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LISTERIA-BASED IMMUNOTHERAPY: OVERVIEW
For more than 50 years, immunologists have used Listeria as a research tool to study the mammalian immune system. Now Aduro BioTech is engineering Listeria to treat cancer and infectious diseases.
There are several properties that make Listeria ideally suited as a platform for engineering active specific immunotherapies.
- Safety: Using Listeria as the basis for a vaccine may seem counter-intuitive, but the safety is well established. The FDA has already approved three bacteria-based vaccines, including vaccines based on cholera and salmonella, which are safe for use in healthy individuals. These bacteria were attenuated (made safe) with old-fashioned selection and/or genetic engineering methods, whereas Aduro used 21st century technology to create defined and stable mutations in Listeria to ensure attenuation and safety (see Product Platforms for more detail).
- Targeting of dendritic cells in vivo: The first genetically-engineered cancer vaccine approved by the FDA, Provenge® from Dendreon, is based on a technology in which dendritic cells are first isolated from patients and then exposed to cancer antigens in vitro. This is a complex and costly process, whereas Aduro’s technology targets dendritic cells in vivo and requires only a simple infusion or injection
- Delivery of antigens and stimulation of T cells: Listeria is initially taken up into a specialized cellular compartment called a vacuole. Listeria then expresses a protein called listeriolysin O (LLO) that allows it to escape from the vacuole and multiply inside the cell. It is in the cytosol that Listeria expresses and secretes antigens. These antigens are processed by the host cellular machinery and presented on the cell’s surface to the immune system. T cells recognize presented antigens and are activated in the context of the inflammatory danger signal induced by Listeria. This ability to express and present antigens to T cells in the appropriate host cell compartment enhances the efficacy of Listeria-based vaccines and therapeutics, and distinguishes Listeria from other microbial vector systems.
- Stimulation of innate immunity: Listeria
signals through multiple pathways to the innate immune system,
activating cell surface Toll-like receptors and intracellular Nod-like
receptors. The ability to stimulate intracellular receptors is critical
to Listeria’s activity and leads to potent expression of
interferons and other cytokines that play a role in fighting infections
and cancer.
- Ability to repeatedly administer: Most microbial vectors, including Listeria, induce an antibody response after administration to a patient. Antibodies against a viral vector can neutralize it, blocking its ability to subsequently enter cells and express its antigenic payload. This is a fundamental limitation since virtually all vaccine and active immunotherapy strategies require multiple immunizations (so-called prime-boost regimens) in order to effectively stimulate immune responses. In contrast, Listeria is not neutralized, even by high levels of antibody. This makes it suitable for developing repeat-dose regimens in the setting of chronic infections and cancer.
- Exceptionally potent at increasing the efficacy of other vaccines/treatments when combined. As explained above, virtually all vaccine and active immunotherapy strategies require multiple immunizations. Traditionally the same vaccines are given repeatedly as a prime followed by homologous boosts. But new research suggests prime-boost with different types of vaccines containing the same antigens can be more immunogenic. Listeria is especially effective at heterologous prime-boost, which creates unique opportunities to make other vaccines and treatments more effective.
- Simplicity of engineering and manufacturing: The process of engineering antigens into Listeria, and thus making disease-specific treatments and vaccines, utilizes molecular techniques that have been developed for bacteria over the last 30 years. Aduro has refined these molecular tools with proprietary methods to enable precise integration of antigens at well-characterized locations on the Listeria chromosome. Antigens are expressed and secreted at robust levels to stimulate potent T cell responses. Manufacturing and purifying engineered Listeria utilizes cost-effective, standard methods of fermentation and separation. Scale-up is predictable, current production takes 16 hours start-to-finish, and yields are in excess of 90%. This simplicity eliminates major sources of risk and cost in the process of developing a biologic therapy.
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