Researchers at the University of California, Berkeley, led by Daniel Portnoy, have developed a new therapy using engineered Listeria bacteria to stimulate the immune system against cancer. This approach follows decades of research into how Listeria monocytogenes interacts with human cells and evades the immune response.
Three years ago, Portnoy co-founded Laguna Biotherapeutics to collaborate with his UC Berkeley lab in modifying Listeria so it could no longer cause disease but would still activate gamma delta T cells. These immune cells are known for their ability to target cancer cells and infected cells.
Laguna Biotherapeutics plans to seek FDA approval to test this therapy in children with leukemia who have undergone unmatched bone marrow transplants. The goal is for the engineered Listeria to increase gamma delta T cell levels in these patients, potentially reducing graft-versus-host disease, combating infections common after transplants, and preventing cancer recurrence.
Portnoy explained the significance of their work: "The issue is that tumors are a suppressive environment, and so the immune system isn't really even working. There are lots of attempts to try to reawaken the immune system, such as using checkpoint inhibitors, which were originally developed at UC Berkeley. The idea is somewhat similar with Listeria: Listeria itself is seen as foreign and induces an innate immune response, which allows the body to overcome the suppression."
Recent studies published by Portnoy’s team showed success using attenuated Listeria therapy in mice. They also demonstrated that engineered Listeria can boost another type of innate immune cell called MAIT (mucosal-associated invariant T cell), which plays a role in defending against infections and possibly cancer.
Laguna Bio CEO Jonathan Kotula commented on their strategy: "What we're doing is based on decades of literature, chief among them Dr. Portnoy's work, showing that Listeria generates a really unique immune response. We believe that if you want to generate a comprehensive immune response, you need to carefully orchestrate the entire immune system. And attenuated Listeria seems to be doing that."
Listeria monocytogenes typically causes foodborne illness but can sometimes lead to severe complications like sepsis or meningitis. Research has shown that after entering human cells, Listeria escapes destruction by hiding inside those cells until it reproduces and spreads.
Earlier efforts by Portnoy included developing a less virulent strain called LADD (Listeria attenuated double deleted) in collaboration with Aduro Biotech for use as a cancer vaccine. While successful in animal models, clinical trials did not produce strong results in humans due partly to insufficient cytotoxic T cell responses.
Learning from these trials, Portnoy’s team shifted focus toward harnessing innate immunity rather than solely adaptive immunity. The latest version of engineered bacteria—called QUAIL (quadruple attenuated intracellular Listeria)—has four gene deletions making it safer for use in humans because it cannot grow outside host cells.
Portnoy described this advance: "We said, 'Oh my gosh, this strain fits the criteria that we were looking for' - a mutant of Listeria that could grow inside of cells but not outside of cells... So that's the new safer strain, QUAIL. We're very excited about that."
Preclinical studies indicate QUAIL retains potency while being unable to proliferate on medical devices used during cancer treatment—a safety improvement over previous versions.
Kotula emphasized their data-driven approach: "Taking all that body of data that existed before from Aduro allowed us to go forward with this plan that I think is really unique in that it's informed by robust human data."
Initial clinical trials will focus on pediatric leukemia patients at Stanford University Medical Center using QUAIL directly to stimulate gamma delta T cell responses when adaptive immunity is suppressed post-transplantation.
If proven safe and effective in these trials, Laguna Bio envisions expanding use of QUAIL-based therapies for other cancers responsive to increased gamma delta T cell activity and potentially as vaccines against certain infectious diseases.
Kotula stated: "Let's reinvigorate the immune system, initially focusing on cancers where just that reinvigoration - the gamma delta T cells - has shown promise of efficacy against disease... I think this can be a part of a broad array of therapies and a piece of a treatment regimen that fits well within how a lot of immune therapies are being administered today. It really works well and complements a lot of the immunotherapy drugs that are already approved."
The research received support from Laguna Biotherapeutics and the National Institutes of Health. Co-first authors include Victoria Chevée and Rafael Rivera-Lugo (graduate students), Mariya Lobanovska (postdoctoral fellow), along with collaborators from UC Berkeley, Michigan State University, and Laguna Biotherapeutics.
