A nano-vaccine for melanoma works for mice

via Tel Aviv University

Injection of nanoparticle has proven effective in mouse models, researchers say

Researchers at Tel Aviv University have developed a novel nano-vaccine for melanoma, the most aggressive type of skin cancer. Their innovative approach has so far proven effective in preventing the development of melanoma in mouse models and in treating primary tumors and metastases that result from melanoma.

The focus of the research is on a nanoparticle that serves as the basis for the new vaccine. The study was led by Prof. Ronit Satchi-Fainaro, chair of the Department of Physiology and Pharmacology and head of the Laboratory for Cancer Research and Nanomedicine at TAU’s Sackler Faculty of Medicine, and Prof. Helena Florindo of the University of Lisbon while on sabbatical at the Satchi-Fainaro lab at TAU; it was conducted by Dr. Anna Scomparin of Prof. Satchi-Fainaro’s TAU lab and postdoctoral fellow Dr. João Conniot. The results were published on August 5 in Nature Nanotechnology.

Melanoma develops in the skin cells that produce melanin or skin pigment. “The war against cancer in general, and melanoma in particular, has advanced over the years through a variety of treatment modalities, such as chemotherapy, radiation therapy and immunotherapy; but the vaccine approach, which has proven so effective against various viral diseases, has not materialized yet against cancer,” says Prof. Satchi-Fainaro. “In our study, we have shown for the first time that it is possible to produce an effective nano-vaccine against melanoma and to sensitize the immune system to immunotherapies.”

The researchers harnessed tiny particles, about 170 nanometers in size, made of a biodegradable polymer. Within each particle, they “packed” two peptides — short chains of amino acids, which are expressed in melanoma cells. They then injected the nanoparticles (or “nano-vaccines”) into a mouse model bearing melanoma.

“The nanoparticles acted just like known vaccines for viral-borne diseases,” Prof. Satchi-Fainaro explains. “They stimulated the immune system of the mice, and the immune cells learned to identify and attack cells containing the two peptides — that is, the melanoma cells. This meant that, from now on, the immune system of the immunized mice will attack melanoma cells if and when they appear in the body.”

The researchers then examined the effectiveness of the vaccine under three different conditions.

First, the vaccine proved to have prophylactic effects. The vaccine was injected into healthy mice, and an injection of melanoma cells followed. “The result was that the mice did not get sick, meaning that the vaccine prevented the disease,” says Prof. Satchi-Fainaro.

Second, the nanoparticle was used to treat a primary tumor: A combination of the innovative vaccine and immunotherapy treatments was tested on melanoma model mice. The synergistic treatment significantly delayed the progression of the disease and greatly extended the lives of all treated mice.

Finally, the researchers validated their approach on tissues taken from patients with melanoma brain metastases. This suggested that the nano-vaccine can be used to treat brain metastases as well. Mouse models with late-stage melanoma brain metastases had already been established following excision of the primary melanoma lesion, mimicking the clinical setting. Research on image-guided surgery of primary melanoma using smart probes was published last year by Prof. Satchi-Fainaro’s lab.

“Our research opens the door to a completely new approach — the vaccine approach — for effective treatment of melanoma, even in the most advanced stages of the disease,” concludes Prof. Satchi-Fainaro. “We believe that our platform may also be suitable for other types of cancer and that our work is a solid foundation for the development of other cancer nano-vaccines.”

Learn more: TAU Scientists Develop Novel Nano-Vaccine for Melanoma

 

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A nanovaccine for the flu

These nanoparticles average just 300 billionths of a meter across and contain vaccine antigens. Larger image. Image courtesy of the Nanovaccine Institute.

For many of us, a flu shot is a fall routine. Roll up a sleeve, take a needle to the upper arm and hope this year’s vaccine matches whichever viruses circulate through the winter.

The most common method to make that vaccine is now more than 70 years old. It requires growing viruses in special, pathogen-free chicken eggs. It’s not a quick and easy manufacturing process. And, at best, it provides incomplete protection.

Researchers from Iowa State University, the University of Iowa and the University of Wisconsin-Madison – all of them affiliated with Iowa State’s Nanovaccine Institute – are  working together to develop and test what they think could be a better way to fight the flu.

Thomas Waldschmidt

Thomas Waldschmidt

“What we’re doing is a completely new approach,” said Thomas Waldschmidt, the associate director of the Nanovaccine Institute, the Clement T. and Sylvia H. Hanson Chair in Immunology and a professor of pathology at Iowa. “This is a completely different ball game.”

