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2022-11-09| R&D

Combining STING Agonists and pHLIPs to Enhance Cancer Treatments

by Richard Chau
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Since the emergence of immune checkpoint inhibitors, immunotherapy has become a mainstay of cancer treatments. Recently, a team of researchers from the University of Rhode Island and Yale University demonstrated a new molecular delivery system that can more effectively target tumor cells and deliver immunotherapeutic drugs to the front line to fight against cancer, bringing hope to the widespread application of immunotherapy.

Related article: Novel Triple Immunotherapy Combo Rekindles Hope for Pancreatic Cancer Patients

Targeting Highly Acidic Tumor Environments Using pHLIPs

Immune checkpoint inhibitors are effective in treating various types of cancers, but the efficacy of these drugs varies depending on the extent of tumor inflammatory responses. Generally speaking, cancer tumors can be characterized as “cold” or “hot,” with the latter being more likely to trigger stronger immune responses and so respond better to cancer immunotherapies. For this reason, scientists developed STING (stimulator of interferon genes) agonists to “heat up” the tumor microenvironment and turn cold tumors into hot tumors

STING is a transmembrane protein that can regulate innate immune response by inducing the secretion of type Ι interferons and other cytokines after recognizing endogenous or exogenous DNA. A STING agonist (STINGa) is a small molecule that can bind to STING proteins, activating the STING signaling pathway which shows therapeutic effects for cancer and infectious diseases caused by pathogens. More importantly, a (STINGa) can turn “cold” tumors into “hot” ones by drawing immune cells to the tumor and inducing anti-tumor immune responses. However, because these effects may also act on healthy cells and result in significant side effects, studies are still underway to search for ways to aim STING agonists at the tumor environment.

In a recent study published in Frontiers of Oncology, the team combined STING agonists with a unique molecule called pHLIP (pH-low insertion peptide). pHLIP can fold and insert across membranes reversibly in response to pH changes, allowing it to serve as a specific ligand to target the tumor acidic microenvironment for tumors at early and metastatic stages. The pHLIP-STINGa combination can deliver immunotherapeutic drugs directly to the cells in the tumor microenvironment (TME), enhancing the efficiency and selectivity of STING agonists and drugs.

To test whether pHLIPs increase the effectiveness of the STING agonist (STINGa), the team gave 20 mice with small colorectal tumors (100 mm³) a single intraperitoneal (IP) (100 μM 300 μl) or intravenous (IV) (200 μM 150 μl) injection of the pHLIP-STINGa combination and observed tumors disappear in 18 of them within a few days. In addition to the treatment of small tumors, the team also treated mice with larger tumors. A single IP injection of pHLIP-STINGa into mice with large tumors (400-700 mm³) led to tumor eradication in 7 out of 10 treated animals. . For comparison, another ten mice received non-targeted STINGa injections, and tumors persisted in all of them, although tumor growth slowed down for a short period.

The team stated in their latest paper that pHLIP extends the lifetime of a STINGa in blood and targets acidic cancer-associated fibroblasts (CAFs), dendritic cells, myeloid-derived suppressor cells, and tumor-associated macrophages. The resulting activation of cytokines within the TME triggers the eradication of small and large tumors in mice after a single dose of pHLIP-STINGa. The combination destroyed tumor stroma (the number of CAFs reduced by 98%), intratumoral hemorrhage developed, and the TME’s acidity level reduced.

Moreover, the treatment mentioned above also appeared to stimulate immune memory in the treated mice. When researchers injected cancer cells into 25 mice after treatment, 20 remained tumor-free for 40 days of follow-up monitoring, indicating that their immune systems continued to recognize and fight against cancer after the disappearance of their initial tumors.

pHLIP-STINGa Combination Value in Immunotherapy

In addition to the high tumor eradication rate, it is surprising that the pHLIP-STINGa combination also appeared to work on various tumor cell types. A few hours after the pHLIP-STINGa combination injection, researchers found significant reductions in the matrix that forms the physical and chemical barrier that protects the tumor from the immune system.

According to senior author Yana Reshetnyak, professor of physics at the University of Rhode Island, the advantage of using pHLIP to target tumors through their acidity is evident from the destruction of the tumor stroma: not just certain cell types but tracking the entire tumor. While the results of mouse experiments are not always transferable to humans, these findings do lay the groundwork for the safety and efficacy of potential cancer clinical trials.

Much research remains before humans can use the pHLIP-STINGa combination, but the researchers believe these preliminary results show considerable potential. With two ongoing clinical trials testing the safety of pHLIP in cancer patients and pHLIP-based therapies approved for clinical trials, the team expects to make expeditious progress in the future.

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