sentinels of the immune system, which is why their promise as a cancer immunotherapy is so tremendous,” he said. “To unleash their full potential – and provide durable benefits for cancer patients with aggressive disease that has spread – we must improve delivery of this treatment.”

Cross-Disciplinary Research Has Three Goals

The first goal of the research involves studying, in very close detail, what happens when the hybrid vehicle comes into contact with dendritic cells. It is important for the researchers to understand this interaction because it could lead to design changes in the hybrid vehicle that promote stronger immune responses.

The second goal is to examine how well the dendritic cells engulf the protein targets delivered by the hybrid vehicle. The intracellular trafficking of genetic information within the dendritic cell is critical because, if not successful, the protein targets will not prompt the desired immune response.

Lastly, the researchers will investigate how well the dendritic cells train the immune system. The goal here, researchers say, is to confirm that the delivery of protein targets was effective – in other words, do the protein targets prompt T cells, which act as soldiers, to attack the cancer?

The collaboration – a chemical engineer, who specializes in cellular and process engineering, working with a tumor immunologist – is the kind of cross-disciplinary approach that is needed to solve the most vexing questions surrounding cancer, the researchers say, noting that cancer is the second-leading cause of death in the U.S.

The testing, which is now underway, is an important step toward proving the efficacy of this proposed treatment. And while researchers stress much work remains before it can be tested in humans, the early results are tantalizing.

“It is our hypothesis that systemically addressing every aspect of how the hybrid vehicle and its cargo interact with dendritic cells could have a transformative impact on cancer immunotherapy,” Muhitch said.