Electrified microneedles get vaccine across the skin for cancer immunotherapy

Electrified microneedles get vaccine across the skin for cancer immunotherapy

Microneedle skin patches combined with a safe electrical current help antigens cross the skin to trigger an immune response against tumors.

Your body is a collective, each individual cell growing, producing, and even dying on command to keep it running. But when this delicate system breaks down, some cells can go rogue, forming tumors that can spread throughout the body and hide from or even manipulate the immune system into defending them.

To help the body deal with these “insurrections”, a team of researchers from Zhejiang University in China have been working on a method that employs microneedle skin patches and an electrical current to painlessly vaccinate against tumors and cancer of the skin.

The idea is that by sending a message through the skin, an immune response can be kick started to combat and even prevent cancer — a well known therapeutic approach known as immunotherapy.

Getting messages across that thick skin

As the skin is the body’s largest organ, the research team rationalized that specific cells called dendrites, which live in the skin, could be harnessed to trigger a type of cancer immunotherapy.

The microneedle vaccine delivery system the team developed and published in Small Science specifically targets dendritic cells that naturally ingest any foreign particles, carrying them to immune cells located in the body’s lymph nodes and spleen. There, the dendritic cells break down the pathogens and present distinct markers on their surface, as if on a platter, to T cells that then track the pathogen down.

The microneedles are virtually painless and this vaccine delivery platform promising as dendritic cells exist in higher numbers in the skin and are more accessible than in the blood.

“[However], up to now, the programmed delivery of [immune-activating molecules known as] antigens and chemokines by a transdermal platform to initiate […] immunization has not been reported,” wrote the authors in their study.

This, say the team, is likely because their delivery through the skin to trigger an immune response against cancerous cells faces a number of hurdles.

“First, the [outer layer of the skin] forms a strict barrier that tightly prevents the skin penetration of proteins,” they wrote. “Second, the cellular uptake of proteins by [dendritic cells] and migration […] to lymph nodes without stimulation will be too limited to induce sufficient […] antigen presentation.”

The microneedle platform

To make their vaccine, Escherichia coli (E.coli)bacteria were genetically modified to produce tiny liquid pouches, called vesicles, that contained one of two proteins: gp100, a tumor antigen; and the chemokine CCL21, a signaling protein that guides dendritic cells to migrate towards areas like the lymph nodes.

These vesicles act as vehicles for protein delivery, improving protein penetration into the skin while making it easier for the dendritic cells to uptake them.

To deliver them, the researchers molded a resin into a porous patch with microscopic needles. When applied on the skin, the microneedles create such small gaps in the epidermis and dermis layers that they cause no pain or injury and require less training to apply compared to injections.

The team combined their patches with a known therapeutic technique called iontophoresis, which uses an electronic current to help introduce ionic medicinal compounds into the body. By coating the patches with graphite plates to make them conductive, safe voltages could be applied to the microneedle patches to help push the negatively charged vesicles deeper into the dermis.

Preliminary mmunization studies

Vaccination is carried out by first placing two microneedle patches on the skin: one loaded with the antigen-carrying vesicles and one empty, before passing a small electrical current between them for 30 minutes. The process is repeated twice: once for vesicles containing gp100 and again for vesicles containing CCL21.

The vesicles exit the first patch and pass along the microneedles through the skin barrier, following the electrical current that leads them through the epidermis and dermis towards the second patch. The idea is that they will get intercepted by dendritic cells, which begin an immune response against the tumor cells harboring those same antigens.

In mice with skin melanoma, the team applied either a blank control solution, solutions with free gp100 and CCL21 proteins, solutions with just the vesicles, and vesicle-loaded microneedle patches. Each vesicle-loaded patch was applied on a tumor site, and the corresponding empty patch on the site’s periphery.

All mice treated with the patches survived for 14 days post-treatment, while mice from the other groups survived up to 10 days. Microneedle patch vaccination stimulated a strong immune response and employed many active T cells, primarily those that directly kill tumor cells, leading to the high degree of tumor cell death.

The team also observed that certain indicators related to the cancer spreading also decreased, and that tumor growth halted.

They also verified activation of other specific T cells and increased production of antibodies necessary for long-term protection. These have the potential to act against cancer recurrence, which in the case of melanoma has a rate of 15-41% or more depending on the stage and tends to occur within five years of treatment.   

While these results are promising for treating skin-based cancers, they are also preliminary, carried out in small animals with only 14 day follow up. There are still hurdles to overcome before human clinical trials, and the authors were not available for comment. Further studies are required before we might see this system implemented as an immunotherapy in a real world setting.

Reference: Lihua Peng, et al., Iontophoresis-Driven Microneedle Arrays Delivering Transgenic Outer Membrane Vesicles in Program that Stimulates Transcutaneous Vaccination for Cancer Immunotherapy, Small Science (2023). DOI: 10.1002/smsc.202300126

Feature image credit: Pawel Czerwinski on Unsplash

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