Liver Cancer Microenvironment Reprogrammed Using mRNA Nanoparticles

The p53 master regulator gene function was restored using mRNA nanoparticles in a study. When used in combination with immune checkpoint blockade (ICB), this nanoparticle approach not only induced suppression of tumor growth but also significantly increased antitumor immune responses in hepatocellular carcinoma (HCC) laboratory models. This approach could have wider application, since p53 is mutated in other types of cancer besides liver.

The researchers are from Massachusetts General Hospital (MGH) and Brigham and Women’s Hospital (BWH). The results of the study were published in Nature Communications.

“The reprogramming of the cellular and molecular components of the tumor microenvironment could be a transformative approach for treating HCC and other cancers,” says co-senior author Jinjun Shi, with the Center for Nanomedicine at BWH, who developed the platform with MGH liver cancer biologist and co-senior author Dan Duda.

Shi added that, “By using this new approach, we’re targeting specific pathways in tumor cells with mRNA nanoparticles. These tiny particles provide the cells with the instructions to build proteins, which, in the case of HCC, delayed tumor growth and rendered the tumor more responsive to treatment with immunotherapy.”

HCC is the most prevalent form of liver cancer, characterized by a high mortality rate and dismal prognosis for patients. Liver cancer is increasing in prevalence in the US and is one of the most common kinds of malignancy around the world.

Immune checkpoint blockers have shown efficacy in treating HCC, but do not benefit most patients. To overcome resistance to these drugs, multiple strategies are being tried to combine them with other existing therapies, such as anti-VEGF drugs and radiotherapy. However, even these approaches are expected to benefit only a small number of patients, creating an urgent need for new combination therapies.

Encouraged by the success of mRNA in COVID-19 vaccines, Shi decided to apply the technology (with certain modifications) to targeting cancer cells. He teamed up with Duda, whose MGH lab had already created animal models to analyze the microenvironment of liver tumors in response to immunotherapy. They developed and optimized an mRNA nanoparticle strategy to restore loss of function of p53, a tumor suppressor gene whose function is lost in more than one-third of HCC cases. In doing so, they uncovered evidence that p53 regulates the tumor microenvironment by modulating the interaction of cancer cells with immune cells as part of ICB therapy.

“In our previous work we had developed nanoparticles to target CXCR4—a chemokine receptor expressed by liver cancer cells—and selectively co-deliver drugs such as kinase inhibitors,” explains Duda. “We’ve now adapted this platform to use CXCR4 as a kind of ZIP code to selectively target the tumor with nanoparticles encapsulating therapeutic mRNAs. When we combined this nanomedicine with anti-programmed death receptor 1 (PD-1) antibodies, a standard immunotherapy for HCC patients, it induced global reprogramming of the tumor microenvironment and tumor response by restoring p53 expression.”

The next step for the team is to transfer their research from animal models to patients in a clinical trial. “Scientists have struggled for decades to find an effective way to target the tumor suppressor pathways,” emphasizes Shi. “Our proof-of-concept study is an exciting development that clearly shows that p53 mRNA nanoparticles in combination with ICB not only works, but also could make a big difference by reversing immunosuppression in HCC and potentially other cancers.”

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