Laguna Bio: Immune Cells Staff Up with Micro organism to Battle Most cancers

Rather than rely on conventional immunotherapies, Laguna Bio is betting on engineered microbes to enhance the immune response against cancer. Founders Jonathan Kotula, Dan Portnoy, and Russell Carrington bring together decades of expertise in microbiology, immunology, and biotechnology. At the heart of their work is a highly attenuated strain of Listeria monocytogenes, capable of safely eliciting a strong, multifactorial reaction that activates rare gamma delta T cells, which proliferate and activate in response to cells that phagocytose Listeria. The Laguna Bio team will soon test their lead Listeria strain in patients with pediatric leukemia, with the goal of long-term cancer control thanks to the immune system’s evolved response to the pathogen.

What makes Laguna Bio unique in the cancer treatment space?

Jonathan Kotula: We think there needs to be a systems-level approach to deal with complex diseases such as cancer. A lot of what has been done so far are reductionist approaches—one small molecule for one pathway or one antibody for one antigen. I think that works well in some cases, but our bodies are really good at adapting and getting back to homeostasis in response to one signal.

It seemed clear to me that microbes can do powerful things to the immune system. Humans have evolved very specific responses to microbes that hit all of the right pathways in the correct context. I have been very motivated by this idea, and it has only been a matter of finding the right project with the right organism and the right indication to make a big difference.

To get a therapy that is substantial and effective, we have combined what is known about immunotherapies, cell therapies, and microbial biotherapeutics, and we’ve developed a living drug from the bacterium Listeria monocytogenes. We’ve engineered the bacterium so that it cannot cause disease. It’s completely safe, and it creates a strong, robust, and multifactorial signal that leads to a huge yet specific immune response. The response is durable, and we can dose with the bacteria over and over again, without exhaustion, because our bodies have evolved a response against this pathogen that doesn’t involve immune memory like a traditional vaccine. We think this unique therapeutic will result in long-term cures for various indications.

Why is L. monocytogenes your microbe of choice?

Dan Portnoy: I’ve been working on Listeria for a long time. It’s easy to genetically modify and grow in vitro and in mice. For decades, immunologists have used Listeria as a discovery agent for understanding the immune system, in part because it can induce cell-mediated immunity. Additionally, it has a biphasic lifestyle, where it is avirulent when growing in the environment, but it has an alternative life as a pathogen. When in a host, it is taken up by phagocytic cells. It doesn’t kill those cells, instead it can escape from the phagosome, grow in the cytosol, and release antigens that the host cell processes and presents. That leads to T cell induction.

Jonathan: Dan previously worked on Listeria as a cancer vaccine. During this time, over 600 patients were treated with bacteria in several trials, and the researchers saw a very specific, strong, and robust gamma delta T cell response. This was completely unexpected because this response does not exist in most other animals such as mice. It was not observed until there was a human clinical study. It’s rare to have an opportunity like this where we can work on something novel that’s initially based on human data.

Inside phagocytes, L. monocytogenes produces a molecule that functions as a signal for intracellular infection, which leads to a big innate immune response and stimulates an active population of gamma delta T cells. These cells have evolved to look for intracellular infection, so they are great at recognizing transformed cells. Certain types of cancer look this way as well, so the gamma delta T cells recognize and kill them.

Russell Carrington: I use this analogy with friends to describe our technology: the immune system has evolved what amounts to multi-factor authentication (MFA) to ensure that it activates and expands only when it should. Other approaches to this activation rely on small molecules or proteins that don’t satisfy the MFA in the way that a pathogen does. We’ve developed a bacterium that triggers the MFA to generate a durable immune response, and we have figured out how to make it safe by attenuating it without compromising its ability to solve that MFA.

Dan: We now have a Listeria strain that cannot grow extracellularly, so we’ve turned it essentially into an obligate intracellular microorganism, and it’s working really well. Jonathan named the strain QUAIL, for quadruple, attenuated, intracellular Listeria.

How did the three of you meet and decide to start a company?

Dan: I had worked with another company for many years, developing Listeria for cancer therapeutic vaccines. That didn’t work out, but the things we learned from that experience led to ideas for how to improve the bacteria and use it in other ways. I’m a professor at the University of California, Berkeley, and I took a sabbatical year to start another company that could build on what I had learned. To do this, I knew that I first needed a CEO.

Jonathan: I had been working for a while in biotech with companies focused on modifying microbes and turning them into drugs. I also did consulting for companies and individuals who had ideas that they wanted to work on, through which I met fairly regularly with Duke University microbiologist Raphael Valdivia who first connected me and Dan.

