A MODERN SCIENCE-DRIVEN REINVENTION
WITH PATENTED TECHNOLOGY
AND CURATIVE POTENTIAL
The Promise and the Pitfalls of Coley's Toxins
Observations of spontaneous tumor regression in the setting of infection have been made and recorded for 4,600 years, starting in ancient Egypt, and were first published in the scientific literature in the 1700’s. As soon as scientists were able to isolate bacteria from infections in the 1800’s, they attempted to treat cancer by inducing infection. Both cancer cures and deaths from infection were reported, until Dr. William Coley, a cancer surgeon at what is now Memorial Sloan Kettering in New York, determined that isolated bacteria didn’t need to be alive to cure cancer. He produced a heat-killed mixture of one strain of Gram-negative and one strain of Gram-positive bacteria and by 1894, was treating and producing durable responses in advanced cancer patients. His product become known as Coley’s toxins and was associated with curing several hundred late-stage cancer patients world-wide over the course of about 70 years.
Coley and others determined that the Gram-negative bacteria represented the active component, but unfortunately, were not able to administer the product under optimal conditions. Coley reported that it worked best when administered intravenously, but was too toxic when given by this route. It was administered intratumorally (i.t.) and subcutaneously (s.c.), but this produced significant variability in clinical response. Lack of understanding regarding the mechanism of action precluded optimization and standardization of manufacturing, which also led to variability in clinical response.
In 1962, the US FDA was given the mandate to approve all new drugs and determine which old drugs to “grandfather in.” They knew that Coley’s toxins could cure a subset of advanced cancer patients, but felt that modern approaches such as chemotherapy and radiation were likely to be much more consistent. They declined to make Coley’s toxins an approved drug and this led to its abandonment by the pharmaceutical industry in 1963.
Modern Science Elucidates Mechanism of Action and Source of Toxicity
We now know that bacteria and viruses contain immune system danger signals, called pathogen-associated molecular patterns (PAMPS), which collectively can activate all of the cellular components of our innate and adaptive immune pathways. These molecules bind to receptors, such as Toll-like (TLR), NOD, STING and RIG-I, which are distributed across all immune cells. It is not surprising that our immune systems have evolved to recognize and be activated by bacteria and viruses that might be potential pathogens. Clearly, Coley’s toxins were acting like a “decoy” to attract and activate systemic anti-tumor immune responses. It is also apparent that the clinical response to Coley’s toxins was highly variable because it was not given by the optimal administration route and was not combined with drugs that reverse tumor-mediated immune suppression.
Research carried out since the 1940’s has suggested that the most potent and most toxic active ingredient of the Gram-negative bacteria in Coley’s toxins is lipopolysaccharide (LPS) or endotoxin, which activates Toll-like receptor 4 (TLR4). TLR4 is found on and involved in activation of many different innate and adaptive immune cells, in addition to being required for dendritic cell activation. LPS is the most potent immune cell activator known and has been shown to produce limited i.v. anti-tumor activity in pre-clinical and clinical settings, but does this with an unacceptable therapeutic index. LPS is much less toxic, but also produces much more limited systemic anti-tumor activity, when administered intratumorally.
Decoy's Modern Science-Driven Approach
Decoy's patented approach is based on the hypothesis that efficient activation of both innate and adaptive immune cells and associated anti-tumor immune responses will require intact bacteria, containing multiple PAMPs, which can be administered safely intravenously. Because LPS appears to be the most important contributor to both toxicity and efficacy, Decoy's patented product is a single strain of killed, non-pathogenic Gram-negative bacteria that have been treated to kill the bacteria and significantly reduce, but not completely eliminate, the cell surface lipopolysaccharide (LPS)-endotoxin activity. Decoy's product is designed to have enhanced i.v. safety and sufficient residual LPS to synergize with other PAMPs in the bacteria to efficiently prime innate and adaptive immune pathways. This leads to broad anti-tumor responses, including safe, synergistic regressions and durable responses with five different classes of existing anti-tumor agents, including checkpoint therapy, targeted antibody therapy and low-dose chemotherapy. Tumor eradication by Decoy technology produces both innate and adaptive immunological memory and, importantly, does not require provision of an exogenous tumor antigen, due to the ability of LPS and other PAMPS to activate dendritic cells that have already captured a tumor antigen.
Decoy's Advantage Over Other Therapies
Decoy bacteria will be cleared very quickly by the liver and spleen, which may reduce the risk of non-specific autoimmune side effects, relative to other types of immunotherapy that are designed for continuous exposure. A short Decoy exposure should be sufficient to act alone and as a “primer” to enhance other products.
Systemically. Synergistically. Safely.
Innate and Adaptive Cellular Anti-Tumor and Anti-Viral Immune Pathways.
All cells can participate in killing of tumors and viruses. Current therapies activate only one or a small subset of both pathways and cure only a small percentage of patients.
Efficient Cure of Cancer or Chronic Viral Infections Requires Safe Activation of Both Innate and Adaptive Pathways.
Decoy may be the first to discover how to do this. Decoy bacteria are engineered to synergize with existing therapies to activate both innate and adaptive immune cells, inducing efficient anti-tumor immune responses with a wide safety margin
Induction of adaptive anti-tumor immune responses and immunological memory by Decoy bacteriadoes not require an exogenous tumor antigen
Most Steps Required for Innate and Adaptive Cellular Immune Responses are Non-Specific.
Innate and adaptive immune responses require identification of a tumor as foreign or not self. However, most steps required for migration and activation of immune cells are unrelated to the tumor or tumor non-specific. All innate and adaptive non-specific steps are induced or promoted by immune system "danger signal" molecules, such as those found in Decoy bacteria. Bacteria-derived danger signals are also able to enhance the processing and recognition of tumor antigens, which are frequently present, but not “seen” by the immune system.