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 biology?

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 detail.

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 way.”
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 cells.

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 far?

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 cancer.

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 difference.

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 work.

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 useful?

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.