I’ve always known of Dan’s work. I wrote my graduate school entrance essays based on his research, on modifying Listeria for the purpose of cancer therapy. After meeting with Dan and hearing about his collaborator’s human clinical trial data, I was really motivated and thought this type of therapeutic could be transformational. Subsequently, we met Russell. It became clear that he had good blend of complementary and overlapping skill sets, and we all could clearly work well together. We decided this was going to be the team that would make it happen.

Russell: In graduate school, I realized that I like learning about science more than doing it, so I pivoted to the business of science. I later worked at Lawrence Berkeley National Laboratory in the tech transfer office. I ended up running the office, but I always wanted to get back to working at a startup. The COVID-19 pandemic hit, and I was sitting at home when I had this realization that now was as good a time as any to make this change.

I quit my job with the goal of finding startups to either found or join. At a networking event, I met one of Dan’s former doctoral students. I was interested in what he was doing and gave him some advice, and he eventually introduced me to Dan. So, Dan and I chatted, and the rest is history. It was serendipitous that Laguna Bio is based on microbes because I’ve always been very interested in microbes and pathogenesis.

What has been the response to your therapeutic strategy so far?

Jonathan: We had the previous human data, so we started talking to clinicians across the country about the potential of gamma delta T cells. We heard a lot of interesting stories about these cells being useful in different blood cancers and some soft tissue solid tumors.

We met with a clinician at Stanford University, Alice Bertaina, who is a pioneer in stem cell transplants for higher-risk pediatric leukemia. She discovered that if you can maximize the number of gamma delta T cells post-transplant, it can be totally transformative for overall survival. Doing this decreases opportunistic infections, which are the second-leading cause of death in these patients, and it reduces the risk of graft-versus-host disease. I told her about our human data and asked if she had any hesitation in using an attenuated pathogen as a therapeutic, especially in pediatric patients. She said that this Listeria therapeutic answers the exact problem that she’s trying to solve, and that she’d try our approach as soon as it is FDA approved. For me, that was the most catalyzing feedback, that we had a clinician prepared to use as soon as possible.

What is on the horizon for Laguna Bio?

Jonathan: We have advanced to the clinic with extreme efficiency. We are in the process of submitting an Investigational New Drug (IND) application. The biggest milestone will be when we dose our first post-transplant pediatric leukemia patient, which is planned for early 2026.

We are building different strains for other cancer indications. The next strain in our pipeline specifically and robustly activates and expands mucosal-associated invariant T (MAIT) cells, which are emerging as an exciting mix between innate and adaptive immune cells that may be uniquely effective for tumors of epithelial origin. We are also trying to take advantage of other aspects of Listeria physiology to create more targeted immune therapies toward specific solid tumors and tissues.

Dan: My vision is that we will have a suite of strains that can activate gamma delta T cells to greater or lesser degrees, and the same goes for MAIT cell-activating strains.

Jonathan: We’re also excited to apply our approach to infectious diseases. Gamma delta T cells and MAIT cells can also clear intracellular infections, and because those are the second leading cause of death in post-transplant leukemia patients, we’ll be gathering both anticancer and anti-infective data during our upcoming study.

Russell: Because of Listeria’s biology, there are some special opportunities related to drug storage. Instead of a frozen, cold-chain drug product, ours could be stored at room or refrigerated temperatures. We can also administer it in different ways. So, we have a sandbox in which to explore the logistical side of things that could make our therapeutics suitable for infectious diseases, which tend to be treated in environments with less infrastructure.

What advice do you have for scientists looking to start their own company?

Jonathan: For an academic, there’s so much more to starting a company than you might think. You achieve a great discovery in the lab, publish it, and get excited about its potential as a therapeutic. You might think that it’s ready to go, but turning that discovery into something that can then be tested in a patient, go through clinical trials, and become an administered drug—it’s an absolutely immense amount of work that requires a lot of different skill sets, experiences, and expertise.

Russell: I second what Jonathan says about it being an immense amount of work, and I think that necessitates being really thoughtful about who you work with. I’ve been through this once or twice before, and part of the reason those opportunities didn’t work is that the team was not right for various technical and interpersonal reasons. Be very thoughtful about who you partner with and make sure that you all have complementary skill sets that are also overlapping, so that you can support each other as needed. Also, find people that you get along with well enough to grab lunch together just to chat. I think that’s all super important to get through the work that needs to be done.

Dan: I found that the people in my lab are very excited to learn what it takes to build a company. It adds significance to their research, and they’re very interested to know what’s going on. We have a lot of exchange between the people in my lab who may go into biotech and those who care about the basic science. There really is no fundamental difference between these two groups, except that they are taking different routes. Working with Laguna Bio has been really, really fun. That’s why we do basic research—to eventually translate it.