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Hacking the immune system

This story was originally published by Knowable Magazine.

The immune system is an essential sentinel: It attacks foreign
pathogens and destroys our own cells when they become a threat. It
runs seamlessly most of the time, but it can also make mistakes,
failing to root out cancer cells or waywardly attacking healthy
tissues. The immune system’s power and perils have inspired
scientists’ quickening efforts to genetically “hack” it, using
viruses and other gene editing technology to endow existing immune
cells with new abilities. The goal is to make cells that can be
deployed like minuscule commandos to seek and destroy tumors,
subdue inflammation and self-destruct on command.

There’s a long way to go before engineered immune cells achieve
that level of precision. Yet the approach, part of a booming branch
of medicine called immunotherapy, has already achieved some
stunning successes. In cancer treatment, for example, white blood
cells engineered to kill cancer cells — known as CAR T cells — have been shown to
effectively treat some blood cancers, including the most common
form of childhood leukemia. But such cells can also have dangerous
— even deadly — side effects and aren’t yet
effective against solid tumors such as colorectal
and breast cancer. Researchers hope to eventually use engineered
immune cells to treat a range of illnesses, not only cancers but
also autoimmune diseases such as diabetes and neuroimmune disorders
such as multiple sclerosis.

Synthetic biologist Wendell Lim of the University of California, San
Francisco, studies how immune cells process information and make
decisions, and how to harness those abilities for medicine. Writing
recently in the Annual Review of Immunology with UCSF
colleague Kole Roybal, he reviewed ongoing
work to engineer immune cells for new
therapies. Here, Lim discusses some of the biggest wins and
failures in this rapidly advancing area of research.

This interview has been edited for length and clarity.

How did you become interested in synthetic

My interest has always been trying to understand how cells make
decisions. Essentially living cells are a type of computer, they
just don’t use electronic circuits — they use molecular circuits.
They have this amazing capability to read what’s going on in their
environment and read signals from other cells and use that
information to make very complicated decisions.

One of the things that I saw as I began my career was that
although there were many different cellular programs, a lot of the
molecules being used and the ways that the circuits were linked
together were very similar. I started to become interested not just
in how one particular molecule or pathway works, but the logic of
how molecular systems can be programmed in different ways. For
example, when I was working on the structure and mechanism of
signal transduction switch proteins — proteins that mediate
communication both within and between cells — I was struck by how
the different molecules that we studied used very similar
conceptual mechanisms despite being completely different in

Cells don’t just say, “I’m going to turn on this response
because I see signal A.” They are usually monitoring many different
signals and integrating that information with basically the
equivalent of Boolean logic, where if inputs A, B and C are there,
then it’s going to have a certain response, whereas if D and E are
there it will do something different. That’s the beauty of living
systems. They can react not in a simple way, but a nuanced and
sophisticated way. It’s been very exciting to realize that we now
understand the principles underlying these behaviors well enough
that we can create cells that do useful things.

What does it mean to “hack” immune cells?

“That’s the beauty of living systems. They
can react not in a simple way, but a nuanced and sophisticated
Wendell Lim

The immune system is a pretty new thing, evolutionarily. It’s an incredible
system that is still evolving to have cells that carry out a lot of
different complex functions. The cells have different capabilities
to sense things, whether it’s other cells that they should be
talking to, or the ability to sense “foreign” from “self.”
Different immune cells can launch killing responses or secrete new
factors that are immunosuppressive and dial down the immune system
itself. What we’re trying to do is to create a new kind of
sensing-response system using the same parts, reconnected in a new
way. If we are programming a T cell — a white blood cell that
fights infection — to recognize some set of cancer antigens and
then kill the cancer cells, that’s hacking — creating a new circuit
that is good at detecting and treating cancer. By the same token,
we could create a cell that would detect some tissue-specific
signal associated with autoimmune disease and have that cell
control the secretion of immunosuppressive factors.

Right now most studies using engineered T cells to address
autoimmune disease are still in cell culture. There has been work
in mice and humans transplanting native, immune-suppressive T
cells, but these cells haven’t been engineered to seek specific
targets or to reshape their behavior.

What would an ideal genetically engineered immune cell
be able to do?

