Gene Summary

Gene:MAGEA3; MAGE family member A3
Aliases: HIP8, HYPD, CT1.3, MAGE3, MAGEA6
Summary:This gene is a member of the MAGEA gene family. The members of this family encode proteins with 50 to 80% sequence identity to each other. The promoters and first exons of the MAGEA genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under different transcriptional controls. The MAGEA genes are clustered at chromosomal location Xq28. They have been implicated in some hereditary disorders, such as dyskeratosis congenita. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:melanoma-associated antigen 3
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
MAGEA3 is implicated in:
- protein binding
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: MAGEA3 (cancer-related)

Chen X, Cai S, Wang L, et al.
Analysis of the function of MAGE-A in esophageal carcinoma by bioinformatics.
Medicine (Baltimore). 2019; 98(21):e15774 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Melanoma-associated antigen-A (MAGE-A) was recognized as high-expressed in many solid tumors including esophageal carcinoma (EC), nevertheless, was reported to be low/not-expressed in normal tissues. Thus, it was considered as an extraordinary appropriate target for treatment especially in immunotherapy. Therefore, it demanded more detail knowledge on the precise function of MAGE-A.
METHODS: In this study, we used the data from the Cancer Genome Atlas dataset (TCGA-ESCA) to analyze the expression and survival for MAGE A3/4/11 (the subtype of MAGE-A) using the online tool of UALCAN. Furthermore, the high-throughput sequencing data of the patients with esophageal squamous-cell carcinoma (ESCC) from TCGA dataset were performed to analyze the correlation test, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of MAGE A3/4/9/11 using LinkeDomics (online tool) and ClueGO (inner software of Cytoscape). Finally, relative gene expressions of MAGE A3/4/9/11 were verified by quantitative real-time PCR (q-PCR) in the patients with EC.
RESULTS: MAGE A3/4/11 was high-expressed in tissues of patients with ESCC, and there was no difference in survival time for patients between the high-expressed with the low/medium-expressed. The Go enrichment analysis showed that the 4 MAGE-A subtypes (MAGE-A3/4/9/11) were enriched in the regulation of the adaptive immune response, translational initiation, interleukin-4 production, response to type I interferon, and skin development, respectively. The KEGG results showed that they were enriched in T cell receptor signaling pathway (MAGE-A3), Th1 and Th2 differentiation, antigen processing and presentation (MAGE-A4), cytokine-cytokine receptor interaction (MAGE-A9), and chemokine signaling pathway (MAGE-A11).
CONCLUSION: MAGE A3/4/9/11 was high-expressed in EC, and were enrolled in the regulation of immune response. They may consider as candidate immune target for EC treatment and provided the messages for further research in the function of MAGE-A.

Shi X, Chen X, Fang B, et al.
Decitabine enhances tumor recognition by T cells through upregulating the MAGE-A3 expression in esophageal carcinoma.
Biomed Pharmacother. 2019; 112:108632 [PubMed] Related Publications
Cancer testis (CT) antigens are expressed in various types of tumors and represent the potential targets for T cell-based immunotherapy. Analysis of CT gene expression and DNA methylation have indicated that certain CT genes are epigenetically regulated and studies have confirmed that certain CT antigens are regulated by DNA methylation. In this study, we explored the epigenetic regulation of MAGE-A3 and improved the clinical outcome of MAGE-A3-specific T cell therapy in esophageal squamous cell carcinoma (ESCC). We used molecular profiling datasets in The Cancer Genome Atlas to analyze CT gene expression in ESCC and its regulation by DNA methylation. We performed quantitative reverse transcription PCR (qRT-PCR), immunohistochemistry and bisulfite sequencing in ESCC cell lines and ESCC tissues. Functional assays, such as flow cytometry, cytotoxicity assays and ELISA, were performed to determine the demethylation agent, decitabine (5-aza-2'-deoxycytidine, DAC)-treated cancer cell improved antigen specific T cells response. ESCC tumor cell-xenograft mouse model and enzyme-linked immunospot (ELISPOT) assays were used to determine the function of DAC treatment in enhancing anti-MAGE-3 T cell responses in ESCC. Furthermore, we performed qRT-PCR and flow cytometry in the peripheral blood mononuclear cells (PBMC) of myelodysplastic syndromes (MDS) patients. MAGE-A3, one of the CT antigens, expressed at various levels in ESCC and was interfered by DNA methylation. We observed an efficient increase in MAGE-A3 expression in tumor cells and tissues after the treatment of decitabine and the expression of MAGE-A3 was affected by DNA methylation. Functional assays showed enhanced secretion of IFN-γ and cytolysis of MAGE-A3 antigen-specific T cells by DAC-treated target cells. In the tumor cell-xenograft mouse model and ELISPOT assays, DAC increased the expression of MAGE-A3 and T cell mediated tumor clearance in ESCC as well. Notably, the proportions of MAGE-A3-responsive T cells were elevated in DAC-treated patients with MDS, indicating DAC dismissed the epigenetic inhibition of MAGE-A3. DAC would probably improve the clinical outcome of MAGE-A3-specific T cell therapy by augmenting the expression of target gene.

