SPONSOR FEATURE SPONSOR FEATURE GcMAF: our next-generation immunotherapy Authors Saisei Mirai, based in Osaka, Japan, is a immunotherapy — such as dendritic cells, Yoshihiro Uto1, Hitoshi Hori1, Kentaro medical organization specializing in cancer autologous lymphocyte-activated killer Kubo2, Masamitsu Ichihashi3, Norihiro immunotherapy. The name Saisei Mirai is (LAK) cells, autologous NK cells, mono- Sakamoto3,4, Martin Mette5, Toshio Inui2,3,5 derived from the Japanese words for regen- clonal antibodies, cancer peptide vaccines, eration and future. It is our mission to cytokines, and biological response modifiers 1 Department of Life System, Institute provide cancer patients with the latest, most (BRM) — is rapidly advancing. However of Technology and Science, Graduate effective treatments while also ensuring the in a clinical setting, the results of cancer School, The University of Tokushima, 2-1 best possible quality of life. Cancer immu- immunotherapy are mixed. Minamijosanjima-cho, Tokushima, Japan. notherapy is the use of the immune system We therefore contend that cancer immu- to reject cancer. In particular, it involves notherapy should be customized to each 2 Saisei Mirai Cell Processing Center, stimulating the patient’s immune system individual patient based on their immune Nature21 Building 3F, 3-34-8 Okubo-cho, to locate and eliminate the cells that are status. We propose our next-generation Gc Moriguchi, Osaka, Japan. cancerous. This is achieved with immune protein-derived macrophage activating fac- cells such as Natural Killer cells (NK cells), tor (GcMAF) as a promising candidate for 3 Kobe Saisei Mirai Clinic, Kobe T Lymphocytes, Dendritic Cells (DC), and a patient-friendly cancer immunotherapy. Commerce Industry and Trade Center macrophages, among others. A variety of GcMAF, also known as vitamin D binding Building 23F, 5-1-14, Hamabe-dori, treatments, such as GcMAF, Hyper T/NK protein-macrophage activating factor (DBP- Chuo-ku, Kobe, Japan. cells, Coley vaccine, gene therapy, cancer maf), is a potent endogenous macrophage vaccines, and intravenous high-dose vita- activator found naturally in the blood. Until 4 Division of Food and Drug Evaluation min C or α-lipoic acid are routinely used to recently, GcMAF was not used in cancer Science, Department of Community stimulate the immune system. immunotherapy in spite of it being a key Medicine and Social Healthcare Science, The immune system is the body’s vital player of our innate immune system. Kobe University Graduate School of self defense that protects against disease. It We will review first-generation GcMAF Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, can recognize a wide variety of pathogens developed by Dr Yamamoto and second- Kobe, Japan found in the environment and even tumor generation GcMAF currently under devel- cells borne within the human body. The opment at Saisei Mirai (Fig. 1). We will also 5 Inui Immunotherapy Clinic, 6-14-17 mechanisms of protection fall into two broad present a number of other therapies used in Kindacho, Moriguchi, Osaka, Japan. categories — innate immunity and adaptive combination with GcMAF. immunity. There are several types of cells At Saisei Mirai, we are currently treating in the innate immune system: phagocytic cancer patients with GcMAF-based cancer neutrophils; macrophages; dendritic cells; immunotherapy. We use GcMAF in combi- mast cells; and natural killer (NK) cells. The nation with other immune system-related adaptive immune system is comprised of the therapies, such as regional and whole-body lymphocytes, both T cells and B cells, which hyperthermia, Coley vaccine, which stimu- are able to recognize and remember specific lates fever within the body, and Hyper-T/ pathogens, and their products, including NK-cell therapy. All of these therapies are antibodies. about strengthening the immune system The progression of many diseases, such and take a holistic approach to fighting as cancer and AIDS, follows the collapse cancer rather than a localized approach that of the immune system. We now know is common with conventional therapies such that stimulating the immune system as radiation and surgery. can halt or even reverse such diseases. Immunotherapy has become an attractive Coley vaccine new strategy in the treatment of cancer1. Coley vaccine — also known as Coley’s The laboratory and clinical study of cancer Toxins and Coley Fluid — was one of the SPONSOR RETAINS SOLE RESPONSIBILITY FOR CONTENT © 2012 Macmillan Publishers Limited. All rights reserved SPONSOR FEATURE first immunotherapies to enter the clinic. Coley-vaccine therapy is a medical treat- ment used to induce a fever to improve the immunological competence of the patient. For hundreds of years, doctors have reported cases of tumors that