The design of this in-situ anti-tumor vaccine is based upon an important paradigm shift in the field of immunology regarding the regulation of immunity.  A new concept has emerged that proposes that the regulation of immunity and tolerance is not only determined by the specificity of immune T-cells as previously thought, but also by the context in which the antigens are presented to the immune system [27, 28].   

The antigens are presented to the immune system by a network of specialized cells that are known as professional antigen-presenting cells (APCs) or dendritic cells (DCs). DCs are responsible for inducing immunity to pathogens or tumors by presenting antigens to naive T cells, resulting in the differentiation of the T cells into effector and memory T cells specific for the antigens. Effector T-cells, mainly CD8+ cytolytic T-cells (CTL), are capable of destroying cells which express the antigens.  Memory T-cells provide immune protection against recurrence or reinfection.   Differentiation of the DCs into potent APCs is triggered by molecular stimuli that are released as a result of the tissue disturbance and a local inflammatory response [28-30].  

The implications are that if a pathogenic infection occurs in the absence of appropriate inflammatory reactions, pathogen-specific T cells will not be activated despite the presence of pathogen-specific foreign antigens, and, conversely, autoreactive T cells, including those that are directed against tumor cells, can be readily activated provided the self (tumor) antigens are presented by DCs during an inflammatory response.  Since tumors produce anti-inflammatory cytokines, they are capable of influencing the immune response by preventing an inflammatory response.

Therefore, successful anti-tumor immunity will develop in the situation where DCs are processing tumor antigens in the presence of an inflammatory reaction (“danger signals”) which is potent enough to also downregulate tumor-mediated immunosuppressive cytokine production.   The magnitude and duration of the immune response will be dependent on the extent and quality of the local inflammatory response and will be contained by a variety of tolerogenic mechanisms.  

In summary, previous attempts at developing therapeutic cancer vaccines have demonstrated that it is possible to elicit specific immunity against self-tumor antigens.  Recent insights on how immunity and tolerance are regulated indicate that the failure of these vaccines in the clinic may be related to the absence of sufficient danger signals at the time tumor antigens are processed by DCs. AlloStim™ is designed to provide the necessary danger signals to elicit anti-tumor immunity.