Wang Y, Song X, Zheng Y, et al.
Cancer/testis Antigen MAGEA3 Interacts with STAT1 and Remodels the Tumor Microenvironment.
Int J Med Sci. 2018; 15(14):1702-1712 [PubMed] Free Access to Full Article Related Publications
Cancer-testis antigen MAGEA3, being restrictedly expressed in testis and various kinds of tumors, has long been considered as an ideal target for immunotherapy. In this study, we report that MAGEA3 interacts with STAT1 and regulates the expression of tyrosine phosphorylated STAT1 (pY-STAT1) in tumor cells. We show that pY-STAT1 is significantly up-regulated when MAGEA3 is silenced by MAGEA3-specific siRNA. RNA sequencing analysis identified 274 STAT1-related genes to be significantly altered in expression level in MAGEA3 knockdown cells. Further analysis of these differentially expressed genes with GO enrichment and KEGG pathway revealed that they are mainly enriched in plasma membrane, extracellular region and MHC class I protein complex, and involved in the interferon signaling pathways, immune response, antigen presentation and cell chemotaxis. The differentially expressed genes associated with chemokines, antigen presentation and vasculogenic mimicry formation were validated by biological experiments. Matrigel matrix-based tube formation assay showed that silencing MAGEA3 in tumor cells impairs tumor vasculogenic mimicry formation. These data indicate that MAGEA3 expression in tumor cells is associated with immune cells infiltration into tumor microenvironment and anti-tumor immune responses, implying that it may play an important role in tumor immune escape. Our findings reveal the potential impact of MAGEA3 on the immunosuppressive tumor microenvironment and will provide promising strategies for improving the efficacy of MAGEA3-targeted immunotherapy.

Vodolazhsky DI, Kutilin DS, Mogushkova KA, Kit OI
Specific Features of Transcription Activity of Cancer-Testis Antigens in Patients with Metastatic and Non-Metastatic Breast Cancer.
Bull Exp Biol Med. 2018; 165(3):382-385 [PubMed] Related Publications
Cancer-testis antigens, effective markers of tissue malignant transformation, are characterized by heterogonous transcription depending on the pathological features of breast cancer. We performed screening of transcription profile of cancer-testis antigens specific for breast tumor tissues in female patients with and without regional metastasis. The relative expression of 16 genes (MAGEA1, MAGEA2, MAGEA3, MAGEA4, MAGEB1, MAGEB2, GAGE1, GAGE3, GAGE4, MAGEC1, BAGE, XAGE3, NY-ESO1, SSX2, SYCP1, and PRAME1) was analyzed by RT-qPCR method in biopsy specimens of the mammary gland tissues obtained during surgery from 25 patients. Differential transcription activity of cancer-testis antigens genes was observed in patients with metastatic (enhanced expression of MAGEA2, MAGEB1, and XAGE3 genes) and non-metastatic (enhanced expression of GAGE3 and PRAME1 genes) breast cancer.

