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A new strategy delivering immunotherapy medicines revealed to treat cancer

by Rishika Choudhury

Date & Time: Oct 23, 2022 12:00 PM

Read Time: 3 minute

Researchers have discovered a possible new method of administering immunotherapy medicines to treat cancer.

The study was led by researchers from the University of Rhode Island and Yale University, and the findings were published in the journal Frontiers in Oncology.

The method entails attaching an immunotherapy agent known as a STING agonist to an acid-seeking molecule known as pHLIP® (pH-low insertion peptide). The pHLIP molecules target the high acidity of cancerous tumours, delivering immunotherapy cargo directly to cells in the tumour microenvironment. Once administered, the STING agonists activate the body's innate immune response to combat the tumour.

The team demonstrated that a single dose of the pHLIP-STING agonist combination eradicated colorectal tumors—even large, advanced tumors—in mice in a study published in Frontiers of Oncology. The mice that were treated also developed long-term immunity, allowing their immune systems to recognise and fight cancer long after the initial tumours had vanished. While the researchers caution that mouse results do not always translate to human results, the findings do lay the groundwork for a potential clinical trial testing the safety and efficacy in cancer patients.

"STING agonists are an important class of immuno-modulators, but research has clearly shown that they often don't work on their own and need to be targeted in some way," said Yana Reshetnyak, a physics professor at URI and a senior author of the new research. "What we show here is that using pHLIP to target tumors through their acidity, we can successfully go after a variety of different cell types within the tumor microenvironment and achieve synergistic and quite dramatic therapeutic effects."

Targeted immunotherapy

Immunotherapy is a new approach to cancer treatment. Tumors must hide from the immune system in order to survive and spread. In some cases, they accomplish this by expressing proteins that serve as immune cloaking devices, fooling the immune system into believing tumour cells are normal, native cells. The goal of immunotherapy is to disable these cloaking devices.

Immune checkpoint inhibitors, which have been shown to be effective in treating a variety of cancers, are one method of uncloaking tumours. However, these drugs do not work on all tumours. They work well on immunologically "hot" tumours with a lot of inflammation, but not so well on "cold," non-inflamed tumours. STING (STimulator of Interferon Gene) agonists were created to convert cold tumours into hot ones, making them more susceptible to immune response. They accomplish this by inducing the release of interferon, a red-flag protein that alerts the immune system to foreign invaders.

The approach has shown promise in the lab, but Reshetnyak says that administering STING agonist to patients has been difficult. The compounds can have an effect on healthy cells, resulting in significant side effects but only minor therapeutic effects.

However, if STING agonists could be specifically targeted to tumour cells—not just cancer cells but also dormant immune cells within a tumor—their effectiveness could be significantly increased. This is where pHLIP comes into play.

PHLIP is an amino acid peptide derived from bacteriorhodopsin, a membrane protein that allows certain single-celled organisms to convert light to energy. pHLIP has a special affinity for acidic environments, according to research led by Donald Engelman at Yale.

"When pHLIP encounters a cell membrane with a neutral pH, it will sit on the surface briefly and then pull away," said Engelman, who is a co-author of this new study. "But if it's in an acidic environment, then the peptide folds into a helix, crosses the cell membrane and stays there."

There are currently two ongoing clinical trials testing the safety of pHLIP compounds in cancer patients. And the team continues to look for new ways of using the peptide. In this new study, the researchers aimed to find out if pHLIP could successfully target immunotherapeutic molecules that cause the immune system to attack tumors.

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