Applying Nanotechnologies for Immunotherapy

Nanotechnological strategies are making preclinical strides toward more effective, and possibly, less toxic, cancer immunotherapies, an international team of authors reported in the Journal of Controlled Release.

The past 5 years have seen in vitro and in vivo advances in peptide- and nucleic acid–based nano-vaccines, and nanoparticle formulations of immune checkpoint inhibitors (ICIs) that might outperform standard formulations, reported Shyh-Dar Li, PhD, of the University of British Columbia, in Vancouver, Canada, and coauthors.

“Nanoparticles resemble viruses to the human immune system and are intrinsically immunogenic,” said Andrew Wang, MD, associate professor at the University Of North Carolina School Of Medicine in Chapel Hill, who was not a coauthor of the paper.

“This unique property makes them excellent antigen-presenting vehicles. I expect nanoparticle-based cancer vaccines will be entering clinical investigation in two or three years.”

ICIs have revolutionized cancer therapy in recent years, dramatically prolonging some patient's lives by countering the molecular mechanisms by which tumor cells evade immune attack.

But, a majority of patients do not benefit from these agents, which can cause severe and even life-threatening immune-related adverse events like autoimmune endocrinopathies. Additional immune-oncology strategies are therefore under development to enhance immune checkpoint blockade or to otherwise enhance anti-tumor immune vigilance.

“There are many emerging technologies and strategies for cancer immunotherapy beyond CTLA-4 and programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibition, such as engineered cell therapies, novel checkpoint targets and T-cell agonists,” Wang told Cancer Network.

Nanotechnological approaches overlap with many of those investigational domains.

Based on findings from lab animal studies, nano-carrier drug delivery might not only improve immunotherapeutic efficacy, but might also reduce immunotherapy-associated toxicities. Li and colleagues cautioned that it will be several years before that can be confirmed in humans.

Clinical translation of nanoparticle immunotherapy “is still in its infancy and has encountered significant challenges,” noted the researchers. “The current animal tumor models are overly simplified and do not exhibit the complicated human tumor microenvironment that is immunosuppressed. Improving the retention of [immunotherapeutic] payloads in the nanoparticles may lead to enhanced and prolonged immuno-response.”

Nanoparticles can accumulate in the liver and spleen, with as-yet unknown safety implications, and can cross the blood-brain barrier, Li’s team added. Biomarkers must be identified for risk-stratification and treatment monitoring, they emphasized.

Wang and colleagues are investigating predictive biomarkers that he hopes will help identify patients who are most likely to benefit from immunotherapy, and nanotechnological approaches to improving immuno-oncology’s toolkit. His team recently showed that newer circulating tumor cell (CTC) capture assays are highly sensitive and can be used to predict immunotherapy outcomes.

“PD-L1 expression in tumor tissue is the only predictive biomarker for cancer immunotherapy,” Wang said. “Moreover, there is a great deal of controversy over how best to examine PD-L1 expression in tumor tissue. Recent research on exosomes showed that exosomal PD-L1 may be an excellent predictor for anti-PD-1 therapy [effectiveness].”