Nanoparticle immunotherapy shows the possibility of stopping the spread of pancreatic cancer

Pancreatic cancer remains one of the most difficult tumors to treat. This is because it is often discovered in progressive stages when the disease has already spread or has metastasized. Approximately half of patients with pancreatic cancer experience liver metastasis, worsening the prognosis of an already life-threatening disease.

However, new techniques from researchers at UCLA’s California Nanosystems Laboratory or CNSI researchers aim to turn the table of tumors that move from the pancreas to the liver.

The liver is in its normal state and vulnerable to cancer. Organs need to process many foreign bodies from the intestines and prevent the immune system from overreacting to harmless compounds in food. Unfortunately, this incorporation suppression also weakens the battle with tumors and causes unchecked tumors to grow.

The CNSI team has developed a patented technology aimed at reprogramming liver immune defenses to attack pancreatic cancer. They create liver targeting nanoparticles of 1 billionth of a meter in size and provide two important components. MRNA vaccines targeting immune activation markers, or small molecules that enhance the antigens and immune responses that are common in pancreatic cancer.

A study published in ACS Nano demonstrated that laboratory model experiments inhibited and prevented the growth of pancreatic cancer in the liver. Importantly, immune memory cells were also produced associated with long-term protection.

“The immunologically suppressive environment of the liver acts as a niche for metastatic cancer cells to grow, but can be reversed by nanoparticles, breaking this resistance and attacking cancer instead.” “This technique can potentially alter the course of metastatic pancreatic cancer, preventing spread to the liver of newly diagnosed patients without metastasis.”

Potential future applications of nanoparticles in cancer treatment

With further research, NEL envisions this nanoparticle as a platform for personalized cancer treatments, bolstering ongoing efforts elsewhere to use mRNA technology to boost anti-cancer immunity against tumor antigens. Oncologists can rapidly test patients’ pancreatic cancers in this study for specific tumor antigenic mutations to KRAS, a gene target that can regulate growth and promote cancer. Comprehensive genetic testing can also identify other immune-activating tumor antigens unique to an individual patient. These insights can guide customization of the content of each patient’s nanoparticles and tailor treatments that are likely to be successful.

This approach can be applied beyond pancreatic cancer, especially for breast and lung cancer, as well as other tumors with well-characterized genetic mutations, including KRA.

The nanoparticles are made of lipids that resemble waxy coatings around the cells, supporting uptake by antigen-presenting cells in the liver. This population of immune cells is directly involved in the normal function of the liver, which suppresses the inflammatory response that develops immune resistance, such as neglecting metastatic cancer cells.

In previous studies, the NEL team exploited the liver’s innate resistance mechanism by using mRNA-carrying nanoparticles to reach liver antigen-presenting cells and successfully suppressing severe allergic reactions such as peanut allergies. In this new study, they showed that the effects can be sequentially altered the immune system instead.

Nanoparticle cancer-fighting mRNA functions similarly to Covid-19 mRNA vaccines. Instead of encoding the coronavirus spike protein, it contains the indication of small fragments of mutated KRAS tumor antigens that frequently appear in pancreatic cancer and, importantly, can trigger a cancer-specific immune response.

Additionally, the researchers have mounted the nanoparticles with a small genetic component called dinucleotides that trigger the biochemical signaling pathway known as antigen-bearing cells stabs. Its stinging activity summons killer T cells of the immune system to attack cancer. In this study, the researchers observed the emergence of killer T cells that recognize and kill KRAS-expressed pancreatic cancer cell metastases in animal models.

“Combining cancer vaccines with immunostimulators in a single nanoparticle provides a promising new strategy,” Nel said. “We envision this combined strategy will provide a major advancement in the fight against metastatic pancreatic cancer.”

The potential importance of timing in nanoparticle delivery

Experiments in mice with pancreatic cancer spreading to the liver showed that nanoparticles were smaller, with smaller undispersed tumors, and longer than controls. When nanoparticles were administered before cancer began, the treated mice survived longer than untreated mice.

The researchers also showed immunological memory effects. When blood from treated mice was transferred to untreated mice before cancer developed, the recipient survived considerably longer than those without transfusion. This suggests that treatment may provide long-term protection against recurrence of pancreatic cancer, indicating that it may be useful as a vaccine.

Toxicity is an important issue in cancer treatment, and powerful stitching routes are known to promote harmful systemic inflammation. However, no toxicity was observed in this study, and the researchers attribute it to sting-activated juncleotides that act locally only in the liver.

Further research is currently underway to apply this technique to other cancers that frequently spread to the liver. The team is also investigating strategies to direct similar nanoparticles towards the spleen. This is an important immune organ that supports immune defense at the original pancreatic cancer site.

This allows for the combination of a new lipid nanoparticle approach with immunostimulating chemotherapy delivered by miniature glass foam-like nanoparticles known as cicasomes, developed by the same group. The potential for one-two punches against pancreatic cancer could pave the way for new treatments that not only fight the disease but provide long-term immunity for its returns.

The first author of this study is Xiao Xu, a former UCLA postdoctoral researcher. Other co-authors are Xiang Wang and Yu-Pei Liao of UCLA Senior Research Associates. Lijia Luo is a postdoctoral researcher at UCLA.