The use of biomaterials, such as microneedles and nanoparticles, in immunotherapy and vaccine research is a hot topic in bioengineering. But to get the maximum return on investment in these ideas, they need to be seeded among clinicians, according to Christopher Jewell, Ph.D., associate professor in the Fischell Department of Bioengineering at the University of Maryland. Jewell is the principal author on a new paper in Trends in Immunology that reviews the current state of biomaterials research with an eye toward inspiring multidisciplinary teams of engineers and clinicians to solve some of the complex problems in immunology today.

“A lot of people reading Trends in Immunology are not engineers. They may be clinicians or immunologists,” he tells GEN. “We really tried to write this from an engineering perspective to try to bring out some of the new ideas in engineering. To expose this audience to things they may not have thought about or seen before.”

Biomaterials is an umbrella term for a wide range of synthetic and natural material structures, ranging from biodegradable nanoparticles and scaffolds, to engineered cells, to dissolvable microneedle arrays applied like band aids. These various structures and their properties can be used to ferry immune pathway stimulating cargos to particular targets in the body and control over time the release of those cargos, among other benefits. Nanoparticles composed of the synthetic polymer poly (lactide-co-glycolide), or PLGA, for instance, can be configured to release their cargo in response to triggers, such as light, or pH. Liposomes, nanoparticles composed of lipids can transport immunological or pharmacological cargos in their aqueous cores and are already in clinical use with the chemotherapeutic doxorubicin and hepatitis A vaccine Epaxal.

The Carrier and the Message

One of the more interesting and potentially confounding new findings with regard to biomaterials, Dr. Jewell says, is that these carriers themselves, and not just their cargo, interact with immune pathways. “It’s the idea we call ‘intrinsic immunogenicity,’” he says, and researchers are now trying to understand just what it is about these biomaterials that provoke this response. “Is it the chemical structure?” he ponders. “Is it the stability, the charge, the size? What features control how it interacts with different immune pathways?”

There is evidence, for instance, that the shape of nanoparticles can affect immune responses, and do so differently across immune pathways. Research published a 2015 paper in the journal Small showed that ellipsoidal artificial antigen presenting cells (aAPCs) composed of PLGA nanoparticles better target and stimulate T cells than can spheroidal aAPCs.

“It was very much an unexpected finding,” says Dr. Jonathan Schneck, M.D., Ph.D., professor of pathology at Johns Hopkins University School of Medicine and a coauthor of the paper in Small. His team’s research was exploring how aAPCs interacted with contact sites on T cells and found “how [aAPCs] sits down on [contact sites] was tremendously important in the ability to stimulate the T cell.” Rather than seeing this intrinsic immunogenicity as a purely confounding factor, Drs. Schneck and Jewell both see opportunities to engineer new tools if all the underlying interactions involving biomaterials can be understood.

Jewell and his coauthors also cite a 2016 study in Biomacromolecules, for instance, that showed ellipsoidal polymer capsules are more resistant to uptake by macrophages than spherical polymer capsules, a result, Dr. Schneck says, is important for his own work on aAPCs. The ellipsoidal shaped aAPCS not only better stimulate T cells, but stick around in the body longer since they are not as easily consumed by macrophages. “I think it’s a very cool finding because you wouldn’t have necessarily have linked the two together,” Schneck says. “It shows the importance of having clinicians and engineers talk to each other.”

Another approach would be to learn from the desirable signaling intrinsic to biomaterial carriers, to mimic it, and then ditch the carrier altogether. Dr. Jewell and his coauthors describe work with immune polyelectrolyte multilayers, (iPEMs), where charged adjuvants and antigens are assembled electrostatically around a template that is later removed. “You have a very high density of cargo,” Jewell says. “If you have a nanoparticle most of what you deliver is your carrier, which you have loaded with a vaccine. If you’ve got something that is assembled from immune signals, now everything is your signal.” In one study looking at a melanoma model, iPEMs improved expansion of antigen-specific T cells.

“We’re going to see a lot in terms of clinical application, which is critical, but we are also going to learn a lot about the basic science,” Dr. Schneck says of this kind of work. “Until now, we have been avoiding those questions of how does the immune system deal with these materials.”

From Infectious Disease Immunology to Cancer Immunotherapies

In preclinical cancer research, biomaterials are being used to extend and enhance immunotherapy concepts already in use in the clinic. CAR-T cell therapy for instance, is typically more effective for blood cancers than for solid tumors. Jewell and his coauthors cite a 2017 paper in the Journal of Clinical Investigation showing that layering CAR-T cells in a scaffold could be used to directly target sold tumors in melanoma. “This is in mice still, but it’s an idea that’s being tested in humans without the biomaterials,” Jewell says. But he says it’s necessary to ask what’s happening in humans, too. Then, he says, innovate medicines can be paired/enhanced with biomaterials.

Dr. Schneck says the approach of using scaffolds for CAR-T makes a lot of sense. So much sense, he says, that in 2009, he founded the company NexImmune, which is working on clinical applications for aAPCs. Dr. Schneck still consults for the company.

Widespread Applications Possible

While most of these lines of research are still preclinical, the bleeding edge for biomaterials is entering the human clinic. In a 2015 Phase I clinical trial, dissolvable microneedle arrays, applied through an adhesive patch on the wrist, were shown to be effective in delivering seasonal influenza vaccine without the pain of injection, which Jewell notes is no small thing if it leads to greater vaccination compliance. “Kids don’t like shots. Let’s make something that kids will take and therefore their parents will be more likely to take them to get the flu shot,” Jewell says. “If you have 10% more people getting the flu vaccine [per year], that’s really improving public health overall.”

And, in an example of the sort of multidisciplinary, cross-pollination of ideas Dr. Jewell endorses, microneedle arrays have been used to deliver iPEMs consisting of melanoma peptides and toll-like receptor agonists into the dermal layer of mice in melanoma models, generating melanoma-specific T cells.

There are still many questions surrounding how readily biomaterial enhanced immunotherapies or vaccines can be extended into the clinic. But Jewell and his coauthors write that given the added control these materials can give over the immune response to antigens and adjuvants, biomaterials can be seen as “platform technologies for extension to a variety of diseases.”

“We’re writing about some things that are very exciting preclinically, and maybe some in our audience aren’t familiar with yet,” Jewell says. “Hopefully when people read it, they realize there actually is a lot of cool and insightful work being done.”


Jon Kelvey is a Freelance Writer for GEN.

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