Unleashing the Power of Engineered Listeria: A Revolutionary Approach to Cancer Immunity
Imagine a bacteria, once a feared enemy, now transformed into a powerful ally in our battle against cancer. This is the incredible journey of Listeria, a pathogen that has undergone a remarkable evolution in the hands of scientists like Daniel Portnoy and his team.
For nearly four decades, Portnoy and his colleagues have delved into the intricate dance between Listeria and our immune system, uncovering its secrets and turning the tables on its ability to cause harm. Three years ago, their groundbreaking work led to the formation of Laguna Biotherapeutics, a startup with a mission to harness the potential of engineered Listeria as a potent immune booster and a potential cancer-fighting weapon.
But here's where it gets controversial... Laguna Bio's approach is unique, focusing on stimulating the body's innate immune system, a strategy that differs from today's typical cancer immunotherapies which target the adaptive immune system.
The key lies in a specific type of immune cell, the gamma delta T cells, which are natural-born killers of cancer cells and infected cells. By eliminating the bacteria's disease-causing abilities while retaining its immune-boosting properties, Portnoy and his team have created a therapy that could revolutionize cancer treatment.
Laguna Bio is set to take this therapy to the next level, aiming to evaluate its effectiveness in children with leukemia who have undergone bone marrow transplants. The hope is that this engineered Listeria will boost gamma delta T cells, helping pediatric patients fight off graft-versus-host disease, deadly infections, and prevent cancer recurrence.
And this is the part most people miss... The beauty of this therapy lies in its ability to target any cell that sends out a distress signal, indicating compromise. It's a broad-spectrum approach, unlike many cancer treatments that are tumor-specific.
Portnoy, a professor at UC Berkeley, explains, "The issue is that tumors create a suppressive environment, hindering the immune system's response. Our approach, inspired by decades of research, including Dr. Portnoy's work, aims to reawaken the immune system, much like checkpoint inhibitors developed at UC Berkeley. Listeria, seen as a foreign invader, induces an innate immune response, overcoming this suppression."
The team's recent publication in the journal mBio details the successful use of their attenuated Listeria therapy in mice. They've also reported that Listeria can be engineered to boost another type of innate immune cell, the mucosal-associated invariant T cell (MAIT), offering additional defense against infections and potentially cancer.
Jonathan Kotula, CEO of Laguna Bio, emphasizes, "Our work is grounded in decades of literature, with Dr. Portnoy's research at the forefront. We believe a comprehensive immune response requires careful orchestration of the entire immune system, and attenuated Listeria seems to achieve this."
Escape from the Phagosome: The story of Listeria's unique behavior begins with its ability to evade digestion by phagocytes, a type of scavenger cell. Portnoy's research revealed that Listeria escapes the phagosome, setting up camp inside the cell, hiding from the immune system until it's ready to reproduce and spread.
This evasion strategy led Portnoy to develop a version of Listeria, called LADD, which couldn't make people sick. By deleting two genes, he created a strain that could still induce a potent immune response but couldn't spread, making it significantly less virulent.
A New Approach: Portnoy's colleagues at Aduro Biotech observed that Listeria induced not only cytotoxic T cells but also other T cells of the innate immune system. This observation inspired Portnoy to explore Listeria as a general immune system booster, leading to the development of the QUAIL strain.
QUAIL, or quadruple attenuated intracellular Listeria, is an improved version of LADD, with two additional genes deleted to enhance safety. This strain lacks enzymes required to synthesize essential nutrient cofactors derived from riboflavin (vitamin B2), making it unable to grow outside cells. Portnoy transformed Listeria from a pathogen that could grow both inside and outside cells to one restricted to the intracellular environment.
The Future of QUAIL: Initial trials in pediatric leukemia patients will use QUAIL to directly elicit a gamma delta T cell response, fighting infection, rejection, and recurrence. If successful, QUAIL could be a game-changer for various diseases, including multiple myeloma, lymphomas, and solid tumors. It may also serve as a prophylactic vaccine against diseases like malaria, tuberculosis, and latent viral infections caused by intracellular pathogens.
Kotula envisions a future where this therapy reinvigorates the immune system, initially targeting cancers where gamma delta T cells have shown promise. "Once you have that reinvigoration, it's helpful to direct it," he says. "This therapy complements existing immunotherapy drugs and could be a powerful addition to treatment regimens."
The work of Portnoy and his team has opened up a new frontier in cancer treatment, offering hope and a unique perspective on harnessing the power of our immune system.
