A new study demonstrates an immunotherapy-based approach to pancreatic cancer treatment 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 CDK4/6 inhibitor palbociclib, known as T/P. Led by scientists at the University of Massachusetts Amherst and the University of Massachusetts Chan Medical School, the combination treatment approach resulted in long-term survival in relevant mouse models of pancreatic ductal adenocarcinoma (PDAC).
Reporting on their studies in Science Translational Medicine, the team, including Prabhani Atukorale, PhD, assistant professor of biomedical engineering at UMass Amherst, and Marcus Ruscetti, PhD, assistant professor of molecular, cell and cancer biology at UMass Chan Medical School, suggest their modular therapeutic approach could feasibly be tailored for individual patients, and also be harnessed to develop treatments for other types of cancer. Atukorale and Ruscetti are co-corresponding authors of the paper.
Pancreatic ductal adenocarcinoma is the most common form of pancreatic cancer that, with a “dismal” 13% five-year survival rate, is the third leading cause of cancer deaths, the authors wrote. One major challenge to treatment is the microenvironment surrounding the tumor. This fibrotic tumor microenvironment (TME) is characterized by dense tissue creating a barrier around the tumor that inhibits blood vessel formation and blocks immune infiltration, which contributes to chemo- and immunotherapy failure, the scientists continued. “… the PDAC TME hinders effective drug delivery, drives chemoresistance, and blocks the activation and infiltration of cytotoxic immune cells.”
Atukorale further commented, “Drug delivery is a huge challenge due to the architecture of these difficult-to-treat tumors’ microenvironment.” Added Ruscetti, “Pancreas 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.”
Ruscetti’s previous research had demonstrated that two cancer drugs, the MEK inhibitor trametinib and CDK4/6 inhibitor palbociclib (T/P in combination), can promote blood vessel development, enabling greater T cell (as well as chemotherapy) delivery into the tumor. However, the cancer “tricks” the immune system into thinking that the tumor is just a regular, healthy clump of cells. Since the T cells aren’t activated, simply having more of them present won’t clear the cancer.
For their reported research the team designed what they described as “a multipronged approach combining innate immune agonist and tumor-targeting senescence-inducing therapies to target many of the immune suppressive mechanisms in PDAC simultaneously.” 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 that there is a viral-type infection, then we harness a very robust anti-tumor immune response to bring in for tumor immunotherapy,” Atukorale explained.
The researchers also wanted to activate the TRL4 pathway because it boosts the effects of STING activation. Their strategy was to use agonists, which are chemicals that can trigger a biological response, in this case, the relevant immune stimulatory pathways. But getting the immunity-triggering chemicals through the tumor’s microenvironment still represented a challenge.
The solution was to encapsulate the STING and TRL4 agonists in a novel design of lipid-based nanoparticles. The nanoparticles offered several benefits. The researchers showed that they were highly effective at delivering the agonists into the challenging tumor microenvironment. The design also allowed both of the agonists to be packaged together, which was a challenge as they are effectively like oil and water.
“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,” said 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.”
The authors further explained, “An innovation of our study is the ability to deliver STING agonists to diverse cell types within the hard-to-penetrate PDAC TME through the design of lipid NPs engineered to preferentially deposit in the “leaky” tumor endothelium. “Moreover, 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 plus T/P therapy proved effective in preclinical tests in relevant mouse models of pancreatic cancer. The treatment, the authors wrote, “… led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other proinflammatory signaling pathways, increased antigen presentation by tumor cells and antigen-presenting cells, and subsequent activation of both innate and adaptive immune responses.” Eight out of nine treated animals demonstrated tumor necrosis and shrinkage. “And we had two mice that had complete responses, meaning the tumors completely went away, which is pretty striking,” noted Ruscetti. “We’ve never seen that in this model before.”
The authors continued, “This two-pronged approach produced potent T cell–driven and type I interferon–mediated tumor regression and long-term survival in preclinical PDAC models 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 limitations of their work, and commented that further research is needed: the tumors returned after treatment was withdrawn. “Further interrogation of the tumor-intrinsic (e.g., genetic) and -extrinsic (e.g., immune) resistance mechanisms leading to relapse after combined T/P and immuno-NP treatment will be important to uncover additional interventions to prolong treatment efficacy,” the team stated. Nevertheless, Ruscetti said the results are still a very encouraging step toward a cure.
Prabhani pointed out that the modular design could allow for treatments that are personalized for patients. “It’s sort of plug and play,” she said. “We can tailor the agonist ratios, the drug combinations, the targeting molecules, but keeping 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.”
The treatment strategy could also potentially be used to tackle other forms of cancer, the scientists suggested. Treatments for cancers like PDAC that could be derived from this study include mutations of colon cancer, lung cancer, liver cancer, and cholangiocarcinoma (cancer of the bile ducts). “If you go beyond pancreas cancer to other cancer types, you need a combination therapy to target the tumor and to target the immune system,” Ruscetti added. “This is a strategy to be able to do that.”
