The rationale for development of cancer vaccines is based on experimental work in animal models, in which it has been demonstrated that specific CD8+ cytotoxic T-cells (CTL) are able to eliminate tumors and develop memory which protects against recurrence. It has also been shown in humans that the addition of recombinant interleukin-2 (IL-2), a T-cell growth factor, to in vitro culture of irradiated tumor cells with autologous lymphocytes from peripheral blood or tumor-infiltrating lymphocytes results in the expansion of T-cells that are mainly CTL, which exert very potent anti-tumor effects in vitro. Moreover, it has been demonstrated that they often recognize tumor-associated antigens.

However, despite the promise of cancer vaccination shown in animal models, pooled results of published vaccine trials reveal a very weak clinical response rate of <1% for active specific immunization procedures in colorectal cancer patients [2], and an objective response rate of 2.6% in other cancer indications, mainly among melanoma patients [3] even though about 50% of these vaccinated patients were shown to have developed CTL killer cells able to specifically recognize and kill tumor cells in-vitro.

The poor clinical results of immunotherapy vaccine approaches to cancer treatment have been attributed to tumor immunoavoidance mechanisms [4]. Tumors employ many escape strategies in order to evade immune attack. These strategies include downregulation of MHC molecules in order to hide from immune recognition [5], expression of inhibitory factors and immunosuppressive cytokines [6] [7, 8], including TGF-β [9, 10], IL-10 [11], and recruitment of regulatory immune cells CD4+CD25+FoxP3+ Tregs [12], Tr1 cells [13], tolerogenic DCs, and myeloid suppressor cells, including immature macrophages, granulocytes, DCs and other myeloid cells at earlier stages of differentiation [14, 15].

These immunoavoidance mechanisms employed by tumors render the immune system tolerant and permit tumors to grow unimpeded by immune surveillance. Establishment of this type of self-tolerance is a part of a natural immune regulatory mechanism which prevents autoimmune disease against organ-specific self-antigens. However, this beneficial effect may be responsible for tumor immune evasion as many of the tolerance mechanisms that prevent autoimmunity are the same as employed by tumors to prevent immune destruction [16, 17].

Therefore, the mechanisms of autoimmune disease serve as a model for developing strategies to break immune tolerance to tumors. A key mechanism for breaking self-tolerance and induction of autoimmunity is related to inflammation [18].  Autoimmune attack of self-tissues requires two conditions, activated T cells and the "conditioning" of the target organ by irradiation or infection [19].

In order to develop an effective immunotherapy strategy for metastatic cancer, new approaches are required that not only can create and enhance tumor-specific immunity, but also are able to counter-act the ability of the tumor to evade immune destruction.  The experimental drug, AlloStim™, is designed to break tolerance to tumor tissues by taking advantage of the known mechanisms of breaking tolerance to self tissue in autoimmune disease.  That is by providing a highly inflammatory environment in the presence of tumor tissue that has died pathologically.