Boosting anti-cancer action by driving up immunity at tumor site
In mouse studies, nanoparticles activate key cancer fighters

Date:
December 14, 2021
Source:
Ohio State University
Summary:
Driving up the immune response at the site of a cancer tumor with
nanotechnology may help enhance immunotherapy treatments in advanced
stages of the disease, new research in mice suggests.



FULL STORY ========================================================================== Driving up the immune response at the site of a cancer tumor with nanotechnology may help enhance immunotherapy treatments in advanced
stages of the disease, new research in mice suggests.


==========================================================================
In mouse models of numerous types of cancer, scientists boosted activation
of T cells, important fighters in an immune response, inside tumors in a
way that improved their interactions with an antibody therapy currently
being tested in clinical trials.

The researchers injected nanobodies carrying messenger RNA, molecules that translate genetic information into functional proteins, directly into the
tumor site to help T cells generate specific receptors on their surfaces.

Experimental monoclonal antibodies delivered six hours later could then
bind to those receptors to carry out their cancer cell-killing functions.

The technique left six of 10 mice with lymphoma tumor-free, and was
effective in melanoma when combined with additional existing drugs that
help amplify the immune response.

"T cells are very important for fighting a lot of diseases -- not
just cancer - - and it's really difficult to modulate their function,"
said Yizhou Dong, senior author of the study and associate professor of pharmaceutics and pharmacology at The Ohio State University.

"After injections of therapeutically relevant mRNA, the T cells
decorate their surfaces with receptors, and that enables their additional functions: proliferating, recruiting other immune cells and production of helpful proteins. And when T cells significantly increase those receptors, antibodies can react with the receptors and carry out all the functions
we know that interaction can produce." The study is published today
(Dec. 14, 2021) in the journal Nature Communications.



========================================================================== While increasing T cell activation was the end goal of the research,
designing the most effective nanoparticle to carry the messenger RNA was equally important. Dong's lab has long focused on nanoparticle delivery
of messenger RNA as a therapeutic strategy, producing promising results
in animal studies against sepsis, genetic disorders and COVID-19.

The team designed nanoparticles for this purpose using one of many
compounds that make up cell membranes.

"The idea was inspired by natural components on a cell membrane --
we designed compounds that can have nice interactions with the cell
membrane and help deliver mRNA into cells. That's the idea," Dong said.

Researchers then loaded the nanoparticle cargo: messenger RNA carrying instructions for the production of molecules that T cells express as
part of their immune system function. These nanoparticles were injected directly into tumors in mouse models of specific cancers, and entered tumor-infiltrating T cells to amplify their expression of the receptors.

"We waited six hours until the cells produced enough receptors, and then injected antibodies into the tumors. They found their receptors on T cells
and that triggered their functions," said Dong, also an investigator in
the Ohio State University Comprehensive Cancer Center.



========================================================================== Tests of the combined treatment produced the best results in mouse models
of melanoma and B cell lymphoma. The nanoparticle and antibody delivery completely eliminated tumors in 60% of the mice -- a significantly better result than treatment with the antibody alone. The immune response
enhancement had staying power, as well: Lymphoma cells injected later
into the treated tumor-free mice were unable to survive long enough to
form tumors.

"If we used untreated mice, the tumor size increased a lot, but for those
mice that had received treatment, it killed the primary tumor and upon rechallenge, tumors cannot grow," Dong said.

Melanoma proved to be a tougher fight. However, when researchers
supplemented the combination treatment with the addition of two antibodies
that disrupt cancer cells' ability to block the immune response, this
approach resulted in a 50% complete response in the mice and protection
against a later tumor re- challenge. This multi-therapy approach also
reduced cancer's spread in a mouse model of metastasis to the lungs.

Focusing treatment directly at the tumor site is a way of training the
immune system to recognize local and circulating cancer cells while
lowering the chances for whole-body side effects, Dong said.

The study provided evidence that this technology platform could be used
to enhance immunotherapy.

"We want to test more materials and see if we can deliver mRNA to even
more T cells to further increase efficiency," Dong said. "Ultimately,
we hope that for certain cancers, this may help produce stronger immune
system function by inducing anti-tumor immunity." This work was supported
by grants from the National Institute of General Medical Sciences, an
Ohio State College of Pharmacy startup fund and the Professor Sylvan
G. Frank Graduate Fellowship.

Co-authors, all from Ohio State, 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 Carson. Dong is a scientific advisory board member of the biopharmaceutical company Oncorus, Inc.

in Cambridge, Massachusetts.

========================================================================== Story Source: Materials provided by Ohio_State_University. Original
written by Emily Caldwell. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Wenqing Li, Xinfu Zhang, Chengxiang Zhang, Jingyue Yan, Xucheng
Hou, Shi
Du, Chunxi Zeng, Weiyu Zhao, Binbin Deng, David W. McComb,
Yuebao Zhang, Diana D. Kang, Junan Li, William E. Carson, Yizhou
Dong. Biomimetic nanoparticles deliver mRNAs encoding costimulatory
receptors and enhance T cell mediated cancer immunotherapy. Nature
Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-27434-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211214084535.htm

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