Dreno B, Thompson JF, Smithers BM, et al.
MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial.
Lancet Oncol. 2018; 19(7):916-929 [PubMed] Related Publications
BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting.
METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with, number NCT00796445.
FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment.
INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped.
FUNDING: GlaxoSmithKline Biologicals SA.

Fan PW, Huang L, Chang XM, et al.
Human Leukocyte Antigen-A Allele Distribution in Nasopharyngeal Carcinoma Patients Showing Anti-Melanoma-Associated Antigen A or Synovial Sarcoma X-2 T Cell Response in Blood.
Chin Med J (Engl). 2018; 131(11):1289-1295 [PubMed] Free Access to Full Article Related Publications
Background: Development of innovative immunotherapy is imperative to improve the poor survival of the nasopharyngeal carcinoma (NPC) patients. In this study, we evaluated the T cell response to melanoma-associated antigen (MAGE)-A1, MAGE-A3, or synovial sarcoma X-2 (SSX-2) in the peripheral blood of treatment-naive NPC patients. The relationship of responses among the three proteins and the human leukocyte antigen (HLA)-A types were analyzed to provide evidence of designing novel therapy.
Methods: Sixty-one NPC patients admitted into the Tumor Hospital affiliated to the Xinjiang Medical University between March 2015 and July 2016 were enrolled. Mononuclear cells were isolated from the peripheral blood before any treatment. HLA-A alleles were typed with Sanger sequence-based typing technique. The T cell response to the MAGE-A1, MAGE-A3, or SSX-2 was evaluated with the Enzyme-Linked ImmunoSpot assay. Mann-Whitney U-test was used to compare the T cell responses from different groups. Spearman's rank correlation was used to analyze the relationship of T cell responses.
Results: HLA-A*02:01, A*02:07, and A*24:02 were the three most frequent alleles (18.9%, 12.3%, and 11.5%, respectively) among the 22 detected alleles. 31.1%, 19.7%, and 16.4% of the patients displayed MAGE-A1, MAGE-A3, or SSX-2-specific T cell response, respectively. The magnitudes of response to the three proteins were 32.5, 38.0, and 28.7 SFC/10
Conclusion: MAGE-A1, MAGE-A3, or SSX-2-specific T cell responses were detectable in a subgroup of NPC patients, the frequency and magnitude of which were correlated.

El-Wahab NM, Rashed HG, El-Sherif WT, et al.
Glypican-3 and Melanoma Antigen Genes 1 and 3 as Tumor Markers for Hepatocellular Carcinoma.
Egypt J Immunol. 2017; 24(2):187-200 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the commonest liver cancer; its incidence and prevalence are continuously increased. Glypican3 (GPC3), melanoma antigen-1, 3 genes (MAGE1 and 3) are tumor markers used in HCC. We evaluated their role in HCC detection and assessed their relation to tumor parameters. Three groups, HCC group, liver cirrhosis group and a control group were studied. AFP, GPC3, and MAGE1 and 3 mRNA were determined in all study subjects. Tissue GPC3 was examined in patients with HCC only. Serum AFP and GPC3 were elevated in HCC group compared to other groups (P < 0.000 and P < 0.001, respectively). AFP at cutoff 44.4ng/ml and GPC3 at cutoff 5.6µg/L resulted in 81% and 90.1% sensitivity, 73.3% and 92.6% specificity, respectively. The combined measurement of both increased the sensitivity and the specificity to 100% and 93.3%, respectively. GPC 3 was detected in tissues of 81.0% of the cases. MAGE-1 and MAGE-3 genes expression were detected in 61.9% and 52.4%, respectively in HCC cases but not in other groups. GPC3, MAGE1and 3 were increased with advanced tumor stage, size, and nodule numbers. We concluded that GPC3 is a promising diagnostic marker for HCC, and MAGE 1 and 3 could be helpful in early detection of extrahepatic metastasis of HCC.

