A New Approach To Personalized Cancer Vaccination

A cancer vaccine approach that uses an injectable scaffold loaded with a selection of tumor-expressed peptides is reported on in a new study from Harvard University.

Immunotherapies are moving to the forefront of cancer treatment. Recent clinical trials have demonstrated that these approaches can be personalized to the unique mutations profile of each individual’s tumor, igniting new hope for many patients, according to the study.

At the core of these developments are tumor-specific “neoantigens,” mutated peptides that tumor cells present on their surfaces. After taking up neoantigens, the immune system’s dendritic cells (DCs) can initiate strong T cell responses to attack the very cancer cells that express them, meaning they stimulate patients’ immune systems to destroy their own tumors.

But despite that success, it has remained difficult to integrate different types of peptides into “cancer vaccines” that the immune system will accept.

Tumor-specific Immune Memory

David Mooney of the Wyss Institute for Biologically Inspired Engineering and his team detail in the research how this strategy proved more effective at stimulating anti-tumor responses and, importantly, a tumor-specific immune memory in mouse models that kept the animals rejecting tumor cells at least half a year later.

“There is tremendous enthusiasm for using neoantigens in immunotherapy as predicting them in individual tumors becomes more and more reliable. Our materials approach is able to mix and match predicted neoantigens very easily and efficiently in a single scaffold that, as a delivery vehicle, could be plugged into existing pipelines to enable more effective personalized cancer treatments,”

said Mooney, who led the study.

MSR-PEI

The scientists used their previously developed programmable biomaterial made from tiny mesoporous silica rods (MSRs) that can be injected under the skin, where they spontaneously assemble into a 3-D scaffold that attracts and stimulates DCs.

They then coated the MSRs with polyethyleneimine (PEI), a polymer used previously to deliver DNA and proteins to cells. PEI has been surmised to have immune-stimulatory effects.

“This allowed us to achieve two things: It enabled ready absorption of multiple peptides regardless of their inherent properties without the need to further modify them; and by being taken up by DCs together with the peptides, PEI enhanced the stimulation of DCs and the ensuing tumor-directed cytotoxic T cell responses in our mouse models,”

said first-author Aileen Li, who performed her graduate work with Mooney and now is a postdoctoral fellow at the University of California, San Francisco.

Complete Eradication Of HPV Tumors

In addition to the PEI coating, the vaccines also contained factors that help them attract DCs and boost immune functions.

Comparing them to control vaccines that lacked PEI but had all the other components, the team found them considerably more efficient in activating DC populations, stimulating interactions with T cells in nearby lymph nodes and driving the generation of circulating killer T cells that recognize tumor-specific peptides.

Raising the strategy’s clinical potential, these advances also translated to mouse models with more relevant tumors that the researchers investigated with a collaborating team lead by Kai Wucherpfennig, chair of the Dana-Farber Cancer Institute’s Department of Cancer Immunology and Virology.

First, they designed a vaccine that presented a model peptide of the well-known E7 oncoprotein from human papilloma virus (HPV), which causes cervical and other cancers. Impressively, a single injection of the vaccine led to rapid and complete eradication of HPV tumors in mice, with 80 percent of the animals living longer than 150 days.

In comparison, most untreated animals succumbed to the cancer by 30 days, and a control vaccine lacking PEI and a traditionally formulated vaccine had effects only about half as strong. Even six months after the injection, the animals vaccinated with the PEI formulation could still destroy tumor cells, showing that they had formed a robust immunological memory of the tumors.

Potential Future Approaches

The team mimicked potential future neoantigen approaches in human patients more closely by carrying out studies in more aggressive and difficult-to-treat tumor models.

“We introduced up to five neoantigens that had been recently identified in mouse melanoma and colorectal tumors into our biomaterial scaffold, and found that a single injection of the vaccines cleared tumor metastases and provided strong immune responses against the tumors that were comparable to multiple injections with existing vaccines,”

said Li.

When combined with immune checkpoint therapy, which can broadly invigorate killer T cell activity against tumors, the effects of both the vaccine and the checkpoint therapy were boosted.

Different immune checkpoint therapies are currently performed in the clinic, but their effects in many patients and tumors remain weak. The team thinks that combining them with their biomaterial-supported neoantigen approach could help treat many patients more effectively.

