Nanodelivery of drug combination shrinks pancreatic cancer tumors in mice

A new study demonstrates an immunotherapy-based approach to treating pancreatic cancer in mice that combines the delivery of STING and TLR4 innate immune agonists using lipid-based nanoparticles (NPs) with the tumor-targeting MEK inhibitor trametinib and the CDK4/6 inhibitor palbociclib, known as T/P. Led by scientists at the University of Massachusetts Amherst and Massachusetts Chan Medical School, this combination therapeutic approach resulted in long-term survival in a relevant mouse model of pancreatic ductal adenocarcinoma (PDAC).

Research Report Science Translational MedicineThe research team, which included Prabhani Atukorale, Ph.D., assistant professor of biomedical engineering at UMass Amherst, and Marcus Russetti, Ph.D., assistant professor of molecular, cellular and cancer biology at UMass Chan Medical School, suggests that this modular therapy could potentially be tailored to individual patients and could also be used to develop treatments for other types of cancer. Atukorale and Russetti are co-corresponding authors of the paper.

Pancreatic ductal adenocarcinoma is the most common type of pancreatic cancer, with a “dismal” 13% five-year survival rate and the third leading cause of cancer death, the authors write. One major challenge in treatment is the microenvironment surrounding the tumor. This fibrotic tumor microenvironment (TME) is characterized by dense tissue that forms a barrier around the tumor, inhibiting angiogenesis and blocking immune infiltration, leading to the failure of chemotherapy and immunotherapy, the scientists continue. “…the PDAC TME impedes effective drug delivery, promotes chemotherapy resistance, and blocks the activation and infiltration of cytotoxic immune cells.”

“Drug delivery is a major challenge due to the structure of the difficult-to-treat tumor microenvironment,” Attukorale added. “Unfortunately, pancreatic cancer is resistant to most traditional therapies, including chemotherapy and immunotherapy, which have revolutionized the treatment of many cancers over the past decade.”

Dr. Russetti's previous research had demonstrated that two anti-cancer drugs, the MEK inhibitor trametinib and the CDK4/6 inhibitor palbociclib (the T/P combination), can promote blood vessel development and enhance the delivery of T cells (and chemotherapy) to tumors. However, cancers can “trick” the immune system into thinking that a tumor is a normal, healthy mass of cells. Because T cells are not activated, simply increasing the number of T cells does not eliminate the cancer.

For the reported study, the team designed what they described as a “multifaceted approach that combines innate immune agonists and tumor-targeted senescence-inducing therapy to simultaneously target many immune suppressive mechanisms in PDAC.” The strategy targeted two pathways. One is the stimulator of interferon genes (STING) pathway. STING recognizes viral infections in the body. “If we can trick the immune system into thinking there is a viral infection, we can harness a very potent anti-tumor immune response and leverage it for tumor immunotherapy,” Atukorale explained.

The researchers wanted to also activate the TRL4 pathway, which enhances the effects of STING activation. Their strategy is to use agonists, chemicals that can trigger a biological response, in this case a related immune-stimulating pathway. However, delivering immune-stimulating chemicals through the tumor microenvironment has remained a challenge.

The solution was to encapsulate the STING and TRL4 agonists in a novel design: a lipid-based nanoparticle. This nanoparticle has several advantages. The researchers showed that it was highly effective at delivering the agonists to the challenging tumor microenvironment. The design also allowed them to package the two agonists together, which had been difficult because they are essentially like oil and water.

“This ensures that the drugs are carried together in the blood circulation, reach the same target cells together, and are taken up together by the same target cells,” Atukorale said. “We're encapsulating drugs that functionally work together but don't like to be next to each other in a biocompatible lipid-based material, and then we can use our engineering capabilities to incorporate different functionalities to direct the drugs to where they are needed.”

The authors further explain that “the innovation of our study is the ability to deliver STING agonists to diverse cell types within the poorly permeable PDAC TME, which we achieved through the engineering of lipid NPs that are engineered to preferentially deposit in the 'leaky' tumor endothelium. Furthermore, our nanomaterial-based drug delivery approach enables us to effectively and safely co-deliver physically and chemically distinct STING (cdGMP) and TLR4 (MPLA) agonists.”

The synergistic effect of the two agonists and T/P therapy proved effective in preclinical studies in a relevant mouse model of pancreatic cancer. The treatment, the authors wrote, “promoted NP uptake by multiple cell types in the PDAC TME, induced type I interferon and other inflammatory signaling pathways, increased antigen presentation by tumor cells and antigen-presenting cells, and subsequently activated both innate and adaptive immune responses.” Eight of nine treated animals experienced tumor necrosis and shrinkage. “And two mice had a complete response, meaning their tumors completely disappeared, which is very surprising,” Ruscetti noted. “We've never seen anything like this in this model before.”

The authors continue, “This two-pronged approach led to robust T cell-driven and type I interferon-mediated tumor regression and long-term survival in preclinical PDAC models that were dependent on both tumor and host STING activation. STING and TLR4-mediated type I interferon signaling was also associated with enhanced natural killer and CD8+ T cell immunity in human PDAC samples.”

The authors acknowledged the limitations of the study and commented that further research is needed. Tumors recurred even after treatment was stopped. “Further investigation of tumor-intrinsic (e.g., genetic) and extrinsic (e.g., immune) resistance mechanisms that lead to recurrence after combined T/P and immune NP treatment will be important in discovering additional interventions to prolong treatment efficacy,” the team said. Nevertheless, Lucetti said the results are a very promising step toward a cure.

Prabhani noted that the modular design allows for tailored treatments for patients. “It's kind of plug-and-play,” he said. “You can customize the agonist ratios, the drug combinations, the target molecules, while still essentially keeping the same platform. This not only enables translational treatments, but also allows them to be tailored for each patient, because many of these cancer treatments need to be personalized.”

The scientists suggest that this treatment strategy could also be applied to other types of cancer. Potential treatments for cancers such as PDAC that could result from this research include mutations in colorectal, lung, liver and cholangiocarcinoma (cancer of the bile duct). “Extending beyond pancreatic cancer will require combination therapies that target the tumor and the immune system,” Lucetti added. “This is a strategy that makes that possible.”