Eber-Schulz P, Tariku W, Reibold C, et al.
Survival of breast cancer patients in rural Ethiopia.
Breast Cancer Res Treat. 2018; 170(1):111-118 [PubMed] Related Publications
PURPOSE: To describe the histopathological characteristics and survival of female breast cancer (BC) patients in a rural setting with limited access to adjuvant treatment.
METHODS: A prospective study of 107 histologically confirmed BC patients treated with surgery from 2010 to 2016 from rural parts of western Ethiopia. Referral pathology was performed, and active follow-up was conducted. Adjusted cox regression analysis (hazard ratio [HR]) was performed.
RESULTS: The median age at diagnosis was 45 (16-83) years; 57% of the patients presented with cT3/4 tumors, 71% with clinically positive lymph nodes, 21% with HER2-overexpression (Dako3+) and 68% with grade 3 tumors. Estrogen and/or progesterone receptor expressions were present in 66% and triple-negative disease in 25%. The estimated 1- and 2-year overall survival probability rates were 78 and 53%, respectively. The 2-year survival for patients with clinically positive lymph nodes was 44% compared to 73% for patients with lymph node-negative disease (HR 2.44; 95% confidence interval [95% CI] 1.19-5.02). The corresponding 2-year survival for patients with cT4 tumors was 25% versus 68% for patients with cT1-2 tumors (cT1-3 vs. cT4 HR 3.86; 95% CI 1.82-13.63). The 2-year survival for patients with hormone receptor-negative disease was 40% compared to 59% for patients with hormone receptor-positive disease (HR 1.92; 95% CI 1.06-3.47).
CONCLUSION: The majority of breast cancer patients treated with surgery in rural parts of western Ethiopia are diagnosed at advanced stage and have hormone receptor-positive disease. Nearly half of the patients die within 2 years. These findings underscore the need for provision of adjuvant hormonal therapy and for the establishment of pathology service including hormone receptor testing.

Gu L, Sang M, Yin D, et al.
MAGE-A gene expression in peripheral blood serves as a poor prognostic marker for patients with lung cancer.
Thorac Cancer. 2018; 9(4):431-438 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MAGE-A genes belong to the cancer/testis antigens family. The prognostic significance of MAGE-A expression in the peripheral blood of patients with lung cancer is unknown. Therefore, this study evaluated the expression and possible prognostic significance of MAGE-A in the peripheral blood of patients with lung cancer.
METHODS: In this study, we detected MAGE-A gene expression in the peripheral blood of 150 patients with lung cancer and 30 healthy donors using multiplex semi-nested PCR and analyzed their correlation with clinicopathological risk factors.
RESULTS: MAGE-A expression was associated with factors indicating poor prognosis. The expression of MAGE-A and each individual MAGE-A gene were also associated with low overall survival in patients with lung cancer.
CONCLUSION: The expression of MAGE-A genes in peripheral blood may act as a poor prognostic marker in patients with lung cancer.

Afsharpad M, Nowroozi MR, Mobasheri MB, et al.
Cancer-Testis Antigens as New Candidate Diagnostic Biomarkers for Transitional Cell Carcinoma of Bladder.
Pathol Oncol Res. 2019; 25(1):191-199 [PubMed] Related Publications
To evaluate the diagnostic potential of 23 candidate genes, belonging to a category of tumor-specific antigens known as cancer-testis antigens (CTAs), in transitional cell carcinoma (TCC) patients. The expression of 16 known candidate CTAs and seven testis restricted/selective genes, predominantly expressed in the testis, was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR). Urinary exfoliated cells (UECs) and cancerous tissues of 73 TCC patients were used as cases, while 25 tumor-free adjacent bladder tissue specimens along with bladder tissue specimens and UECs of five non-TCC individuals were analyzed as controls. Among the known CTAs only MAGEA3, MAGEB4, TSGA10, PIWIL2, OIP5, and ODF4 were expressed specifically in TCC tissues and UEC samples. ACTL7A, AURKC, and CGB2 were testis-restricted/selective genes that indicated specific expression in cases in comparison to controls. MAGEA3, MAGEB4, and ODF4 mRNA was detectable in more than 50% of both TCC tissues, and UEC samples. Slight differences were detected in the mRNA expression pattern of candidate genes between the UEC samples and tumor tissues. Different panels formed by combinations of these genes can show up to 95.9% and 94.5% of positivity in TCC tissues and UEC samples, respectively, suggesting their diagnostic and surveillance potential. Meanwhile the RT-PCR assay of at least MAGEA3, MAGEB4, and ODF4 may be particularly useful for diagnostic and surveillance of TCC in the form of a multi-biomarker panel.

