Nanoparticle therapy fights tumours in mouse models

Wednesday, 03 April, 2024

Nanoparticle therapy fights tumours in mouse models

A nanoparticle-based therapy, developed at the University of Texas Southwestern Medical Center (UTSW), has successfully stimulated an immune pathway that eradicated tumours in mouse models of various cancer types, offering a new way to harness the power of the immune system against cancer.

In the past couple of decades, researchers at UTSW and elsewhere have learned more about the immune system’s role in fighting cancer; indeed, several anti-tumour immunotherapies based on this work have been approved by the US FDA and are now regularly used to treat some cancer types. However, these therapies largely fall into a category called checkpoint inhibitors, which block proteins that prevent immune cells from attacking cancer cells. Only about 20–30% of cancer patients respond to these therapies.

This new nanoparticle-based therapy, on the other hand, activates a molecule known as the stimulator of interferon genes (STING) — an evolutionarily ancient molecule that responds to a molecular signal called cGAMP. Generated when cells sense an infection or cancer, and discovered by UTSW biochemist Professor Zhijian “James” Chen, cGAMP signals immune cells to ready for battle.

Activating STING to fight cancer isn’t a new concept, but molecules developed to target STING have largely been ineffective for a variety of reasons, including for draining too quickly from the tumour site or for killing CD8+ T cells in the immune system that attack cancer cells. In 2017, UTSW researchers led by Professor Jinming Gao discovered that a polymer nanoparticle they designed, called PC7A, activated STING even without stimulation by cGAMP. A follow-up study in 2021 showed that PC7A polymerised STING to continue this activation for over 48 hours, causing a sustained effect.

In their latest study, published in the journal Science Immunology, Gao’s team created a new experimental therapy that embedded cGAMP in PC7A nanoparticles. The combination initially stimulated STING activation with cGAMP and then locked in this strong activation for an extended period.

“The gold standard of current cancer immunotherapies releases the brakes on the immune defence against tumours,” Gao said. “Our strategy steps on the gas to drive immune activation.”

Experiments in mouse models of various cancers showed that this strategy shrank tumours so effectively that it cured some animals of disease; prevented metastasis, or the spread of cancerous tumours; and prevented relapse when cured mice were re-exposed to the same types of cancer cells. Gao said the nanoparticle treatment also worked for immunologically ‘cold’ tumour types that usually don’t respond to checkpoint inhibitors.

Searching for the mechanism behind this effect, the researchers found that the nanoparticles preferentially accumulate and act on type 1 conventional dendritic cells, an immune cell type that helps prime CD8+ T cells to fight tumours. Surprisingly, these cells were found to be elevated in cancer patients with longer progression-free survival after treatment with checkpoint inhibitors, Gao said, confirming that these cells are important for anti-cancer immunity in a clinical setting.

Illustration depicts a nanoparticle (purple) activating the stimulator of interferon genes (STING) proteins (yellow) in dendritic cells to recruit cytotoxic T cells into an immune ‘cold’ tumour. Image credit: UT Southwestern.

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