New Nanoparticles Reactivate Cancer-Fighting T Cells Shut Down by Tumors

Last year, the Nobel Prize for Medicine was awarded for a revolutionary new way to trigger the immune system response to attack cancer cells. The promise of immunotherapy is extraordinary and marks a major turning point in the fight against cancer as it prevents cancer cells from shutting down the body’s immune system response.

This week, a team at Vanderbilt University announced that they have found another way to engage the immune system in a battle with malignant cancer cells by reactivating T cells that cancer cells have already shut down.

Cancer: A Cunning Foe

Cancer cells are insidious for many reasons, but one of the more discouraging characteristics of cancer is how it can hide from, shutdown, or otherwise thwart the body’s immune response that is responsible for clearing out infections and other malignancies in the body.

One of the ways it does this is by invading the T cell itself with tumor cells. This causes the immune system’s response to ignore the tumor cells its supposed to be fighting. The technique that won the Nobel Prize, called Checkpoint Blockade, is meant to prevent this infiltration from occurring, allowing the immune system to do what it was always supposed to do: kill cancer cells.

“Tumors are pretty conniving and have evolved many ways to evade detection from our immune system," said assistant professor of chemical and biomolecular engineering and biomedical engineering at Vanderbilt, John T. Wilson. "Our goal is to rearm the immune system with the tools it needs to destroy cancer cells.”

Liberating the T Cells

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In a paper titled "Endosomolytic Polymersomes Increase the Activity of Cyclic Dinucleotide STING Agonists to Enhance Cancer Immunotherapy" in the journal Nature Nanotechnology, the Vanderbilt team showed that it is possible to reactivate T cells that had been shut down by the tumors they were fighting.

They did this by targeting the T cells that tumors had already infiltrated and disarmed. To do this, they designed a nanoscale particle that could tell the disabled T cells to fight back, reigniting the short-circuited immune response after it had been disabled by cancer.

“Checkpoint blockade has been a major breakthrough,” said Wilson, “but despite the huge impact it continues to have, we also know that there are a lot of patients who don't respond to these therapies. We've developed a nanoparticle to find tumors and deliver a specific type of molecule that's produced naturally by our bodies to fight off cancer.”

That molecule, cGAMP, is crucial in that it acts as the switch for what's known as the stimulator of interferon genes (STING) pathway. STING is a mechanism the body uses to initiate a response to an infection or cluster of malignant cells. Essentially, cGAMP is the general on the horse shouting “charge!” to an army of T cells ready to fight off threats to the body.

Successful Tests Encourage Further Study

The team crafted the nanoparticle that delivered cGAMP to infiltrated cells out of so-called “smart polymers,” that react to changes in pH levels. Daniel Shae, a Ph.D. candidate on Wilson’s team, engineered the nanoparticle to enhance the power of the cGAMP contained inside, and after nearly two dozen refinements, the nanoparticle they built effectively activated STING first in the T cells of mice, then within the tumors themselves the mice carried, and finally in cancerous human tissue samples.

The test on human tissue was limited to melanoma, but according to Wilson, the technique should be similarly effective against other forms of cancer.

“That's really exciting" Shae added, "because it demonstrates that, one day, this technology may have success in patients.”