pHLIP and STING agonists together eradicate even advanced cancers in mice

Good news! Cancer is history (soon)! Fascinating approach! Possibly a breakthrough?

"... Immunotherapy provides that helping hand, with one method being what are called immune checkpoint inhibitors. These drugs effectively take the natural brakes off the immune response, allowing it to battle against cancer for longer. ...

they don’t work on “cold” tumors that have little immune activity to start with. So another type of drug known as STING agonists are designed to fire up these cold tumors into hot ones that are more receptive to immunotherapy. But these also have their drawbacks – namely, it’s hard to target them to cancer cells.

And that’s where the new study comes in. The researchers ... used a molecule called pH-low insertion peptide (pHLIP) to guide the drug to where it needs to go. pHLIP is drawn to acidic environments, conveniently like the kind that cancer makes around itself. ...
“But if it’s in an acidic environment, then the peptide folds into a helix, crosses the cell membrane and stays there.” ...
The team coupled pHLIP to STING agonists, so that the former carries the latter to cancer cells and helps them inside to get to work. And tests in mice proved promising – the researchers administered pHLIP-STING to 20 mice with small colorectal tumors and found that after a single injection, the tumors disappeared entirely in 18 mice within a few days. In another group with larger tumors, seven out of 10 mice saw their tumors disappear completely. ..."

From the abstract:

"Despite significant progress in the development of novel STING agonists (STINGa), applications appear to be challenged by the low efficiency and poor selectivity of these agents. A pH Low Insertion Peptide (pHLIP) extends the lifetime of a STINGa in the blood and targets it to acidic cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid derived suppressor cells (mMDSCs) and dendritic cells (DCs). CAFs constitute 25% of all live cells within CT26 tumors, and M2-type TAMs and mMDSCs are the most abundant among the immune cells. The resulting activation of cytokines within the tumor microenvironment (TME) triggers the eradication of small (100 mm3) and large (400-700 mm3) CT26 tumors in mice after a single dose of pHLIP-STINGa. The tumor stroma was destroyed (the number of CAFs was reduced by 98%), intratumoral hemorrhage developed, and the level of acidity within the TME was reduced. Further, no tumors developed in 20 out of 25 tumor-free mice re-challenged by an additional injection of cancer cells. The therapeutic effect on CT26 tumors was insignificant in nude mice, lacking T-cells. Thus, targeted delivery of STINGa to tumor stroma and TAMs induces activation of signaling, potentially resulting in the recruitment and infiltration of T-cells, which gain access to the tumor core. The cytotoxic activity of T-cells is not impaired by an acidic environment and immune memory is developed."

Homing missile molecule eradicates even advanced cancers in mice Researchers at Yale and the University of Rhode Island (URI) have demonstrated a new technique to fight cancer by attaching immunotherapy drugs to a molecule that seeks out the acidic environment of cancer cells. In tests in mice, a single dose was enough to eradicate even advanced tumors.

Eradication of tumors and development of anti-cancer immunity using STINGa targeted by pHLIP (open access)

FIGURE 3 Eradication of CT26 tumors and development of immune memory.