In a new study, a multi-prong treatment combined with a clever delivery method has shown promise against one of the deadliest cancers [1].
Lethal and barely treatable
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer. It is rarely diagnosed early and very aggressive. It also responds poorly to treatment, primarily because its fibrotic tumor microenvironment (TME) hinders infiltration by immune cells.
Overall, the five-year survival rate for pancreatic cancer is slightly above 10%. Even for patients who were diagnosed early, it stands at just 37%, making this a high-priority target for cancer researchers.
One novel approach involves inducing senescence in cancer cells [2], causing them to produce the senescence-associated secretory phenotype (SASP). SASP factors are highly inflammatory, which helps remodel the TME and increase its susceptibility to infiltration by immune cells.
This approach works reasonably well in some cancer types. However, in PDAC, TME suppresses proinflammatory SASP components and the immune system activation that they are supposed to trigger.
The immune response can be bolstered by activating the stimulator of interferon genes (STING) pathway. This increases production of interferon and some other pro-inflammatory cytokines [3]. STING agonists showed some promise against PDAC, but their use is limited by their poor uptake by cells and short half-life (they are excreted quickly). The pancreas is also very hard to reach for direct intratumoral delivery.
Multiple approaches
In this study published in Science Translational Medicine, scientists from the University of Massachusetts tested a novel combination therapy in a mouse model of PDAC. One element of the combination consisted of two drugs: a STING agonist and a toll-like receptor 4 (TLR4) agonist. TLR4 agonists can additionally stimulate interferon responses. The other half was a popular duo of senescence-inducing compounds, trametinib and palbociclib (T/P).
Importantly, the STING agonist cdGMP and the TLR4 agonist MPLA were encapsulated together in nanoparticles (NPs) to overcome the usual delivery limitations. Achieving this was not an easy task since cdGMP is hydrophilic and TLR4 is hydrophobic. The researchers solved this problem by loading the two molecules into different compartments: cdGMP into the aqueous NP core and MPLA into the lipid bilayer shell.
Although NPs were administered intravenously, they found their way to the tumor area and infiltrated numerous cell types, including macrophages and antigen-presenting dendritic cells. NPs hardly accumulated in organs and did not cause toxicity.
Just as the researchers hoped, combining NPs with the pro-SASP treatment led to a synergistic effect. Pretreatment with the senescence-inducing duo T/P for 12 days increased the uptake of NPs by both tumor cells and immune cells. Moreover, it worked both ways: SASP induction was stronger with the combination therapy than with T/P alone.
“Together,” the paper says, “these findings demonstrate that combinatorial T/P and immuno-NP treatment, through both tumor cell autonomous and non–cell autonomous molecular mechanisms, enhances IFN signaling, proinflammatory cytokine production, and antigen presentation in the PDAC TME.”
An encouraging proof of concept
However, the important test is the therapy’s anti-tumor effectiveness. Here, too, the combination was more effective than NP or T/P treatments alone, leading to massive tumor necrosis in just 48 hours and significantly improved survival times. Moreover, some mice had complete response (full eradication of tumors), although the cancer returned after the treatment stopped.
“This is pretty striking,” said Marcus Ruscetti, assistant professor of molecular, cell and cancer biology at UMass Chan Medical School, and a corresponding author on the study. “We’ve never seen that in this model before.”
Ruscetti said that although all animals eventually succumbed to cancer, the results still were “a very encouraging step toward a cure.”
“If you go beyond pancreas cancer to other cancer types, you need a combination therapy to target the tumor and the immune system,” he added. “This is a strategy to be able to do that.”
Collectively, our results suggest that engineering approaches to target multiple cell types and immune suppressive barriers through induction of type I IFN signaling in the PDAC TME could pave the way for coordinated innate and adaptive immune responses to achieve immunotherapy successes that have thus far been elusive for patients with PDAC.
Literature
[1] Chibaya, L., DeMarco, K. D., Lusi, C. F., Kane, G. I., Brassil, M. L., Parikh, C. N., … & Ruscetti, M. (2024). Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer. Science Translational Medicine, 16(762), eadj9366.
[2] Ruscetti, M., Morris, J. P., Mezzadra, R., Russell, J., Leibold, J., Romesser, P. B., … & Lowe, S. W. (2020). Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell, 181(2), 424-441.
[3] Vonderhaar, E. P., Barnekow, N. S., McAllister, D., McOlash, L., Eid, M. A., Riese, M. J., … & Dwinell, M. B. (2021). STING activated tumor-intrinsic type I interferon signaling promotes CXCR3 dependent antitumor immunity in pancreatic cancer. Cellular and molecular gastroenterology and hepatology, 12(1), 41-58.