disappeared, apparently spontaneously after patients developed high SPONSOR FEATURE fevers from infection. In many cases, when fever subsided, tumors had broken down and been absorbed or sloughed off. Infection seemed to be key to these miraculous cures. It was not until 1893 when Dr William Coley began injecting a sterile mixture of Streptococcus pyogenes and Serratia marcescens bacteria into cancer patients to induce fevers, that this observation was put into clinical practice. By using a suspension of killed bacteria, Coley was able to mimic an acute infection, without the risks of an actual pathogen. Hyperthermia Hyperthermia heat therapy, also called Figure 1: Research map of Gc protein and GcMAF. First-generation GcMAF developed by thermotherapy, is the application of heat to Dr Nobuto Yamamoto. Second-generation GcMAF proposed by Dr Yoshihiro Uto, Dr. Hitoshi the body in order to treat a medical condi- Hori, DrToshio Inui and Dr Kentaro Kubo. tion (Fig 2). It is used to activate a patient’s immunological competence and is often utilized in combination with other medical treatments at Saisei Mirai. At Saisei Mirai a patient can select from a wide range of suitable and compassionate integrative medical treatments in consulta- tion with doctors experienced with cancer immunotherapy. Recently, immunotherapy treatments are being administered to people living with with infections, such as HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV). Saisei Mirai has a rich history in cancer research. It has collaborated with a num- ber of renowned research centers such as Tokushima University, Kagoshima University Figure 2: Whole body hyperthermia. This equipment can heat tumors within the patient’s and Kobe University and has contributed body with a special heat control system. significantly to the clinical application of new cancer therapies. and has been demonstrated to have anti- with these clinical trials: there were no clear angiogenic and anti-tumor activity in vivo5. classifications of patients’ histopathological Discovery and basic study of fi rst- GcMAF also directly inhibits proliferation types, grades, and stages, and the curative generation GcMAF and migration of human prostate cancer judgment was based solely on a patient’s GcMAF, discovered by Dr Nobuto Yamamoto cells or human breast cancer cells independ- N-acetylgalactosaminidase (Nagalase) activ- in 1991, is derived from the group specific ent of its macrophage activation ability6. ity, and neither tumor markers or cytokine component (Gc) protein (vitamin D binding levels were measured, and there was no protein), a member of the albumin super- Clinical study of fi rst-generation control group. family2. GcMAF is an interesting serum gly- GcMAF for cancer and HIV There is also an interesting clinical report coprotein with various biological activities. treatment of HIV treatment using GcMAF10. The It is reported that during an inflammatory Clinical trials using GcMAF in patients with weekly administration of 100 ng of GcMAF response, β-galactosidase of an activated metastatic breast cancer7, prostate cancer8, to 15 non-anemic HIV-infected patients B-cell and sialidase of a T-cell hydrolyze and metastatic colorectal cancer9 have been showed that the number of CD4+ cells the terminal galactose and sialic acid sac- conducted. Cancer did not recur over a four increased to normal levels within 6 weeks, charides of Gc protein to produce GcMAF3. to seven year period in all subjects adminis- and were maintained for the entire 7 years GcMAF has interesting biological activity; it trated weekly doses of 100 ng of GcMAF for after GcMAF therapy, while the number activates macrophages via superoxide radi- 7 to 19 weeks; a result that took everyone by of CD8+ cells decreased to normal levels, cal generation and phagocytic activation4, surprise. However, there are some problems and the amount of HIV-1 RNA and p24 SPONSOR RETAINS SOLE RESPONSIBILITY FOR CONTENT © 2012 Macmillan Publishers Limited. All rights reserved SPONSOR FEATURE antigen were detectable in these patients blood stream. It is believed that this posi- tive effect resulted from GcMAF-activated macrophages phagocytosizing and destroy- ing the HIV virus. GcMAF was active in the monocytes/macrophages isolated from AIDS 11 SPONSOR FEATURE patients . Pharmaceutical development of first-generation GcMAF for immunotherapy There is little or no research being con- ducted on the pharmaceutical develop- ment of GcMAF as a biological drug. The pharmaceutical development of GcMAF with its high homogeneity and purity from human serum is very difficult owing to its parent Gc protein having six major subtypes, namely homodimer or heterodimer of 1f, 1s, and 2, each with a different sugar moiety (Fig. 3). In order to overcome