Three-Dimensional Vaccines Sensitize the Immune System to Cancer


Cancer has the capacity to fool the immune system and evade attack from immune cells. This act of immune system evasion allows tumors to grow and spread throughout the body without any resistance. A relatively new strategy called immunotherapy attempts to stimulate the patient’s immune system to mount an immune response against the tumor and sensitize it to the tumor. However, a new protocol developed by a research teams at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard’s School of Engineering and Applied Sciences (SEAS) uses a three-dimensional structure to program the immune system to attack and destroy tumors.

The senior author of this study, David Mooney, who is a Wyss Institute Core Faculty member and the Robert P. Pinkas Professor of Bioengineering at Harvard SEAS, described this new technique: “We can create 3D structures using minimally–invasive delivery to enrich and activate a host’s immune cells to target and attack harmful cells in vivo.”

This 3-D structure consists of tiny, biodegradable rod–like structures made from silica, known as mesoporous silica rods (MSRs). These MSRs can be loaded with biological and chemical drug components, and then injected by needle just underneath the skin. These rods spontaneously assemble at the injection site to form a three–dimensional scaffold (think of pouring a box of match sticks into a pile on a table). The porous spaces between the MSRs are large enough to recruit and fill with dendritic cells. Dendritic cells are immune cells that play the part of surveillance cells that identify foreign cells and substances and trigger an immune response to those things identified as foreign.

Mesoporous silica rods (MSRs) spontaneously assemble to form a porous 3D scaffold, as seen in this SEM image. The 3D scaffold has many nooks and crannies and is large enough to house tens of millions of recruited immune cells. Credit: Wyss Institute at Harvard University
Mesoporous silica rods (MSRs) spontaneously assemble to form a porous 3D scaffold, as seen in this SEM image. The 3D scaffold has many nooks and crannies and is large enough to house tens of millions of recruited immune cells.
Credit: Wyss Institute at Harvard University

“Nano–sized mesoporous silica particles have already been established as useful for manipulating individual cells from the inside, but this is the first time that larger particles, in the micron–sized range, are used to create a 3D in vivo scaffold that can recruit and attract tens of millions of immune cells,” said co-lead author Jaeyun Kim, Ph.D., an Assistant Professor of Chemical Engineering at Sungkyunkwan University and a former Wyss Institute Postdoctoral Fellow.

MSRs are made in the lab with nanopores, which are small holes that can be filled with specific cytokines, oligonucleotides, large protein antigens, or any variety of drugs. Thus, these structures are excellent repositories that can present a vast range of possible combinations to treat a range of infections or stimulate the immune system to attack several different invading elements.

“Although right now we are focusing on developing a cancer vaccine, in the future we could be able to manipulate which type of dendritic cells or other types of immune cells are recruited to the 3D scaffold by using different kinds of cytokines released from the MSRs,” said co-lead author Aileen Li, a graduate student pursuing her Ph.D. in bioengineering at Harvard SEAS. “By tuning the surface properties and pore size of the MSRs, and therefore controlling the introduction and release of various proteins and drugs, we can manipulate the immune system to treat multiple diseases.”

Once the 3D scaffold has recruited dendritic cells from the body, the drugs contained in the MSRs are released. These drugs activate the dendritic cells and initiate an immune response. The activated dendritic cells then leave the MSR-based scaffolds and travel to the lymph nodes, where they raise alarm and direct the body’s immune system to attack specific cells, such as cancerous cells. Within a few months, the body naturally degrades the MSRs, and they dissolve and leave no trace of their presence.

To date, this team has only tested their 3D vaccines in mice, but these 3D vaccines have proven to be remarkably effective. Injectable 3D scaffolds recruited and attracted millions of dendritic cells in a host mouse, before dispersing the cells to the lymph nodes and triggering a powerful immune response.

These vaccines are easily and rapidly manufactured so that they could potentially be widely available very quickly in the face of an emerging infectious disease. “We anticipate 3D vaccines could be broadly useful for many settings, and their injectable nature would also make them easy to administer both inside and outside a clinic,” said Mooney.

Since the vaccine works by triggering an immune response, the method could even be used preventively by building the body’s immune resistance prior to infection.

“Injectable immunotherapies that use programmable biomaterials as a powerful vehicle to deliver targeted treatment and preventative care could help fight a whole range of deadly infections, including common worldwide killers like HIV and Ebola, as well as cancer,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D. who is also Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and Professor of Bioengineering at Harvard SEAS. “These injectable 3D vaccines offer a minimally invasive and scalable way to deliver therapies that work by mimicking the body’s own powerful immune–response in diseases that have previously been able to skirt immune detection.”

University of Pittsburgh Team Uses Patient’s Own Stem Cells to Clear Cloudy Corneas


The transparent portion of the center of our eyes is called the cornea. Scars on the cornea can cause an infuriating haziness across the eye. However, healing these cloudy corneas might be as simple as growing stem cells from a tiny biopsy of the patient’s undamaged eye and placing them on the injury site. This hope comes from experiments in a mouse model system conducted by researchers at the University of Pittsburgh School of Medicine. These findings were published in Science Translational Medicine and could one day rescue vision for millions of people worldwide and decrease the need for corneal transplants.

According to statistics compiled by the National Eye Institute, which is a branch of the National Institutes of Health, globally, corneal infectious diseases have compromised the vision of more than 250 million people and have blinded over 6 million of them. Additionally, trauma from burns is also a leading cause of corneal scarring.

James L. Funderburgh, Ph.D., professor of ophthalmology at Pitt and associate director of the Louis J. Fox Center for Vision Restoration of UPMC and the University of Pittsburgh, a joint program of UPMC Eye Center and the McGowan Institute for Regenerative Medicine, said, “The cornea is a living window to the world, and damage to it leads to cloudiness or haziness that makes it hard or impossible to see. The body usually responds to corneal injuries by making scar tissue. We found that delivery of stem cells initiates regeneration of healthy corneal tissue rather than scar leaving a clear, smooth surface.”

The lead author of this study, Sayan Basu, is a corneal surgeon who works at the L.V. Prasad Eye Institute in Hyderabad, India. Dr. Basu who joined with Dr. Funderburgh’s lab, has developed a technique to isolate ocular stem cells from tiny biopsies from the surface of the eye and a region between the cornea and sclera known as the limbus. Such a small biopsy heals rapidly with little discomfort and no disruption of vision. Such biopsies are banked in tissue banks and then expanded in culture, and several tests shows that even after isolation and expansion, these cells are still corneal stem cells.

limbal-stem-cells

“Using the patient’s own cells from the uninjured eye for this process could let us bypass rejection concerns,” Dr. Basu noted. “That could be very helpful, particularly in places that don’t have corneal tissue banks for transplant.”

Basu in collaboration with Funderburgh’s team tested these human limbal stem cells in a mouse model of corneal injury. This team used goo made of fibrin to glue the cells to the injury site. Fibrin is the protein found in blood clots, but it is also commonly used as a surgical adhesive. Application of these limbal stem cells not only induced healing of the mouse corneas, their eyes became clear again within four weeks of treatment. On the other hand, the eyes of mice that were not treated with limbal stem cells remained cloudy.

Fibrin

In fact, the healing was so good that Funderburgh said: “Even at the microscopic level, we couldn’t tell the difference between the tissues that were treated with stem cells and undamaged cornea. We were also excited to see that the stem cells appeared to induce healing beyond the immediate vicinity of where they were placed. That suggests the cells are producing factors that promote regeneration, not just replacing lost tissue.”

This work is the impetus behind a small pilot study presently underway in Hyderabad which will treat a handful of patients with their own corneal stem cells.