What the researchers are doing is loading synthesized influenza proteins into nanoparticles. Those nanoparticles are about 300 billionths of a meter across and are made from biodegradable polymers. The nanoparticles are incorporated into a nasal spray and delivered with a sniff. Based on preliminary studies, researchers believe the nanovaccine will activate both kinds of immune cells (T cells and B cells) and provide protection in the upper airway (the nose, throat and voice box) and the lower airway (the windpipe and lungs).

All of that could mean better flu protection than today’s typical flu shot.

Looking for more complete protection

The National Institutes of Health is supporting the study of a flu nanovaccine with a five-year, $2.8 million grant.

Kevin Legge

Kevin Legge

Kevin Legge, an associate professor of pathology at Iowa, is leading the study. The research team also includes Waldschmidt; Balaji Narasimhan, the director of the Nanovaccine Institute and an Anson Marston Distinguished Professor in Engineering and the Vlasta Klima Balloun Chair in Chemical and Biological Engineering at Iowa State; and Thomas Friedrich, an associate professor of pathobiological sciences at Wisconsin.

So far, the researchers have tested a flu nanovaccine on mice, ferrets and pigs. The current study also calls for tests on monkeys.

Legge said today’s flu vaccines activate B cells and their production of antibodies. Those antibodies circulate throughout the body and attack viruses by binding to them, coating them and disabling them. Antibodies also signal other defensive cells to attack and destroy the virus.

Rodent studies have shown that the flu nanovaccine drives B cell as well as T cell activity, Legge said. T cells fight disease by attacking cells that have been infected by a virus.

Activating both B cells and T cells provides “a greater level of protection,” Legge said. “This is a more complete, robust response to vaccination.”

Balaji Narasimhan

Balaji Narasimhan

Legge and Narasimhan said the nanovaccine also seems to be better at building immunity in the lungs than current flu shots or the flu mist that was common several years ago and is no longer recommended by the Centers for Disease Control and Prevention.

Narasimhan said there are other advantages to a flu nanovaccine: it can easily be loaded with proteins synthesized from many different types of flu, it can be modified and produced quickly (the researchers call it “plug-and-play” technology) and it can be safely stored for long periods at room temperature.

The technology, he said, has the potential to check all the boxes for a better flu vaccine.

 

Learning the mechanisms, testing different types

But there’s more to learn about a flu nanovaccine before it’s available every fall.

Legge and Waldschmidt said they want to understand how, exactly, the nanovaccine provides protection from the flu. They also want to further define how the vaccine activates an immune response from B cells and T cells.

They’ll also study nanovaccine effectiveness against different types of influenza, including deadly strains such as H5N1, or bird flu.

“We want to confirm that this vaccine platform will work with any influenza payload,” Waldschmidt said.

Narasimhan said it’s also important to find just the right size of nanoparticles for a flu nanovaccine.

“It’s the ‘Goldilocks problem,’” he said. “Too big is not good and too small is not good. We’re looking for just right.”

And, the project will include tests of the flu nanovaccine on some of the monkeys studied by Friedrich at Wisconsin.

Thomas Friedrich

Thomas Friedrich

It’s important to study the nanovaccine in monkeys because their respiratory tracts and immune systems are similar to those in humans, Friedrich said.

“Monkeys are there to give us confidence that what is found in mice studies is truly relevant to humans,” he said. “And if problems are found in monkey studies, the vaccine can be tweaked to make it more effective before it goes to human trials.”

Friedrich also said that the monkeys used in this study are expected to recover from any illness and will be used in other studies.

Learn more: Novel Nanovaccine Could Fight Off Flu

 

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New nanovaccine can carry multiple weapons to fight tumors

Large particles (left) containing the DNA and RNA components are coated with electronically charged molecules that shrink the particle. The tumor-specific neoantigen is then complexed with the surface to complete construction of the nanovaccine. Upper left: electron micrograph of large particle. Credit: Zhu, et al. Nat Comm

Vaccine stimulates multi-pronged immune attack, inhibits tumor-induced immune suppression

Scientists are using their increasing knowledge of the complex interaction between cancer and the immune system to engineer increasingly potent anti-cancer vaccines. Now researchers at the National Institute of Biomedical Imaging and Bioengineering (NIBIB) have developed a synergistic nanovaccine packing DNA and RNA sequences that modulate the immune response, along with anti-tumor antigens, into one small nanoparticle. The nanovaccine produced an immune response that specifically killed tumor tissue, while simultaneously inhibiting tumor-induced immune suppression. Together this blocked lung tumor growth in a mouse model of metastatic colon cancer.

