Why Advaxis Vaccines Work
Strong Stimulation of Classic Immune Mechanisms, Non-Classic Mechanisms, and Changes in the Tumor Microenvironment
Most bacteria stimulate innate immunity, but Listeria is an unusually strong stimulator of innate immunity. Unlike many other immune therapies which require the administration of an additional immune adjuvant in order to boost the response to the therapeutic agent, Advaxis vaccines do not require additional adjuvants as our vaccines are unusually strong stimulators of innate immunity all by themselves.
Listeria has a unique life cycle in that it stimulates both arms of the adaptive immune reponse. It infects Antigen Presenting Cells (APC), which are the cells that activate immune cells and tell them what to attack. Because of this, Listeria becomes perfectly positioned to have the maximum effect on the immune system by directing it to attack specific targets. Even more unusual is Listeria's ability to stimulate both helper T cells (CD4+) and killer T cells (CD8+), since both are necessary for an antitumor response and it is unusual for a single pathogen to stimulate both in the way Listeria does.
In this way we can use the strong stimulation of a cell mediated response that we have evolved, which enables us to co-exist with Listeria, and redirect it against a specific tumor type. And we can improve upon the normal response to Listeria by increasing the efficiency of generating specific antigen fragments for the immune system to use in activating cancer killing T cells to attack the specific cancer to which the Listeria has been engineered to mimic.
But there is even more to this story. Not only are we able to stimulate innate immunity and both endogenous and exogenous adaptive immune pathways to stimulate the activation of tumor specific CD4+ and CD8+ T cells, but LLO fusion proteins have other effects as well.
It has recently been shown that LLO has a variety of other effects that have utility in the treatment of cancer. These include the stimulation of a variety of chemical messengers called cytokines, chemokines and co-stimulatory molecules that facilitate a therapeutic immune response. Although activated T cells are necessary to treat cancer immunologically, they need an environment conductive to the promotion of a therapeutic effect. The mediators released in LLO (and the LLO fraction of the antigen fusion protein) create such an environment, not the least of which is a local tissue environment within the tumor that enables activated T cells to kill tumor cells and clear them from the body.
One singularly interesting finding that we have published is the effect of our antigen LLO fusion protein on the generation of regulatory T cells (Tregs). These Tregs are activated by the same stimuli that activate helper and killer T cells, however they serve to inhibit the immune response, thus lessening the attack against cancer. It is believed that these cells serve to inhibit the immune response so as to control potentially fatal autoimmune responses. When we compared Listeria that have been modified to secrete just an antigen with Listeria that have been modified to secrete an LLO-antigen fusion protein, we have found that Listeria secreting the fusion protein decreases the number of Tregs, thus increasing the strength of the cancer directed immune attack.
Other effects of Advaxis Listeria vaccines include increasing the number of myeloid cells like Dendritic Cells, Macrophages, and others, that are necessary for a strong immune response. These vaccines also cause the maturation of immature myeloid cells which can inhibit the immune response like Tregs (MDSC, myeloid derived suppressor cells), thus turning them from immuno-inhibitory cells into immuno-stimulatory cells.
Live Listeria vaccines also cause the release of certain chemicals (chemokines) that facilitate the ability of the immune cells that are activated by the vaccine to leave the circulation and enter into tumors.
Listeria also causes decreases in certain cell types that are found within tumors (Tregs and MDSC) that turn off activated immune cells, thus bestowing tumors with an immune privilege that otherwise protects them from immune attack. This change in the tumor microenvironment is unusual and has been found to be essential to a therapeutic response.
Finally, Listeria vaccines are associated with a very useful phenomenon called epitope spreading. An epitope is a portion of an antigen that is recognized by the immune system. Thus, the immune system attacks specific epitopes on antigens. Any given antigen may have many different epitopes. Epitope spreading occurs when the immune system is activated at a very high level such that when an immune therapy begins to kill tumor cells and they are broken down, portions of the destroyed cells are recognized by the immune system as foreign and become new targets of attack. In this way, an immuno-therapy may attack sites beyond the ones that it was built to attack. This can dramatically amplify the immune attack and thus magnify therapeutic response.
It is in this way that our engineered Listeria stimulates multiple reinforcing immune mechanisms to attack existing cancers.
