A new technology from researchers at the California NanoSystems Institute at UCLA, (CNSI) aims to help the liver literally “wake up” to invading metastasis—something it usually does not respond to.

In a study newly published in ACS Nano, experiments in lab models demonstrated that a loaded nanoparticle both inhibited and prevented the growth of pancreatic cancer in the liver. Importantly, it also generated immune memory cells associated with long-term protection.

Pancreatic cancer remains one of the most challenging tumors to treat, partly because it is often discovered at advanced stages when the disease has already spread, or metastasized. About half of pancreatic cancer patients experience metastasis to the liver, which worsens the prognosis for an already life-threatening disease.

The liver is particularly vulnerable to cancer under normal conditions. The organ processes many foreign substances from the gut and so prevents the immune system from overreacting to harmless compounds in food. This built-in feature also weakens the fight against tumors, allowing them to grow unchecked.

The CNSI team developed a technology aimed at reprogramming the liver’s immune defense to attack pancreatic cancer. They created a liver-targeting nanoparticle, billionths of a meter in size, that delivers two key components: an mRNA vaccine targeting an immune-activating marker, or antigen, commonly found in pancreatic cancer, and a small molecule that boosts the immune response.

“The liver’s immunologically suppressive environment acts as a niche for the metastatic cancer cells to grow, but it could be reversed by the nanoparticles, breaking this tolerance and causing the body to instead attack the cancer,” said corresponding author André Nel, MD, PhD, a UCLA distinguished professor of medicine at the David Geffen School of Medicine at UCLA and director of research at CNSI. “This technology could potentially change the course of metastatic pancreatic cancer as well as prevent spread to the liver in newly diagnosed patients without metastases.”

With further research, Nel envisions this nanoparticle as a platform for personalized cancer treatment, augmenting efforts underway elsewhere to use mRNA technology for raising anticancer immunity against tumor antigens. Oncologists could quickly test a patient’s pancreatic cancer for specific tumor antigen mutations to KRAS, a gene targeted in this study that regulates growth and can drive cancer. Comprehensive genetic testing could also identify other immune-activating tumor antigens unique to the individual patient.

These insights could guide the customization of the nanoparticle’s contents for each patient, tailoring treatment for the highest chance of success.

This approach could also be applied beyond pancreatic cancer, particularly for breast and lung cancer and other tumors that have well-characterized genetic mutations, including KRAS.

The nanoparticles are made of lipids, similar to the waxy coating around cells, which favors their uptake by antigen-presenting cells in the liver, which are responsible for the liver’s usual function of suppressing responses to foreign invaders, including metastatic cancer cells.

In previous work, Nel’s team leveraged the liver’s natural tolerance mechanisms by using mRNA-carrying nanoparticles to reach liver antigen-presenting cells and successfully suppress severe allergic reactions, such as peanut allergies. In this study, they showed that they could reprogram that effect to instead turn on the immune system.

The cancer-fighting mRNA in the nanoparticle functions similarly to COVID-19 mRNA vaccines. Instead of encoding the coronavirus’ spike protein, it contains instructions for a small fragment of the mutated KRAS tumor antigen that frequently appears in pancreatic cancer and, importantly, can turn on a cancer-specific immune response.

Additionally, researchers loaded the nanoparticle with a genetic building block, called a dinucleotide, that triggers a biochemical signaling pathway known as STING in the antigen-presenting cells. That STING activity summons killer T cells in the immune system to attack the cancer. In the study, the researchers observed the appearance of killer T cells that recognize and kill KRAS-expressing pancreatic cancer cell metastases in an animal model.

“Combining a cancer vaccine with an immune-stimulating agent in a single nanoparticle offers a promising new strategy,” Nel said. “We envisage this combination strategy will provide a major step forward in the fight against metastatic pancreatic cancer.”