The tumor microenvironment is not conducive to the emigration and optimal activation of DCs, so the ensuing immune response is weak and ineffective. Tumors actively produce immunosuppressive Type 2 cytokines as a strategy to avoid immune elimination [11]. Activated tumor-associated macrophages and most human tumors produce immunosuppressive cytokines, such as IL-10 and TGF-β, which inhibit antigen presentation by DC and induce Treg cells [31, 32]. TGF-β also suppresses the transcription of genes encoding multiple key proteins of CD8+ cytotoxic T cells (CTL), such as perforin and granzymes [33]. Macrophages from cancer patients also are key components of suppressed anti-tumor immunity. They produce enzymes which lead to profound suppression of T cell proliferation [34] and induce T cell death by apoptosis [35].

The purpose of specific active immunotherapy is to stimulate an antitumor immune response by channeling the tumor antigens into the appropriate DC subset and providing the optimal conditions for the maturation of the DC into a potent immunostimulatory APC.  This requires changing the tumor microenvironment from immunosuppressive Type 2, to an inflammatory Type 1 environment.  An ineffective Type 2 immune response is detected in most patients with advanced cancer and metastatic disease [36-39].  

Inflammation progresses by the action of inflammatory Type 1 cytokines, including IL-1, TNF, IFN-γ, IL-12, IL-18, and GM-CSF, and is resolved by Type 2 cytokines such as IL-4, IL-10, IL-13 and TGF-β [40].  Type 1 cytokines such as IFN-γ, IL-2 and GM-CSF in the tumor microenvironment have been shown to cause the accumulation and activation of NK cells, neutrophils and monocytes [41-43].

Intravenous infusion of AlloStim™ is expected to activate NK cells and macrophages due to the production of Type 1 cytokines.  NK cells can be directly cytotoxic to tumors that down regulate MHC class I molecules as an immunoavoidance strategy [44] and can also produce Type 1 cytokines of their own [45]. Type 1 cytokine release in the tumor microenvironment can have a direct antitumor effect without T-cell recognition via MHC I or MHC II [46, 47].