I’ll talk about cancer, because that’s the lead application.
Immune cells are so powerful that they seem to be in some cases
able to eliminate and cure cancer. We want them to be powerful, but
of course the big danger is that if they attack any of our
critical, normal tissues, that could be lethal. It’s really about
combining control and precision with the effectiveness of the

For the most part, the therapeutic cells that are in clinical
trials now, or have been approved, are not extremely smart. They
may simply include one receptor that is put on the cell and, if it
recognizes the antigen it was designed to detect on a cancer cell,
it will kill it. But we’re developing technologies to build more
sophisticated sensing circuits that can detect two or three
different inputs, which could allow engineered cells to be
eliminated or turned off if needed for safety.

Right now we mostly use viruses to put new genetic material into
the cells. There is a payload limit for these viruses, but we can
get on the order of two new sensors into the cell’s genome. How
much genetic material we can insert is one of several bottlenecks.
But it is possible that in the future the amounts we can insert
will grow with Moore’s-law-like behavior. The genetic
engineering tool CRISPR is certainly one of several exciting new
ways to insert and integrate DNA, for example. In the next couple
of years, as we develop better ways to transfer genetic material
into cells, we’ll find some diseases for which this added
sophistication will make a huge difference.

How is cancer immunotherapy currently being performed in
patients, and what’s the next frontier?

In the last several years there has been a big explosion in the
concept of engineering T cells to treat cancer. What’s done
nowadays is that you take a patient’s own immune cells and modify
those and then put them back into the patient — this is what is
called an autologous transplant. People are working towards the
possibility of more off-the-shelf therapeutic immune cells that
could come from a universal donor. But we need to figure out a
reliable way to modify the donor cells so that they are not
rejected by the patient’s immune system.

What are some of the biggest successes in the field so

It’s been a huge success to have CAR T cells — T cells
engineered to bind to proteins called antigens on cancer cells —
that can treat certain blood cell cancers with a 70 to 80 percent success rate. The therapies
being marketed by Novartis [tisagenlecleucel] and Kite Pharma
[axicabtagene ciloleucel] for B-cell lymphoma have shown
spectacular results — these are going to become the first-line
therapies for these diseases. Clinical trials have also been
reporting some great results with multiple myeloma, another blood

Non-engineered killer T cells surround a cancer cell, preparing to destroy it

Non-engineered killer T cells surround a cancer cell, preparing
to destroy it. Tapping into such immune cells’ natural abilities,
and honing them through genetic engineering, has already proved
successful against some blood cancers. With more sophistication,
the next-generation immunotherapies might be used to treat solid
tumors and Type I diabetes.


The biggest failures?

We’re seeing great results in blood cancers. But we haven’t
really seen any significant results in solid cancers. There have
been a number of mouse studies and some human clinical studies, but
so far the results on solid tumors have been disappointing — they
have not seen the spectacular results and reproducibility that we
have seen in a few blood cancers. That’s where we need much more
precision, because solid cancers have a lot of molecular antigens
that look like those of normal tissue. I think that’s where a lot
of the technology that we’re working on is going to make a

The biggest failures are where there’s been some cross-reaction
that’s been lethal, or the tumors have developed resistance to the
engineered immune cells. But since we have such flexibility in how
we program things, we can start trying to take these problems into
account. I’m pretty optimistic — the tools that we’re developing
are based on a very deep fundamental understanding of how cells

What about cost?

There’s been a lot of criticism about the cost of these
therapies — the immunotherapies that were just approved are about
$300,000 to $500,000. But I think the cost will go down. The
molecular parts and sensors that we’re developing are going to be
reused in different cancers, so I’m optimistic that this kind of
platform will lend itself to broad applications across many
different diseases in a way that can bring costs down.

Are there other diseases where these cells could be

There’s a lot of interest in autoimmune disorders such as Type I
diabetes and severe dermatological autoimmune diseases such as
pemphigus. We’re also starting to get interested in engineered
cells that could address neuroinflammatory diseases such as
multiple sclerosis. It’s hard to get a lot of drugs and biologics
into the brain but we do know that we can get T cells into the
brain. So if we could target them to particular parts of the brain,
to diseased tissues, it could be extremely powerful. The other
things on the horizon are regeneration and repair with stem cells.
The use of engineered cells for immunotherapy is really just at the
beginning and it will evolve over decades.

This story was originally published by Knowable Magazine. Knowable Magazine is an independent journalistic endeavor from Annual Reviews.

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