Researchers at the University of Arizona R. Ken Coit College of Pharmacy have developed a new strategy that helps the immune system recognize and attack lung cancer tumors more effectively. By packaging a chemotherapy drug and an RNA molecule in a tiny lipid carrier, the team boosted an immune response that slowed tumor growth and enhanced the effects of immunotherapy.
The findings, published in Nature Communications , describe a nanotechnology-based platform that combines the chemotherapy drug paclitaxel with a gene-silencing molecule known as siRNA. The lipid package improves delivery of both therapies to lung tumor cells.
The approach enhances a process called immunogenic cell death, or ICD, a form of cancer cell death that alerts the immune system to the presence of tumors. Researchers increasingly view ICD as a promising way to help the body recognize, attack and remember cancer cells.
Jianqin Lu, John A. and Frances P. Ware Endowed Associate Professor of Pharmaceutical Sciences in the U of A College of Pharmacy and a member of the U of A Comprehensive Cancer Center, led the research.
"Despite the significant potential of ICD-enabled immunotherapy, its therapeutic applications remain underused," Lu said. "Since we know paclitaxel can induce ICD, we improved the delivery of the drug to the tumor by attaching a fatty molecule called a sphingolipid to form a fatty bubble, or nanovesicle. We can deliver more drugs to the tumor site."
As the drug kills cancer cells, a protein called calreticulin, or CRT, moves to the surface of dying cells, creating what researchers describe as an "eat me" signal that attracts immune cells. CRT acts as a beacon for cells called phagocytes, which engulf dying tumor cells and help initiate the ICD response.
Some tumors evade this response by using a molecule called STC1, which prevents CRT from reaching the cell surface. As a result, the immune response is weakened and cell-killing T cell activity is reduced.
To counter that effect, the researchers used an siRNA molecule called siSTC1 to silence STC1 gene activity by co-delivering it with paclitaxel.
The team tested the strategy in two cancer cell lines: Lewis lung cancer cells, which have high STC1 gene expression, and MC38 colon cancer cells, which have lower STC1 expression of these genes. They found the combination of the drug and the siRNA silencing the STC1 gene was much more effective against the lung cancer cells than the MC38 cells.
"If you trigger an ICD immune response, there should be no tumor development or delayed tumor development," Lu said.
Using mouse models of lung cancer, Lu and his colleagues found that the combination of SCT1 siRNA and paclitaxel eradicated three out of five tumors and, in some cases, four out of five tumors, depending on the cancer type.
The researchers also found that the siSTC1-paclitaxel package increased tumor sensitivity to PD-1 blockade treatment, a type of cancer immunotherapy that allows the immune system to better recognize and destroy cancer cells.
"You're really changing the tumor microenvironment," Lu said. "The paclitaxel-siSTC1 combination potentiates the PD-1 blockade therapy, and the cancer immunotherapy. That's how this kind of process can have an impact."
Lu said the platform could be used to treat many cancer types with high STC1 expression, including non-small cell lung cancer, some colon cancer types, breast cancer, liver cancer and ovarian cancer.
The team hopes to collaborate with clinical oncologists and eventually advance the platform in a phase 1 clinical trial.
Other co-authors from the U of A College of Pharmacy include Wenpan Li, researcher/scientist III; Zhiren Wang, former postdoctoral research associate; Mengwen Li, doctoral student in pharmaceutical sciences; Yanhao Jiang, doctoral student in pharmaceutical sciences; Shuang Wu, doctoral student in pharmaceutical sciences; Leyla Cordova, master's degree student in pharmaceutical sciences; and MinHyeok Kim, former undergraduate student researcher.
This work was funded in part by Startup and Retention Funds from the R. Ken Coit College of Pharmacy at The University of Arizona, a PhRMA Foundation Faculty Starter Grant in Drug Delivery, U of A Comprehensive Cancer Center Internal Pilot and Within Reach Awards, and the National Institutes of General Medical Sciences (NIGMS) and the National Cancer Institute (NCI) through grant nos. R35GM147002 and R01CA272487. NIGMS and NCI are both divisions of the National Institutes of Health.
