Macrophage Activation May Suppress Breast Cancer Metastasis
By David Douglas
NEW YORK FEB 20, 2008 (Reuters Health) – Vitamin D-binding protein-derived macrophage activating factor (Gc-MAF) appears to be an effective immunotherapeutic agent in patients with metastatic breast cancer, according to US and Japanese researchers.
“Serum vitamin D-binding protein – known as Gc protein – is the precursor of the principal macrophage activating factor,” lead investigator Dr. Nobuto Yamamoto told Reuters Health.
“Treatment of purified Gc protein with beta-galactosidase and sialidase generates Gc-MAF,” he added, “the most potent macrophage activating factor ever discovered, which produces no side effect in humans.”
Dr. Yamamoto of the Socrates Institute for Therapeutic Immunology, Philadelphia and colleagues note that in vitro studies show that macrophages treated with Gc-MAF have a highly tumoricidal effect in mammary adenocarcinomas.
To investigate whether the approach can be effective in humans, the researchers studied 16 non-anemic breast cancer patients who were given “a minute amount – 100 nanograms per week – of Gc-MAF,” Dr. Yamamoto said.
The researchers found that after 16 to 22 Gc-MAF doses, initially elevated nagalase levels, which reflect the tumor burden, fell to those found in healthy controls. Follow-up over 4 years showed that the level remained low and that there was no tumor recurrence, they report in the January 15th issue of The International Journal of Cancer.
The findings, the team concludes, clearly demonstrate “the importance of focusing cancer immunotherapy on macrophage activation.”
International Journal Cancer. 2008 Jan 15; 122(2):461-7.
Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (Gc-MAF).
Yamamoto N, Suyama H, Yamamoto N, Ushijima N.
Division of Cancer Immunology and Molecular Biology, Socrates Institute for Therapeutic Immunology, Philadelphia, PA 19126-3305, USA. firstname.lastname@example.org
Serum vitamin D3-binding protein (Gc protein) is the precursor for the principal macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of breast cancer patients was lost or reduced because Gc protein was deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Patient serum Nagalase activity is proportional to tumor burden. The deglycosylated Gc protein cannot be converted to MAF, resulting in no macrophage activation and immunosuppression. Stepwise incubation of purified Gc protein with immobilized beta-galactosidase and sialidase generated probably the most potent macrophage activating factor (termed Gc-MAF) ever discovered, which produces no adverse effect in humans. Macrophages treated in vitro with Gc-MAF (100 pg/ml) are highly tumoricidal to mammary adenocarcinomas. Efficacy of Gc-MAF for treatment of metastatic breast cancer was investigated with 16 nonanemic patients who received weekly administration of Gc-MAF (100 ng). As Gc-MAF therapy progresses, the MAF precursor activity of patient Gc protein increased with a concomitant decrease in serum Nagalase. Because of proportionality of serum Nagalase activity to tumor burden, the time course progress of Gc-MAF therapy was assessed by serum Nagalase activity as a prognostic index. These patients had the initial Nagalase activities ranging from 2.32 to 6.28 nmole/min/mg protein. After about 16-22 administrations (approximately 3.5-5 months) of Gc-MAF, these patients had insignificantly low serum enzyme levels equivalent to healthy control enzyme levels, ranging from 0.38 to 0.63 nmole/min/mg protein, indicating eradication of the tumors. This therapeutic procedure resulted in no recurrence for more than 4 years. Copyright 2007 Wiley-Liss, Inc.
Cancer Immunology, Immunotherapy 2008 July 57 (7): online
Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, Gc-MAF
Nobuto Yamamoto, Hirofumi Suyama, Hiroaki Nakazato, Nobuyuki Yamamoto and Yoshihiko Koga
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 (Gc-MAF) ever discovered, but it produces no side effect in humans. Macrophages treated with Gc-MAF (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 Gc-MAF 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 Gc-MAF 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 Gc-MAF therapy. After 32–50 weekly administrations of 100 ng Gc-MAF, 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 Gc-MAF 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.
May 22, 2008