“Listeria induces a strong, cell-mediated immune response that results from its unusual life cycle and is particularly suited to killing cancer cells,” says John Rothman, Ph.D., vp of clinical development. The bacterium preferentially infects antigen-presenting cells (APC), which activate the immune system and present specific antigens for the immune system to attack.
A fraction of ingested Listeria avoids digestion in APCs by escaping to the cytosol, where it reproduces and can infect adjacent cells by a cell-to-cell transmission. This capability enables the microbe to activate both helper and killer T cells for specific antigens, which is one of the reasons Listeria vaccines are so effective.
Since Listeria is a bacterium, it also stimulates innate immunity, which viruses do not. Innate immunity involves non-specific activation of the entire immune system to support the activated or adaptive immune response. Listeria also stimulates the Th-1-like cytokine cascade, which liberates chemical messengers that support a therapeutic immune response. Taken together, these immune-stimulating mechanisms provide a directed, powerful, concerted, and integrated cellular immune response capable of killing cancer cells, says Advaxis.
Advaxis has improved upon this panel of immune responses through the use of an antigen fusion protein based on the Listeria enzyme listeriolysin O (LLO). When the APC ingests a foreign Listeria and tries to kill it, ingested Listeria secretes this enzyme, which eats a hole in the wall of the digestive vacuole and allows the bacterium to escape into the cytoplasm.
LLO is potentially dangerous to the host cell because it can compromise the outer cell membrane and may kill the host cell. The body protects itself from this consequence by recognizing an amino acid sequence in the enzyme and rapidly degrading and inactivating it.
Advaxis saw this mechanism as useful because activation of killer T cells requires that the antigen be cleared through a similar mechanism to produce peptide fragments such as antigenic epitopes.
Fusing the antigen to an LLO fragment recruits recognition of LLO to accelerate the breakdown and delivery of antigen. A fragment of LLO that does not puncture membranes is fused to the cancer antigen. This increases the rate of delivery of antigen fragments through the class-1 adaptive pathway, which creates activated killer T cells and generates a robust population of the specific immune cells that destroy the target cancer.