Neoantigens

In immunology, an antigen is a molecule capable of inducing an immune response (to produce an antibody) in the host organism. Sometimes antigens are part of the host itself in an autoimmune disease.

Antibody antigen diagramAntigens are “targeted” by antibodies. Each antibody (immune response) is specifically produced by the immune system to match an antigen after cells in the immune system come into contact with it; this allows a precise identification or matching of the antigen and the initiation of a tailored response.

The antibody is said to “match” the antigen in the sense that it can bind to it due to an adaptation performed to a region of the antibody. Because of this, many different antibodies are produced, each with specificity to bind a different antigen while sharing the same basic structure.

In most cases, an adapted antibody can only react to and bind one specific antigen; in some instances, however, antibodies may cross-react to and bind more than one antigen.

A neoantigens is one that is entirely absent from the normal human genome. As compared with nonmutated self-antigens, neoantigens are of relevance to tumor control, as the quality of the T cell pool that is available for these antigens is not affected by central T cell tolerance. Technology to systematically analyze T cell reactivity against neoantigens became available only recently.

Mesoporous Silica

Mesoporous silica is a mesoporous form of silica and a recent development in nanotechnology. The most common types of mesoporous nanoparticles are MCM-41 and SBA-15. Research continues on the particles, which have applications in catalysis, drug delivery and imaging.

TEM of a mesoporous silica nanoparticle

TEM of a mesoporous silica nanoparticle

Mesoporous silica nanoparticles are synthesized by reacting tetraethyl orthosilicate with a template made of micellar rods. The result is a collection of nano-sized spheres or rods that are filled with a regular arrangement of pores. The template can then be removed by washing with a solvent adjusted to the proper pH.

Mesoporous particles can also be synthesized using a simple sol-gel method such as the Stöber process, or a spray drying method. Tetraethyl orthosilicate is also used with an additional polymer monomer (as a template).

The large surface area of the pores allows the particles to be filled with a drug or a cytotoxin. Like a Trojan Horse, the particles will be taken up by certain biological cells through endocytosis, depending on what chemicals are attached to the outside of the spheres.

Some types of cancer cells will take up more of the particles than healthy cells will, giving researchers hope that MCM-41 will one day be used to treat certain types of cancer.

Ordered mesoporous silica (e.g. SBA-15, TUD-1, HMM-33, and FSM-16 also show potential to boost the in vitro and in vivo dissolution of poorly water-soluble drugs. Many drug-candidates coming from drug discovery suffer from a poor water solubility.

An insufficient dissolution of these hydrophobic drugs in the gastrointestinal fluids strongly limits the oral bioavailability. One example is itraconazole which is an antimycoticum known for its poor aqueous solubility. Upon introduction of itraconazole-on-SBA-15 formulation in simulated gastrointestinal fluids, a supersaturated solution is obtained giving rise to enhanced transepithelial intestinal transport.

Also the efficient uptake into the systemic circulation of SBA-15 formulated itraconazole has been demonstrated in vivo (rabbits and dogs). This approach based on SBA-15 yields stable formulations and can be used for a wide variety of poorly water-soluble compounds.

The research was supported by the National Institutes of Health (NIH), the Melanoma Research Alliance Foundation, the National Science Foundation (NSF) Graduate Research Fellowship Program (AWL) and the Wyss Institute for Biologically Inspired Engineering.

Aileen Weiwei Li, Miguel C. Sobral, Soumya Badrinath, Youngjin Choi, Amanda Graveline, Alexander G. Stafford, James C. Weaver, Maxence O. Dellacherie, Ting-Yu Shih, Omar A. Ali, Jaeyun Kim, Kai W. Wucherpfennig & David J. Mooney
A facile approach to enhance antigen response for personalized cancer vaccination
Nature Materials (2018) doi:10.1038/s41563-018-0028-2

Top Image: scanning electron micrograph image showing the MSR-PEI scaffold presenting tumor-expressed peptides. After it’s injected under the skin of mice, the biomaterial fills with dendritic cells that can be seen here as small, round shapes interacting with the spiky scaffold structure. Credit: Wyss Institute at Harvard University