Early-stage research demonstrated the synergistic effects of a novel nanoparticle drug–delivery system to activate an immune pathway in combination with tumor-targeting agents in mice with pancreatic ductal adenocarcinoma, according to a preclinical study published by Chibaya et al in Science Translational Medicine.
Background
Pancreatic ductal adenocarcinoma—the most common type of pancreatic cancer—has a 5-year survival rate of 13% and is the third leading cause of cancer-related mortality.
A significant challenge in treating this cancer type involves the microenvironment surrounding the tumor, which is characterized by dense tissue that creates a barrier around the tumor and inhibits blood vessel formation.
“Drug delivery is a huge challenge [because of] the architecture of these difficult-to-treat tumors’ microenvironments,” stressed co–senior study author Prabhani Atukorale, BEng, MSE, PhD, Assistant Professor of Biomedical Engineering at the University of Massachusetts (UMass) Amherst.
The tumor microenvironment also blocks the activation of the body’s immune cells and their infiltration into the tumor.
“Pancreatic cancer, unfortunately, doesn’t respond to most conventional therapies like chemotherapy or even immunotherapy, which has revolutionized a lot of cancer therapy in the last 10 years,” explained co–senior study author Marcus Ruscetti, PhD, Assistant Professor of Molecular, Cell, and Cancer Biology at the UMass Chan Medical School.
Previous research has shown that two cancer drugs—the MEK inhibitor trametinib and the CDK4/6 inhibitor palbociclib—can promote blood vessel development, enabling greater T-cell as well as chemotherapy delivery into the tumor. However, these cancer cells are capable of “tricking” the immune system into viewing the tumors as healthy cells. Since the T cells aren’t activated, having more of them present won’t clear the cancer.
Study Methods and Results
In the preclinical study, the researchers devised a novel treatment strategy by utilizing two pathways. They noted that the first, the stimulator of interferon genes (STING) pathway, recognizes viral infections in the body. Further, activation of the TRL4 pathway may enhance the effects of STING activation.
“If we can trick the immune system into thinking that there is a viral-type infection, then we harness a very robust antitumor immune response to bring in for tumor immunotherapy,” Dr. Atukorale detailed.
The researchers used agonists that could trigger a biological response in immune stimulatory pathways. Nonetheless, they revealed that getting these immunity-triggering chemicals through the tumor’s microenvironment was still challenging.
By encapsulating the STING and TRL4 agonists in a design of lipid-based nanoparticles, the researchers discovered that the nanoparticles were highly effective at delivering the agonists into the tumor microenvironment. The nanoparticle design also allowed both of the agonists to be packaged together.
“It ensures that they are carried within the blood circulation together, they reach the same target cell together and are taken up together by the same target cell,” stated Dr. Atukorale. “We’re using biocompatible, lipid-based materials to encapsulate drugs that functionally work together but don’t like to be next to each other, and then we are able to use engineering capabilities to build in various functionalities to direct them where they need to go,” she continued.
The researchers found that the synergistic effects of the two agonists in combination with the trametinib and palbociclib therapy proved effective: about 89% (n = 8/9) of the mice experienced tumor necrosis and shrinkage.
“And we had two mice that had complete responses, meaning the tumors completely went away, which is pretty striking. We’ve never seen that in this model before,” Dr. Ruscetti highlighted.
Conclusions
Although more research is needed because the cancer recurred after the mice ceased use of the therapy, the researchers indicated that the positive findings represented a step toward a cure.
“If you go beyond pancreatic cancer to other cancer types, you need a combination therapy to target the tumor and to target the immune system. This is a strategy to be able to do that,” Dr. Ruscetti underscored.
The researchers noted that treatments for cancers like pancreatic ductal adenocarcinoma that could be derived from this study include mutations of colorectal cancer, lung cancer, hepatic cancer, and cholangiocarcinoma. The modular nature of the novel nanoparticle design may allow for therapies that can be personalized to address individual patient needs.
“We can tailor the agonist ratios, the drug combinations, and the targeting molecules but keep essentially the same platform. This is what will make it hopefully translational but also tunable on a per patient basis, because many of these cancer therapies need to be personalized,” outlined Dr. Atukorale. “This type of system is easily built when you have complementary, but multidisciplinary and cross-disciplinary, expertise,” she concluded.
Disclosure: For full disclosures of the study authors, visit science.org.
