New studies in mice suggest that promoting immune responses at the site of cancer tumors with nanotechnology may help enhance immunotherapeutic treatment at advanced stages of the disease.
In mouse models of many types of cancer, scientists promoted T activation cell, An important fighter in the immune response, in ways to improve interactions within tumors Antibody therapy Currently being tested in clinical trials.
Researchers directly carry Nanobodies that carry messenger RNA, a molecule that converts genetic information into functional proteins. tumor A site that helps T cells produce specific receptors on their surface. Experimental monoclonal antibodies delivered 6 hours later can bind to these receptors and perform the function of killing cancer cells.
This technique left tumor-free lymphoma in 6 of 10 mice and was effective against melanoma when combined with additional existing drugs that help amplify the immune response.
“T cells are very important for fighting many diseases, not just cancer, and their function is very difficult to regulate,” said the senior author of the study, Pharmaceutics at The Ohio State University. And Echo Don, an associate professor of pharmacology, said.
“After injecting treatment-related mRNA, T cells decorate their surface with receptors, which allows for their additional function: proliferation, mobilization of others. Immune cells Production of useful proteins. And when T cells significantly increase these receptors, the antibody can react with the receptors and perform all the functions we know that interactions can produce. “
The study was published in the journal today Nature Communications..
While increasing T cell activation was the ultimate goal of the study, designing the most effective nanoparticles to carry messenger RNA was just as important. Don’s lab has long focused on delivering messenger RNA nanoparticles as a therapeutic strategy. Sepsis, Hereditary disease When COVID-19 (new coronavirus infection)..
The team used one of the many compounds that make up the cell membrane to design nanoparticles for this purpose.
“This idea is Cell membrane— We designed a compound that interacts well with the cell membrane and helps deliver mRNA to the cell. That’s the idea. “
Next, researchers loaded a nanoparticle cargo: messenger RNA that carries instructions for the production of molecules that T cells express as part of immune system function. These nanoparticles were injected directly into the tumor of a mouse model of a particular cancer, entered tumor-infiltrating T cells, and amplified receptor expression.
“We waited six hours for the cells to produce enough receptors before injecting the antibody into the tumor. The receptors were found in the T cells, which was found,” said Don, a researcher at The Ohio State University Center for Cancer. It caused the function. “
The combination therapy trial gave the best results in a mouse model of melanoma and B-cell lymphoma. Delivery of nanoparticles and antibodies completely eliminated tumors in 60% of mice. This is a significantly better result than treatment with the antibody alone. It was also persistent in enhancing the immune response. Lymphoma cells that were later injected into treated tumor-free mice could not survive long enough to form a tumor.
“When using untreated mice, the size of the tumor increased significantly, but in treated mice, the primary tumor died and re-challenge did not grow the tumor,” Don said.
Melanoma has proven to be a tougher battle.However, if the researchers supplement the combination therapy with the addition of two antibodies that destroy it. cancer cell‘Ability to block Immune responseThis approach provided a 50% complete response in mice and protection against subsequent tumor re-challenge. This multi-therapeutic approach also reduced the spread of cancer in a mouse model of lung metastasis.
Focusing treatment directly on the tumor site is a way to train the immune system to recognize local and circulating cancer cells while reducing the likelihood of systemic side effects, Don said.
This study provided evidence that this technology platform can be used to enhance immunotherapy.
“We want to test more materials to see if we can deliver mRNA to more T cells for even greater efficiency,” Don said. “Ultimately, for certain cancers, we hope this helps to generate stronger immune system functions by inducing anti-tumor immunity.”
This work was supported by grants from the National Institute of Medical Sciences, The Ohio State University Faculty of Pharmaceutical Sciences Startup Fund, and Sylvan G. Frank Graduate Fellowship Professor.
All Ohio co-authors include Wenqing Li, Xinfu Zhang, Chengxiang Zhang, Jingyue Yan, Xucheng Hou, Shi Du, Chunxi Zeng, Weiyu Zhao, Binbin Deng, David McComb, Yuebao Zhang, Diana Kang, Junan Li and William. included. Carson. Don is a biopharmacy company Oncorus, Inc. located in Cambridge, Massachusetts. I am a member of the Scientific Advisory Group.
Nature Communications (2021). DOI: 10.1038 / s41467-021-27434-x
Ohio State University
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