Engineered Listeria Bacteria Show Promise as Next-Generation Cancer Therapy
A novel approach to cancer treatment, leveraging a modified form of the common foodborne bacterium Listeria, is gaining momentum after decades of research. Scientists at the University of California, Berkeley, and the startup Laguna Biotherapeutics have discovered a way to harness Listeria’s unique ability to stimulate the immune system, potentially offering a powerful new weapon against a range of cancers and infectious diseases.
The breakthrough centers around manipulating Listeria monocytogenes, a bacterium known for its ability to evade the body’s defenses and thrive within cells. For nearly 40 years, researchers led by Daniel Portnoy have studied how Listeria interacts with the immune system. This extensive research has culminated in a therapy designed to boost the body’s natural defenses without causing illness.
Laguna Bio is preparing to submit an application to the Food and Drug Administration (FDA) seeking clearance to test this innovative therapy in children with leukemia undergoing bone marrow transplants. Doctors at Stanford University Medical Center are optimistic that the engineered Listeria will enhance gamma delta T cells – a type of immune cell crucial for fighting cancer and infection – in young patients, helping them combat graft-versus-host disease and prevent cancer recurrence.
Unlike many current immunotherapies that focus on activating the “adaptive” immune system to target specific cancer cells, this approach aims to stimulate the “innate” immune system – the body’s first line of defense. “The issue is that tumors are a suppressive environment, and so the immune system isn’t really even working,” explained a senior researcher involved in the project. “Listeria itself is seen as foreign and induces an innate immune response, which allows the body to overcome the suppression.”
From Failed Vaccine to Immune Booster
The journey to this potential breakthrough was not without its challenges. In the 2000s, Portnoy collaborated with Aduro Biotech to develop a cancer vaccine using a modified Listeria strain, dubbed LADD (Listeria attenuated double deleted). While promising in mouse models, LADD failed to elicit a strong enough response in human patients.
However, analysis of the Aduro trials revealed an unexpected benefit: LADD stimulated not only the adaptive immune system but also key cells of the innate immune system, including gamma delta T cells. This observation prompted a shift in strategy, focusing on Listeria’s ability to broadly invigorate the immune system.
Introducing QUAIL: A Safer, More Potent Strain
Building on the lessons learned from LADD, Laguna Bio developed a further attenuated strain called QUAIL (quadruple attenuated intracellular Listeria). This new strain has been engineered to be even safer by deleting two additional genes essential for synthesizing vital nutrient cofactors. “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,” Portnoy stated.
QUAIL is designed to grow exclusively within cells, preventing it from spreading throughout the body and causing illness. Recent studies in mice have demonstrated that QUAIL is as potent as LADD in stimulating an immune response, while significantly reducing the risk of adverse effects.
Beyond Leukemia: A Broad Spectrum of Potential Applications
The potential applications of this Listeria-based therapy extend far beyond leukemia. Researchers envision treatments for a wide range of cancers, including multiple myeloma, lymphomas, neuroblastoma, and sarcomas. Furthermore, the therapy could potentially be used as a prophylactic vaccine against infectious diseases like malaria, tuberculosis, and latent viral infections.
“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,” said Jonathan Kotula, CEO of Laguna Bio. “Then, once you have that reinvigoration, it’s always helpful to direct it somewhere.”
Initial trials will focus on leveraging QUAIL to boost gamma delta T cell responses in pediatric leukemia patients undergoing bone marrow transplants, where immune systems are particularly vulnerable. The hope is that these reinvigorated T cells will directly kill cancer cells, fight off infections, and prevent transplant rejection.
The research, supported by Laguna Bio and the National Institutes of Health, represents a significant step forward in the field of immunotherapy. The success of QUAIL in clinical trials could pave the way for a new generation of cancer treatments that harness the power of the innate immune system to fight disease.
