IngentaConnect Immunotherapy of metastatic colorectal cancer with vitamin D-bind...

Authors: Yamamoto, Nobuto¹; Suyama, Hirofumi²; Nakazato, Hiroaki³; Yamamoto, Nobuyuki⁴; Koga, Yoshihiko⁵

Source: Cancer Immunology, Immunotherapy, Volume 57, Number 7, July 2008 , pp. 1007-1016(10)

Publisher: Springer

Abstract:

Serum vitamin D binding protein (Gc protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of colorectal cancer patients was lost or reduced because Gc protein is deglycosylated by serum α-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Deglycosylated Gc protein cannot be converted to MAF, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized β-galactosidase and sialidase generated the most potent macrophage-activating factor (GcMAF) ever discovered, but it produces no side effect in humans. Macrophages treated with GcMAF (100 pg/ml) develop an enormous variation of receptors and are highly tumoricidal to a variety of cancers indiscriminately. Administration of 100 nanogram (ng)/human maximally activates systemic macrophages that can kill cancerous cells. Since the half-life of the activated macrophages is approximately 6 days, 100 ng GcMAF was administered weekly to eight nonanemic colorectal cancer patients who had previously received tumor-resection but still carried significant amounts of metastatic tumor cells. As GcMAF therapy progressed, the MAF precursor activities of all patients increased and conversely their serum Nagalase activities decreased. Since serum Nagalase is proportional to tumor burden, serum Nagalase activity was used as a prognostic index for time course analysis of GcMAF therapy. After 32-50 weekly administrations of 100 ng GcMAF, all colorectal cancer patients exhibited healthy control levels of the serum Nagalase activity, indicating eradication of metastatic tumor cells. During 7 years after the completion of GcMAF therapy, their serum Nagalase activity did not increase, indicating no recurrence of cancer, which was also supported by the annual CT scans of these patients.

Keywords: Colorectal cancer; Macrophages; Macrophage-activating factor; Immunotherapy; Deglycosylation; α-N-acetylgalactosaminidase; Immunosuppression

Document Type: Research article

DOI: 10.1007/s00262-007-0431-z

Affiliations: 1: Division of Cancer Immunology and Molecular Immunology, Socrates Institute for Therapeutic Immunology, Philadelphia, PA, 19126, USA, Email: nobutoyama@verizon.net 2: Nagasaki Immunotherapy Research Group, Yokoh, Nagasaki, Japan 3: Yokoyama Gastroenterology Hospital, Nagoya, Japan 4: Division of Cancer Immunology and Molecular Immunology, Socrates Institute for Therapeutic Immunology, Philadelphia, PA, 19126, USA 5: Nakagawa Hospital, Fukuoka City, 811-1345, Japan

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Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF