March 30, 2016
RALEIGH, NC – Biomedical engineers at North Carolina State University and the UNC School of Medicine have developed a technique that uses a patch embedded with microneedles to deliver cancer immunotherapy treatment directly to the site of melanoma skin cancer. In animal studies, the innovative technique more effectively targeted melanoma than did other immunotherapy treatments.
The study, published in the journal Nano Letters, shows the potential to better target melanoma, which the National Cancer Institute estimated affected more nearly 74,000 people in the United States in 2015.
“This technique creates a steady, sustained release of antibodies directly into the tumor,” said Zhen Gu, PhD, assistant professor in the UNC / NC State Department Biomedical Engineering and senior author of the paper. “It is an efficient approach with enhanced retention of antibodies in the tumor microenvironment.”
If caught early, melanoma patients have a 5-year survival rate of more than 98 percent, according to the National Cancer Institute. That number dips to 16.6 percent if the cancer metastasizes before diagnosis and treatment. Melanoma treatments include surgery, chemotherapy, and radiation; each comes with a risk of various side effects. A promising new field of cancer treatment is cancer immunotherapy, which helps the body’s own immune system fight off cancer.
In the immune system, T cells use specialized receptors to differentiate healthy cells from cancer cells. But cancer cells can trick T cells. For example, cancer cells can express a protein ligand that binds to a receptor on the T cells to prevent the T cells from recognizing and attacking the cancer cells.
Recently, cancer immunotherapy research has focused on using “anti-PD-1” (or programmed cell death) antibodies to prevent cancer cells from tricking T cells.
“However, this poses several challenges,” says Chao Wang, PhD, co-lead author of the Nano Letters paper on the microneedle research and a postdoctoral researcher in the UNC / NC State joint biomedical engineering program. “First, the anti-PD-1 antibodies are usually injected into the bloodstream, so they cannot target the tumor site effectively. Second, the overdose of antibodies can cause side effects such as an autoimmune disorder.”
To address these challenges, the researchers developed a patch that uses microneedles to deliver anti-PD-1 antibodies locally to the skin tumor. The microneedles are made from hyaluronic acid, a biocompatible material.
The anti-PD-1 antibodies are embedded in nanoparticles, along with glucose oxidase – an enzyme that produces acid when it comes into contact with glucose. These nanoparticles are then loaded into microneedles, which are arrayed on the surface of a patch.
When the patch is applied to a melanoma, blood enters the microneedles. The glucose in the blood makes the glucose oxidase produce acid, which slowly breaks down the nanoparticles. As the nanoparticles degrade, the anti-PD-1 antibodies are released into the tumor.
The researchers tested the technique against melanoma in a mouse model. The control group was given anti-PD-1 antibodies injected into the blood stream. Yanqi Ye, a graduate student in Gu’s lab and co-lead author of the paper, said, “After 40 days, 40 percent of the mice treated using the microneedle patch had no detectable remaining melanoma – compared to a zero percent survival rate for the control group.”
The researchers also created a drug cocktail, consisting of anti-PD-1 antibodies and another antibody called anti-CTLA-4, which also helps T cells attack the cancer cells.
“Using a combination of anti-PD-1 and anti-CTLA-4 in the microneedle patch, 70 percent of the mice survived and had no detectable melanoma after 40 days,” Wang said.
Gu added, “Because of the sustained and localized release manner, mediated by microneedles, we were able to achieve desirable therapeutic effects with a relatively low dosage, which should reduce the risk of auto-immune disorders. We’re excited about this technique and are seeking funding to pursue further studies and potential clinical translation.”
The Nano Letters paper was co-authored by Gabrielle Hochu, an undergraduate in the UNC / NC State Department of Biomedical Engineering, and Hasan Sadeghifa, PhD, a postdoctoral researcher at NC State. The work was supported through grants from NC TraCS, home of the NIH Clinical and Translational Science Award at UNC.
Here is a summary of Zhen Gu’s recent research exploits, including his Sloan Fellowship and his inclusion in the MIT Review’s Top Innovators Under 35 annual list.