Cancer therapies exist on a spectrum that spans levels of complexity, from the simplest small molecules on one end to heavily engineered cell therapies and living microbial therapies on the other. Small molecules interact with specific cellular pathways and carry consistent clearance kinetics, which may provide the perception of being well understood, and thus safe and effective. Engineered living cell therapies and microbial therapies, by contrast, exist within the intersections of biological ecosystems such as the tumor microenvironment and the immune system. This gives them the power to enact systemic change, but they may carry risks of persistence or inconsistent and unpredictable kinetics, which can carry a perception of being less understood, and thus higher risk. The reality is that methods across the spectrum have unique risks and benefits, and when we want to eliminate an ecosystem such as a tumor microenvironment it may take a therapy built to impact that same scale.
The perceived precision of small molecules depends on predicting not only how a drug acts on its target, but whether the intended effect ripples into unintended secondary and tertiary consequences or has additional off-target effects. The off-target effects of chemotherapies are well known, and this risk extends into biologics such as antibody-based drugs as well. That difficulty in fully predicting a therapy's downstream effects has not gone away, yet moving further across the spectrum toward more complex, systems-level tools has still produced real gains in efficacy. On-target but off-tumor toxicities have so far prevented immunotherapy (both T cell engagers and CAR-T) from helping AML patients, since the antigens most commonly targeted on leukemic blasts are also expressed on the healthy blood-forming stem cells a patient depends on to recover. CAR-T cells and T cell engagers can also cause severe, on-target inflammatory toxicity, such as cytokine release syndrome, that can arise simply from the therapies working exactly as intended. In addition to these biological limitations, CAR-T therapies also come with significant cost, logistics, and manufacturing limitations. Yet some people with B cell lymphomas or multiple myeloma may have been cured by CAR-T therapies. These gains support a growing appreciation that curing complex, systemic diseases like cancer requires systems-level, living therapies.
Homeostasis is the reason systems-level diseases demand systems-level therapies. Nearly all of our physiology has evolved to maintain a stable equilibrium, often through mechanisms that work against themselves once their job has been initiated. When a T cell is activated, for example, it also turns on the very programs that lead to its own destruction, a built-in check that prevents the immune system from running rampant and causing autoimmunity. Cancer exploits this same tendency toward equilibrium in reverse. As mutations slowly accumulate, they don't just create malignant cells, they gradually reshape the surrounding tissue, the immune system, and the body's broader physiology into a new homeostasis, one that favors the tumor's survival rather than its elimination. Curing cancer, or truly clearing a tumor, requires shifting that homeostasis back toward a pre-cancer state; something only a systemic-scale intervention can achieve. This is why circulating T cells are able to shift the homeostasis of hematologic malignancies, curing some patients, because those malignancies primarily affect the lymph nodes and bone marrow, environments T cells have evolved to surveil and reside in, but struggle to do the same in solid tumors. A solid tumor is a completely novel environment that has been shaped by the tumor to exclude and evade the immune system. Therefore, a single type of immune cell cannot provide a large enough or durable enough systemic change to shift the tumor’s microenvironment away from a pro-cancer homeostasis.
Nothing creates a systemic shift throughout the entire immune system better than a microbial pathogen. Living microbial therapies also carry a structural advantage that neither a molecule nor an engineered cell therapy fully replicates. Small molecules, and the signaling domains built onto engineered cells like CAR-T, are designed by human engineers and refined over years of trial and error. A microbe's ability to engage a host's tissue and immune system, by contrast, is the product of millions of years of evolutionary pressure between hosts and the microbes that infect them. That's a longer and more rigorous R&D program than any human effort could run. That difference matters most for the homeostasis-shifting changes required to cure cancer. Evolution has been tuning these systemic, whole-organism interactions for as long as infection has existed. Human engineering is still working out how to add a single costimulatory signal without causing toxicity. By developing a therapeutic living microbe, we are co-opting a self-contained biological agent for immune activation and expansion that has been tuned by millions of years of evolution, and precisely attenuating it so that it cannot cause disease. That systemic reach does not depend on the organism persisting. The shift it leaves behind, an immune system reorganized and re-engaged, is what endures, sustained by the patient's own response long after the organism itself has cleared. An attenuated microbial therapy has a defined composition, reliable clearance kinetics, and carefully measured impacts on the patient's own immune system.
At Laguna, we believe living, systems-level therapies are necessary to clear systems-level disease, and that engineered microbes are the best vehicle for delivering the systemic immune changes cancer requires, without inheriting the toxicity and manufacturing burden that limit engineered cell therapies today. Our QUAIL platform generates engineered microbes that have been attenuated to not cause disease and cleared from the body with the predictable kinetics of small molecules, while penetrating the tumor microenvironment to attract, activate, and expand multiple populations of the innate immune system at once. That breadth, engaging many immune cell types rather than depending on the single engineered cell type a CAR-T product relies on, is what generates a robust, effective, and durable response against cancer. We've also designed our manufacturing process to avoid the patient-specific bottlenecks that limit living cell therapies. Because our strains are produced through standard microbial fermentation, batches can be made at scale well ahead of patient need, the way a small-molecule or biologic drug is today.
Cancer built an ecosystem to survive. We co-opted evolution to build a therapy that can dismantle it.
