Eradication of prostate cancer by immunotherapy using the most potent macrophage activating factor, GcMAF

Abstract

1869

Highly activated macrophages are tumoricidal. Inflammation-derived macrophage activation is the principal macrophage activation process that requires serum vitamin D-binding protein (known as Gc protein) and participation of B and T lymphocytes. A trisaccharide composed of N-acetylgalactosamine with dibranched galactose and sialic acid termini at 420 threonine residue of Gc protein is hydrolyzed by the inducible ß-galactosidase (Bgl) of inflammation-primed B cells and the Neu-1 sialidase of T cells to yield the macrophage activating factor (MAF). Thus, Gc protein is the precursor for the principal MAF. However, the MAF precursor activity of Gc protein of cancer patients was lost or reduced because Gc protein is deglycosylated by serum α-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells but not from healthy cells. Thus, serum Nagalase activity is proportional to tumor burden and serves as a prognostic index. Exogenously given macrophage activating factor can bypass deglycosylated serum Gc protein and directly acts on macrophages for activation. Stepwise treatment of highly purified Gc protein with immobilized ß-galactosidase and sialidase generated the most potent macrophage activating factor (GcMAF) ever discovered which produces no side effect in humans. Administration of 100 ng GcMAF per human results in the maximal activation of systemic macrophages, which develop enormous variation of receptors that recognize a variety of abnormalities, i.e., tumor associated antigens, in cancerous cell surface. When sixteen nonanemic prostate cancer patients were treated with 14-25 weekly administrations of 100 ng GcMAF (intramuscularly once a week), all cancer patients exhibited healthy control levels of the serum Nagalase activity, indicating eradication of tumors. During two years after GcMAF therapy, their serum Nagalase activity did not increase, indicating no recurrence. Poorly differentiated (termed undifferentiated) cancer cells should have more abnormality in cell surface than moderately or immediate differentiated (differentiated for short) cancer cells. Since the activated macrophages efficiently recognize and kill cancer cells having more abnormality, the activated macrophages cure patients with undifferentiated tumors more rapidly than those with differentiated tumors. However, the serum Nagalase activity of the majority of patients decreased rapidly in the first few weeks (up to 4 weeks) and followed by slow decrease during remaining therapeutic period (10-20 weeks). The result suggests that undifferentiated cells were mixed with differentiated cells in same tumor. These mixed cell population appeared to be developed by differentiation during growth of the undifferentiated tumor cells.