Despite advances in melanoma treatment, mainly as a consequence of anti-PD-1 (aPD1) immunotherapy, the approach still needs improvement. Now, North Carolina State University and the University of North Carolina at Chapel Hill researchers have developed a self-degradable microneedle (MN) patch for the sustained delivery of aPD1 in a physiologically controllable manner. Using a mouse model, the method was seen to be more efficient in targeting melanoma then other immunotherapy approaches.
The study, “Enhanced Cancer Immunotherapy by Microneedle Patch-Assisted Delivery of Anti-PD-1 Antibody,” was published in the journal Nano Letters.
Immunotherapies have been intensively studied over the past several years for the treatment of skin cancers. Among these, checkpoint inhibitors that block the programmed death-1 (PD-1) pathway show clinical potential. PD-1 receptors expressed on T-cells play a pivotal role in the downregulation of the immune system by triggering inhibitory signaling downstream of the T-cell receptor (TCR), preventing the activation of T-lymphocytes. Anti-PD-1 antibodies that target the inhibitory receptors have shown striking anti-tumor activity in Phase 2 and 3 clinical trials of advanced melanoma.
“However, this poses several challenges,” Chao Wang, the study’s co-lead author and a postdoctoral researcher in the joint biomedical engineering program at NC State and UNC-Chapel Hill, said in a news release. “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 team of biomedical engineers developed a patch that utilizes microneedles to locally deliver anti-PD-1 antibodies to melanoma cells. The microneedle is composed of biocompatible hyaluronic acid integrated with pH-sensitive dextran nanoparticles (NPs) that encapsulate aPD1 and glucose oxidase (GOx). When the patch is applied to a skin tumor, it converts blood glucose to gluconic acid. As the nanoparticles degrade, the anti-PD-1 antibodies are released into the tumor.
“This technique creates a steady, sustained release of antibodies directly into the tumor site; it is an efficient approach with enhanced retention of anti-PD-1 antibodies in the tumor microenvironment,” said Zhen Gu, an assistant professor in the biomedical engineering program, and senior author of the paper.
The scientists examined the method in a melanoma mouse model. The efficacy of the microneedle patch with anti-PD-1 nanoparticles was compared to both injection of anti-PD-1 antibodies into the bloodstream and of anti-PD-1 nanoparticles directly into the melanoma.
“After 40 days, 40 percent of the mice who were treated using the microneedle patch survived and had no detectable remaining melanoma – compared to a zero percent survival rate for the control groups,” said Yanqi Ye, a Ph.D. student in Gu’s lab, and a co-lead author.
The team also made a drug cocktail, containing anti-PD-1 antibodies and anti-CTLA-4 (an antibody that 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,” Dr. Wang said.
“Because of the sustained and localized release manner, mediated by microneedles, we are able to achieve desirable therapeutic effects with a relatively low dosage, which reduces the risk of auto-immune disorders,” Dr. Gu added. “We’re excited about this technique, and are seeking funding to pursue further studies and potential clinical translation.”
