Jungbluth AA, Ely S, DiLiberto M, Niesvizky R, Williamson B, Frosina D et al.The cancer-testis antigens CT7 (MAGE-C1) and MAGE-A3/6 are commonly expressed in multiple myeloma and correlate with plasma-cell proliferation. Blood 106:167-174

Cornell University, Итак, New York, United States
Blood (Impact Factor: 10.45). 08/2005; 106(1):167-74. DOI: 10.1182/blood-2004-12-4931
Source: PubMed


Multiple myeloma is a malignancy of plasma cells. Vaccine immunotherapy is among the novel therapeutic strategies under investigation for this disease. To identify myeloma-associated antigens as potential targets for vaccine immunotherapy, we surveyed a comprehensive panel of bone marrow specimens from patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma for expression of cancer-testis (CT) antigens. Immunohistochemistry (IHC) demonstrated that 82% of stage-III myeloma specimens expressed the CT antigen CT7 (also known as melanoma antigen C1 [MAGE-C1]) and 70% expressed MAGE-A3/6. Messenger RNA for CT7 and MAGE-A family members was detected in 87% and 100% of stage-III samples, respectively. CT7 protein expression increased with advanced stage of disease. Higher levels of CT7 and MAGE-A3/6 proteins also correlated with elevated plasma-cell proliferation. These results show that CT7 and MAGE-A3/6 are promising myeloma-associated antigens for application in vaccine immunotherapy. Furthermore, the common expression and correlation with proliferation suggest a possible pathogenic role for these proteins in myeloma.

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Available from: Achim A Jungbluth
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    • "The expression of MAGE-A3 is correlated with the frequency of proliferating malignant cells [17]. MAGE-A3 has ability to inhibit apoptosis through repression of BAX protein by inhibition of p53-dependent up-regulation and maintenance of survivin expression [18]. "
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    ABSTRACT: The modifications of the immune system with immunomodulatory drugs or monoclonal antibodies are still insufficient to obtain long-lasting complete remissions in most of the multiple myeloma patients (MM). Peptide-based immunotherapy combined with an autologous hematopoietic stem cell transplantation, immunomodulatory drugs or monoclonal antibodies might represent novel therapeutic strategies, that might retain immune control on disease development and progression resulting in prolonged overall survival. New epitopes derived from tumor-associated antigens (TAA), that are able to induce strong and long-term immune response against MM cells are under investigation. Peptide modifications or targeting multiple epitopes on MM cells could efficiently induce stronger immune response in comparison with single and natural antigens. In this work we have summarized the results of latest studies regarding characterization of TAA that could be used as targets for peptide-based immunotherapy as well as clinical trials utilizing peptide immunotherapy in MM.
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    • "The cancer/testis MAGE-A3 tumor antigen is a potential target for cancer immunotherapy, as it is specifically expressed in various tumor types, including melanoma, non-small cell lung cancer or bladder cancer (Brasseur et al., 1995; De Pas et al. 2009; Knuth et al., 1989; Patard et al., 1995; Sharma et al., 2006; Van den Eynde and van der Bruggen, 1997; van der Bruggen et al., 2002; Yin et al., 2012). The only normal adult human cells expressing MAGE-A3 are male germ cells and trophoblast cells of the placenta; however, in these cells the lack of classical class I (A, B and C) human leukocyte antigen expression should prevent antigen presentation, excluding the potential risk of developing an immune-related toxicity upon MAGE- A3 immunotherapy (Jungbluth et al., 2005; Scanlan et al., 2002). Although spontaneous immune responses against tumor antigens have been reported, these antigens are usually poorly immunogenic and may not elicit immune responses sufficient to eradicate tumor cells (Lasaro and Ertl, 2010). "
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    ABSTRACT: The MAGE-A3 recombinant protein combined with AS15 immunostimulant (MAGE-A3 Cancer Immunotherapeutic) is under development by GlaxoSmithKline for the treatment of lung cancer and melanoma. We performed non-clinical safety studies evaluating potential local and systemic toxic effects induced by MAGE-A3 Cancer Immunotherapeutic in rabbits (study 1) and cynomolgus monkeys (study 2). Animals were allocated to two groups to receive a single (rabbits) or 25 repeated (every 2 weeks) injections (monkeys) of MAGE-A3 Cancer Immunotherapeutic (treatment groups) or saline (control groups). All rabbits were sacrificed 3 days post-injection and monkeys 3 days following last injection (3/5 per gender per group) or after a 3-month treatment-free period (2/5 per gender per group). Local and systemic reactions and MAGE-A3-specific immune responses (monkeys) were assessed. Macroscopic and microscopic (for rabbits, injection site only) post-mortem examinations were performed on all animals. No systemic toxicity or unscheduled mortalities were recorded. Single (rabbits) and repeated (monkeys; up to four times at the same site) injections were well tolerated. Following five to seven repeated injections, limb circumferences increased up to 26% (5 h post-injection), but returned to normal after 1–8 days. Three days after the last injection, enlargements of iliac, popliteal, axillary and inguinal lymph nodes, and increased incidence or severity of mononuclear inflammatory cell infiltrates was observed in injected muscles of treated monkeys. No treatment-related macroscopic findings were recorded after the treatment-free period. MAGE-A3-specific antibody and T-cell responses were raised in all treated monkeys, confirming test item exposure. Single or repeated intramuscular injections of MAGE-A3 Cancer Immunotherapeutic were well tolerated in rabbits and monkeys. Copyright © 2014 GlaxoSmithKline Vaccines. Journal of Applied Toxicology published by John Wiley & Sons, Ltd.
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    • "This finding suggested that patients expressing multiple and/or high levels of CT antigens had a higher load of myeloma cells. Previous results had demonstrated that the MAGE-C1/CT7 and MAGE-A3 were expressed in isolated plasma cells using anti-CD138–conjugated magnetic beads [15], and the expression levels of both genes were associated with the numbers of CD138-positive plasma cells. "
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    ABSTRACT: Cancer-testis (CT) antigen genes might promote the progression of multiple myeloma (MM). CT antigens may act as diagnostic and prognostic markers in MM, but their expression levels and clinical implications in this disease are not fully understood. This study measured the expression levels of four CT antigen genes in Chinese patients with MM and explored their clinical implications. Real-time quantitative polymerase chain reaction (qPCR) was used to quantify the expression of MAGE-C1/CT7, MAGE-A3, MAGE-C2/CT10 and SSX-2 mRNA in 256 bone marrow samples from 144 MM patients. In the newly diagnosed patients, the positive expression rates were 88.5% for MAGE-C1/CT7, 82.1% for MAGE-C2/CT10, 76.9% for MAGE-A3 and 25.6% for SSX-2. The expression levels and the number of co-expressed CT antigens correlated significantly with several clinical indicators, including the percentage of plasma cells infiltrating the bone marrow, abnormal chromosome karyotypes and the clinical course. MAGE-C1/CT7, MAGE-A3, MAGE-C2/CT10 and SSX-2 expression levels provide potentially effective clinical indicators for the auxiliary diagnosis and monitoring of treatment efficacy in MM.
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