Weekly cycles of intradermal and intravenous AlloStim® infusions can create amplifying waves of innate immune activation, followed by in-situ vaccination and tumor-specific adaptive immunity.
AlloStim® is living, activated, intentionally mismatched foreign Th1-like cells derived from healthy blood donors. These living and activated cells express cytokines, such as interferon-gamma and GM-CSF and surface markers such as CD40L The immune system is alerted to these living foreign cells which triggers a powerful immune response to reject them. When AlloStim® is injected under the skin, these foreign cells attract an immune rejection response, mostly from resident NK cells and macrophages. The rejection causes the release of the internal contents of the AlloStim®, including HSP-chaperoned alloantigens and ‘danger signals’. Langerhans’s cells (local APC) in the skin process the released HSP and present the alloantigens on both MHC I and MHC II. The local danger signals and inflammatory cytokines support the differentiation and maturation of the APC to DC1 IL-12+ phenotype and upregulation of co-stimulatory and MHC molecules. These mature DC1 traffic to a draining lymph node. In the lymph node, a T-cell response (both CD8/CTL and CD4/Th1) is initiated which activates anti-alloantigen immunity. Each time the AlloStim® is injected in the skin, this T-cell response is amplified, increasing the systemic titer of allo-specific Th1 cells.
The increase in systemic allo-specific Th1/CTL immune cells releases inflammatory cytokines which non-specifically activate innate NK cells and memory T-cells. These activated NK cells and memory T-cells traffic to sites of inflammation, including metastatic tumors. Within the tumor, the activated NK cells and memory cells can non-specifically lyse tumor cells. NK cells detect tumors that have down-regulated MHC I molecules to avoid immune recognition for elimination. The NK cells produce cytokines in the local tumor microenvironment which upregulate ‘death receptors’, on tumors (e.g. FAS-FASL, TRAIL/TRAIL-L, TWEAK/TWEAK-L). Thus both NK cells and activated T-cells can act to lyse tumor cells by necrosis (immunological cell death). In the context of ‘danger signals’, local DC in the microenvironment process released HSP-chaperoned tumor neoantigens. This initiates an ‘in-situ vaccine’ process that leads to tumor-specific memory.
The intravenous infusion of AlloStim® in subjects primed with intradermal AlloStim® injections causes a non-toxic ‘cytokine storm’ and increases the infiltration of memory immune cells into the tumor microenvironment, changing “cold” tumors to “hot” tumors. The infiltrating memory immune cells change the tumor microenvironment to down-regulate suppression and upregulate inflammation permitting immune-mediate tumor killing.