Darrell Irvine - Freshly squeezed vaccines
Microfluidic cell-squeezing device opens new possibilities for cell-based vaccines.
Kevin Leonardi | Koch Institute
May 22, 2015
researchers have shown that they can use a microfluidic cell-squeezing
device to introduce specific antigens inside the immune system’s B
cells, providing a new approach to developing and implementing
antigen-presenting cell vaccines.
Such vaccines, created by reprogramming a patient’s own immune cells
to fight invaders, hold great promise for treating cancer and other
diseases. However, several inefficiencies have limited their translation
to the clinic, and only one therapy has been approved by the Food and
While most of these vaccines are created with dendritic cells, a
class of antigen-presenting cells with broad functionality in the immune
system, the researchers demonstrate in a study published in Scientific Reports that B cells can be engineered to serve as an alternative.
“We wanted to remove an important barrier in using B cells as an
antigen-presenting cell population, helping them complement or replace
dendritic cells,” says Gregory Szeto, a postdoc at MIT’s Koch Institute
for Integrative Cancer Research and the paper’s lead author.
Darrell Irvine, a member of the Koch Institute and a professor of
biological engineering and of materials sciences and engineering, is the
paper’s senior author.
A new vaccine-preparation approach
Dendritic cells are the most naturally versatile antigen-presenting
cells. In the body, they continuously sample antigens from potential
invaders, which they process and present on their cell surface. The
cells then migrate to the spleen or the lymph nodes, where they prime T
cells to mount an attack against cells that are cancerous or infected,
targeting the specific antigens that are ingested and presented.
Despite their critical role in the immune system, dendritic cells
have drawbacks when used for cell-based vaccines: They have a short
lifespan, they do not divide when activated, and they are relatively
sparse in the bloodstream.
B cells are also antigen-presenting cells, but in contrast to
dendritic cells, they can proliferate when activated and are abundant in
the bloodstream. However, their functionality is more limited: Whereas
dendritic cells constantly sample antigens they encounter, a B cell is
genetically programmed only to bind to a specific antigen that matches
the receptor on its surface. As such, a B cell generally will not ingest
and display an antigen if it does not match its receptor.
Using a microfluidic device, MIT researchers were able to overcome
this genetically programmed barrier to antigen uptake — by squeezing the
Through “CellSqueeze,” the device platform originally developed at
MIT, the researchers pass a suspension of B cells and target antigen
through tiny, parallel channels etched on a chip. A positive-pressure
system moves the suspension through these channels, which gradually
narrow, applying a gentle pressure to the B cells. This “squeeze” opens
small, temporary holes in their membranes, allowing the target antigen
to enter by diffusion.
This process effectively loads the cells with antigens to prime a
response of CD8 — or “killer” — T cells, which can then kill cancer
cells or other target cells.
The researchers studied the squeezed B cells in culture and found
that they could expand antigen-specific T cells at least as well as
existing methods using antibody-coated beads. As proof of concept, the
researchers then transferred squeezed B cells and antigen-specific T
cells into mice, observing that the squeezed B cells could expand T
cells in the spleen and in lymph nodes.
The researchers also say that this is the first method that decouples
antigen delivery from B-cell activation. A B cell becomes activated
when ingesting its antigen or when encountering a foreign stimulus that
forces it to ingest nearby antigen. This activation causes B cells to
carry out very specific functions, which has limited options for
B-cell-based vaccine programming. Using CellSqueeze circumvents this
problem, and by being able to separately configure delivery and
activation, researchers have greater control over vaccine design.
Gail Bishop, a professor of microbiology at the University of Iowa
Carver School of Medicine and director of the school’s Center for
Immunology and Immune-Based Diseases, says that this paper presents a
“creative new approach with considerable potential in the development of
antigen-presenting cell vaccines.”
“The antigen-presenting capabilities of B cells have often been
underestimated, but they are being increasingly appreciated for their
practical advantages in therapies,” says Bishop, who was not involved in
this research. “This new technical approach permits loading B cells
effectively with virtually any antigen and has the additional benefit of
targeting the antigens to the CD8 T-cell presentation pathway, thus
facilitating the activation of the killer T cells desired in many
Armon Sharei, now a visiting scientist at the Koch Institute,
developed CellSqueeze while he was a graduate student in the
laboratories of Klavs Jensen, the Warren K. Lewis Professor of Chemical
Engineering and a professor of materials science and engineering, and
Robert Langer, the David H. Koch Institute Professor and a member of the
Koch Institute. Sharei, Jensen, and Langer are also authors of this
In a separate study published last month in the journal PLoS ONE,
Sharei and his colleagues first demonstrated that CellSqueeze can
deliver functional macromolecules into immune cells. The platform
has benefits over existing delivery methods, including electroporation
and genetically engineered viruses, which are limited to delivering
nucleic acids. While nucleic acids can code a cell for a target antigen,
these indirect methods have drawbacks: They have limited ability in
coding for difficult-to-identify antigens, and using nucleic acids bears
a risk for accidental genome editing. These methods are also toxic, and
can cause cell damage and death. By delivering proteins directly into
cells with minimal toxicity, CellSqueeze avoids these shortcomings and,
in this new study, demonstrates promise as a versatile platform for
creating more effective cell-based vaccines.
“Our dream is to spawn out a whole class of therapies which involve
taking out your own cells, telling them what to do, and putting them
back into your body to fight your disease, whatever that may be,” Sharei
After developing CellSqueeze at MIT, Sharei co-founded SQZ Biotech
in 2013 to further develop and commercialize the platform. Just as the
company has grown since then — now up to 13 employees — the device has
also evolved. Sharei, now the company’s CEO, says that by improving the
design and increasing the number of channels, the current generation has
a throughput of 1 million cells per second.
The researchers say they now plan to refine their B-cell-based
vaccine to optimize distribution and function of the immune cells in the
body. A B-cell-based approach could also reduce the amount of patient
blood required to prepare a vaccine. At present, patients receiving
cell-based vaccines must have blood drawn over several hours each time a
new dose must be prepared.
Meanwhile, SQZ Biotech aims to reduce the footprint of its device,
which could potentially lower the time and cost required to engineer
“We envision a future system, if we can take advantage of its
microfluidic nature, as a bedside or field-deployable device,” Sharei
says. “Instead of shipping your cells off to this big, centralized
facility, you could do it in your hospital or your doctor’s office.”
As the biology and technology become further refined, the authors say
that their approach could potentially be a more efficient, more
effective, and less expensive method for developing cell-based therapies
“Down the road, you could potentially get enough cells from just a
normal syringe-based blood draw, run it through a bedside device that
has the antigen you want to vaccinate against, and then you’d have the
vaccine,” Szeto says.
This research was funded by the Kathy and Curt Marble Cancer Research
Fund through the Koch Institute Frontier Research Program, the National
Cancer Institute, the National Institute of General Medicine Sciences,
and the Howard Hughes Medical Institute.