UMass Chan Medical School scientists have developed a dual immunotherapy approach that shows promise in treating pancreatic cancer. The strategy combines antagonists that suppress the immune-evading ability of tumor cells with nanoparticle delivery of agonists that stimulate the immune system to fight the cancer.
The research, published in Science Translational Medicine, demonstrated that animal models treated with the dual therapy experienced shrinkage or elimination of pancreatic cancer tumors in eight of nine cases. This innovative approach addresses the challenges of treating pancreatic cancer by targeting the tumor microenvironment and activating the immune system.
Overcoming the Challenges of Pancreatic Cancer Treatment
Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, has a five-year survival rate of only 13 percent and is the third leading cause of cancer deaths. One of the significant challenges in treating PDAC is the microenvironment surrounding the tumor cells, which inhibits the delivery of therapeutic agents and immune cell infiltration.
"Pancreatic cancers are challenging to treat, in part because the microenvironment surrounding the tumor is dense and hard to access," said Dr. Marcus Ruscetti, assistant professor of molecular, cell & cancer biology. "This makes drug delivery and immune infiltration difficult. Our dual therapy approach shows promise as a strategy to get to the cancer cells and fight them."
A Dual-Action Therapeutic Approach
The researchers utilized a biocompatible, lipid-based nanomaterial to encapsulate two molecules that activate the stimulator of interferon genes (STING) pathway, which in turn activates the immune system. Dr. Prabhani Atukorale, assistant professor of biomedical engineering at UMass Amherst and adjunct assistant professor of molecular, cell & cancer biology at UMass Chan, modified the nanomaterials to penetrate the dense tumor microenvironment and reach their intended target.
Remodeling the Microenvironment
Cancer-suppressing molecules (MEK inhibitor trametinib and CDK4/6 inhibitor palbociclib, or T/P) were used to remodel the microenvironment, allowing the immune system to send T cells and enhance the delivery of the nanoparticles containing the immune agonists to the PDAC tumor. Once awakened by the combination therapy, the body’s T cells could begin fighting off the cancer cells.
"The tumor cells have developed a way to evade or shut down the body’s immune system...They’re shielded," said Ruscetti. "Just getting more T cells into the tumor microenvironment is only the first step. We still have to wake them up. That’s what this second therapeutic does. It allows the immune system to see the cancer cells so they can do their job and get rid of the cancer cells."
Implications for Other Cancers
This dual strategy of targeting the tumor microenvironment with immune system activation may also have implications for other cancers such as colon, lung, liver and cholangiocarcinoma (cancer of the bile ducts).
With funding from the BRIDGE Innovation and Business Development at UMass Chan Medical School, the team aims to attract industry partners and optimize their nanoparticle approaches for testing in human clinical trials.
