Abstract 5532: Immunotherapy of breast cancer with Gc protein-derived macrophage activating factor, GcMAF
Authors: Nobuto Yamamoto, Masumi Ueda, Kazuya Hashinaka
Journal: Cancer Research (2011)

Abstract Serum Gc protein (known as vitamin D-binding protein) is the precursor for the principal macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of cancer patients was lost or reduced because Gc protein was deglycosylated by serum α-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Thus, serum Nagalase activity is directly proportional to tumor burden. Macrophages of cancer patients having deglycosylated Gc protein cannot be activated. Since macrophage activation for phagocytosis and antigen-presentation to B cells and T cells is the first indispensable step for development of both humoral and cellular immunities, lack of macrophage activation leads to immunosuppression. Advanced cancer patients have high serum Nagalase activity, resulting in no macrophage activation and severe immunosuppression that explain why cancer patients die with overwhelming infection (e.g., pneumonia). Stepwise treatment of purified Gc protein with immobilized β-galactosidase and sialidase generated probably the most potent macrophage activating factor (termed GcMAF) ever discovered. Because GcMAF is structurally identical to the native human MAF, GcMAF produces no side effect in humans. Macrophages activated by GcMAF develop an enormous variation of receptors that recognize the abnormality in malignant cell surface and are highly tumoricidal to a variety of cancers indiscriminately. When human macrophages were treated in vitro with GcMAF (100 picogram/ml) for 3 hr and a breast cancer cell line MCF-7 was added with effector/target ratio of 1.5, 60% and 86% of MCF-7 cells were killed in 4 hr and 18 hr incubation, respectively. Administration of 100 nanogram (ng) GcMAF per human results in the maximal level of macrophage activation. Because the activated state of macrophages is approximately 6 days, sixteen breast cancer patients received weekly administration of 100 ng GcMAF. They regressed in biphasic pattern due to the mixed population of undifferentiated and differentiated cells. After 16-23 weekly administrations of GcMAF (100 ng/week), all sixteen patients had very low serum Nagalase levels equivalent to those of healthy control values, indicating that these patients are tumor free. No recurrence occurred for more than ten years. GcMAF also has a potent mitogenic capacity to act on the myeloid progenitor cells, resulting in a 40-fold increase in systemic macrophage cell counts in 4 days. Such highly activated systemic macrophages are chemotactically recruited to inflamed lesions by 180-fold increase of macrophage cell counts. Since intravenous administration of GcMAF allows a rapid interaction of GcMAF with myeloid progenitor cells in bone marrow, the systemic cell counts of the activated macrophages increased to more than 100-fold in 2 days. Weekly intravenous administration of 100 ng GcMAF to metastatic breast cancer patients (n=8) eradicates tumors in 7-15 weeks. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5532. doi:10.1158/1538-7445.AM2011-5532