The molecular dance between cancer and the immune system is a complex one and scientists continue to identify the specific molecular pathways that rev up or tamp down the immune system. Biomedical engineers are using this knowledge to create nanoparticles that can carry different molecular agents that target these pathways. The goal is to simultaneously stimulate the immune system to specifically attack the tumor while also inhibiting the suppression of the immune system, which often occurs in cancer patients. The aim is to press on the gas pedal of the immune system while also releasing the emergency brake.

A key hurdle is to design a system to reproducibly and efficiently create a nanoparticle loaded with multiple agents that synergize to mount an enhanced immune attack on the tumor. Engineers at the NIBIB report the development and testing of such a nanovaccine in the November issue of Nature Communications.1

Making all the parts fit

Guizhi Zhu, Ph.D., a post-doctoral fellow in the NIBIB Laboratory of Molecular Imaging and Nanomedicine (LOMIN) and lead author on the study, explains the challenge. “We are very excited about putting multiple cooperating molecules that have anti-cancer activity into one nanovaccine to increase effectiveness. However, the bioengineering challenge is fitting everything in to a small particle and designing a way to maintain its structural integrity and biological activity.”

Zhu and his colleagues have created what they call a “self-assembling, intertwining DNA-RNA nanocapsule loaded with tumor neoantigens.” They describe it as a synergistic vaccine because the components work together to stimulate and enhance an immune attack against a tumor.

Shematic of nanovaccine stimulation of CTLs in lymph nodes

Small green nanovaccine particles deliver the tumor neoantigen to the lymph nodes (left) to stimulate the expansion of cytotoxic T lymphocytes (CTLs) specific for the tumor. The CTLs infiltrate the tumor at the right and kill tumor cells carrying the neoantigen (gray) but do not harm normal healthy cells (yellow). Credit: Zhu, et al. Nat Comm, November 2017.

The DNA component of the vaccine is known to stimulate immune cells to work with partner immune cells for antitumor activation. The tumor neoantigens are pieces of proteins that are only present in the tumor; so, when the DNA attracts the immune cells, the immune cells interact with the tumor neoantigens and mount an expanded and specific immune response against the tumor. The RNA is the component that inhibits suppression of the immune system. The engineered RNA binds to and degrades the tumor’s mRNA that makes a protein called STAT3. Thus, the bound mRNA is blocked from making STAT3, which may suppress the immune system. The result is an enhanced immune response that is specific to the tumor and does not harm healthy tissues.

In addition to engineering a system where the DNA, RNA and tumor neoantigens self-assemble into a stable nanoparticle, an important final step in the process is shrinking the particle. Zhu explains: “Shrinking the particle is a critical step for activating an immune response. This is because a very small nanoparticlecan more readily move through the lymphatic vessels to reach the parts of the immune system such as lymph nodes. A process that is essential for immune activation.”

The method for shrinking also had to be engineered. This was achieved by coating the particle with a positively charged polypeptide that interacts with the negatively charged DNA and RNA components to condense it to one-tenth of its original size.

Testing the vaccine
To create a model of metastatic colon cancer, the researchers injected human colon cancer cells into the circulation of mice. The cells infiltrate different organs and grow as metastatic colon cancer. One of the prime sites of metastasis is the lung.

Control and treated lung tumors from mice

Tumor (T) and lung (L) from control treated mice (top two) and nanovaccine treated mice (bottom) show a 10-fold reduction in tumor tissue in the lung of the nanovaccine treated animal. Credit: Zhu, et al. Nat Comm, November 2017.

The nanovaccine was injected under the skin of the mice 10, 16, and 22 days after the colon cancer cells were injected. To compare to the nanovaccine, two control groups of mice were analyzed; one group was injected with just the DNA and the neoantigen in solution but not formed into a nanovaccine particle, and the second control group was injected with an inert buffer solution.

At 40 days into the experiment, lung tumors from the nanovaccine-treated and the control groups were assessed by PET-CT imaging, and then removed and weighed. In mice treated with the nanovaccine, tumors were consistently one tenth the size of the tumors that were found in mice in both control groups.

Further testing revealed that mice receiving the nanovaccine had a significant increase in circulating cytotoxic T lymphocytes (CTLs) that specifically targeted the neoantigen on the colon cancer cells. CTLs are cells that attack and kill virus-infected cells and those damaged in other ways, such as cancerous cells.

An important aspect of the nanovaccine approach is that it mounts an anti-tumor immune response that circulates through the system, and therefore is particularly valuable for finding and inhibiting metastatic tumors growing throughout the body.

The researchers view their nanovaccine as an important part of eventual therapies combining immunotherapy with other cancer killing approaches.

Learn more: “Swiss army knife” nanovaccine carries multiple weapons to battle tumors

 

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