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Mechanism of Action

Advaxis uses live, attenuated bioengineered Listeria monocytogenes as a therapeutic agent. We start with a live, attenuated strain of Listeria then add multiple copies of a plasmid that encodes a fusion protein sequence including a fragment of the LLO (listeriolysin O) molecule joined to the antigen of interest. This fusion protein is secreted by the Listeria inside the antigen presenting cells, and other cells, which has been shown to result in a strong stimulation of both the innate and adaptive arms of the immune system and a reduction in tumor defense mechanisms.

Live attenuated bioengineered Lm (Lm-LLO) being phagocytosed by an APC  leading to the stimulation of CD4+ and CD8+ T cells. Lm-LLO being phagocytosed by the APC and either escaping from the phagosome or being killed and degraded.LM-LLO near an APC.
LM-LLO being phagocytosed by an APCLM-LLO being phagocytosed by an APC.Phagosome containing Lm-LLO fusing with an acidic lysosome.Killing and degradation of Lm-LLO within a phagolysosome.Escape of some Lm-LLO from the phagolysosme into the cytosol of the APC.Production of LLO-TAA (tumor associated antigen) as Lm-LLO escapes into the cytosol.LLO-TAA fusion protein in the APC cytosol.
The LLO-TAA fusion proteins being tagged (ubiquitinated) for degradation.
Tagging of LLO-TAA fusion protein for proteasomal degradation.Tagged LLO-TAA fusion protein entering the proteasome for degradation.Degradation of LLO-TAA fusion protein into peptides for the MHC class I pathway.Peptides from the LLO-TAA entering the endoplasmic reticulum and being loaded onto MHC class I molecules.Peptide-loaded MHC class I molecules travelling to and  being exposed on the surface of the APC.Peptide-MHC I complexes on the APC coming into contact with appropriate T cell receptors on CD8+ T cells.A tumor with a growing blood supply.

T cells activated from the peptide-MHC complex (derived from the LLO-TAA) migrating to the tumor.T cells activated from the peptide-MHC complex (derived from the LLO-TAA) migrating to the tumor.T cells activated from the peptide-MHC complex (derived from the LLO-TAA) migrating to the tumor and entering the tumor microenvironment.The CD8+ T cells targeting the tumor leading to the death of tumor cells and destruction of the tumor.

Advaxis immunotherapies are designed to stimulate many complementary immune mechanisms of action, including:

  • Strong innate immune effects
  • Strong adaptive immune effects
  • Reduction of both Tregs and MDSCs in tumors but not in other tissues or systemically
  • Memory generation that is not impaired by antibiotics administered immediately after dosing
  • Chemotaxis and extravasation of activated immune cells
  • Upregulation of tumor chemokines and chemokines receptors
  • Epitope and antigen spreading
  • A predominantly cellular immune response with little antibody formation