Team builds on COVID-19 mRNA vaccine technology to target specific pathways driving hepatocellular carcinoma

A team of researchers from Massachusetts General Hospital (MGH) and Brigham and Women’s Hospital (BWH) have reprogrammed the tumor microenvironment of liver cancer using mRNA nanoparticles. This technology, similar to that used in COVID-19 vaccines, restored the function of the p53 master regulator gene, a mutated tumor suppressor not only in the liver but also in other types of cancer. When used in combination with immune checkpoint blockade (ICB), the p53 mRNA nanoparticle approach not only induced tumor growth suppression but also significantly increased anti-tumor immune responses in laboratory models of hepatocellular carcinoma (HCC). The results of the study were published in Nature Communication.

“Reprogramming the cellular and molecular components of the tumor microenvironment could be a transformative approach for the treatment of HCC and other cancers,” says co-lead author Jinjun Shi, PhD, with the Center for Nanomedicine at BWH, who developed the platform with the MGH. liver cancer biologist and co-lead author Dan G. Duda, DMD, PhD. “Using this novel approach, we are targeting specific pathways in tumor cells with mRNA nanoparticles. These tiny particles provide the cells with the instructions to build proteins that, in the case of HCC, retard tumor growth and make the tumor more responsive. immunotherapy treatment.

HCC is the most common form of liver cancer, characterized by a high mortality rate and a poor prognosis for patients. Immune checkpoint blockers, a revolutionary new class of drugs that allow the immune system to recognize and attack cancer cells, have been shown to be effective in treating HCC, but most patients do not benefit from them. To overcome this resistance, multiple strategies are being developed to improve ICBs by combining 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 some modifications) to targeting cancer cells. He partnered with Duda, whose MGH lab had previously created sophisticated animal models to analyze the microenvironment of liver tumors in response to immunotherapy. They developed and optimized an mRNA nanoparticle strategy to restore the loss of function of p53, a tumor suppressor gene whose function is lost in more than a 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 developed nanoparticles to target CXCR4 – a chemokine receptor expressed by liver cancer cells – and selectively co-deliver drugs such as kinase inhibitors,” Duda explains. “We have 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 tumor suppressor pathways,” Shi points out. “Our proof-of-concept study is an exciting development that clearly shows that p53 mRNA nanoparticles in combination with ICB not only work, but could also make a big difference in reversing immunosuppression in HCC and potentially other cancers.

Shi is an Associate Professor of Anesthesia at Harvard Medical School (HMS). Duda is Associate Professor of Radiation Oncology at HMS and Director of Translational Research in Gastrointestinal Radiation Oncology at MGH. Yuling Xiao, PhD, and Jiang Chen, MD, PhD, are the study’s lead authors and HMS postdoctoral fellows.

The study was supported by an idea award from the US Department of Defense Peer-Reviewed Cancer Research Program (PRCRP).

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Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.

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