Lin M, Liang SZ, Shi J, et al.
Circulating tumor cell as a biomarker for evaluating allogenic NK cell immunotherapy on stage IV non-small cell lung cancer.
Immunol Lett. 2017; 191:10-15 [PubMed] Related Publications
In this study, we determined the number of peripheral blood circulating tumor cells (CTCs) pre- and post-NK in patients with stage IV non- small cell lung cancer (NSCLC) as a reference for understanding the relevance of any changes to the efficacy of NK cells therapy. The patients were given one to three courses of immunotherapy. CTC numbers and CTC-related gene expression were measured in the peripheral blood of 31 patients with stage IV NSCLC at 1day before and 7 and 30d after NK cells therapy using magnetic activated cell sorting (MACS) and fluorescence activated cell sorting (FACS) combined with real-time quantitative PCR (RT-qPCR). Throughout the research, fever was the most common reaction (34.6%). The number of CTCs was 18.11±5.813, 15.13±5.984 and 10.32±5.623, respectively, and this decreased significantly over time. ΔCt values for the CTC-related genes CEA, MAGE-3 and CK18 increased significantly after NK cells infusion. The expression of CEA, CK18 and MAGE-3 decreased significantly with time after NK. CTC was a useful biomarker for evaluating the efficacy of NK cells therapy on stage IV NSCLC.

Lu YC, Parker LL, Lu T, et al.
Treatment of Patients With Metastatic Cancer Using a Major Histocompatibility Complex Class II-Restricted T-Cell Receptor Targeting the Cancer Germline Antigen MAGE-A3.
J Clin Oncol. 2017; 35(29):3322-3329 [PubMed] Free Access to Full Article Related Publications
Purpose Adoptive transfer of genetically modified T cells is being explored as a treatment for patients with metastatic cancer. Most current strategies use genes that encode major histocompatibility complex (MHC) class I-restricted T-cell receptors (TCRs) or chimeric antigen receptors to genetically modify CD8

Chen Q, Li W, Wang P, et al.
Induction of Humoral and Cellular Immune Responses in Mice by Multiepitope Vaccines Composing of Both T and B Lymphocyte Epitopes of MAGE-A3 which are Recombined into HBcAg.
Protein Pept Lett. 2017; 24(10):947-954 [PubMed] Related Publications
BACKGROUND: Melanoma-associated antigen-A3 (MAGE-A3) is a tumor specific antigen and a potential candidate for cancer immunotherapy. We had screened three immunodominant multiepitopes of MAGE-A3, and identified these multiepitope peptides had significantly higher reactivity to serum samples from gastric cancer patients. However, the immune responses of three multiepitope peptides carried by HBcAg in mice have not been investigated.
OBJECTIVES: The main objective of this study was to analyze the humoral and cellular immune responses in mice induced by these three multiepitope vaccines of MAGE-A3.
METHODS: Three multiepitopes of MAGE-A3 (MAGE-A3(EPI-1, or -2, or -3)) were respectively inserted at HBcAg major immunodominant region (HBcAg(MIR)) of the pET21a(+)/HBcAg(MIR) recombinant plasmid. These recombinant chimeras were identified by PCR, and transfected respectively into E. Coli Ressotta strain. The expression products of rHBcAg(MIR)/MAGE-A3(EPI-1, or -2, or -3) were purified respectively by Ni2+ chelated affinity column, and then confirmed by SDS-PAGE and Western-blot analysis.Purified three rHBcAg(MIR)/MAGE-A3 multiepitopes were administrated respectively into BALB/c (H-2Kd) mice by intradermal injection. The production of rHBcAg(MIR)/MAGE-A3(EPI-1, or -2, or -3) specific IgG in serum from immunized mice were measured by ELISA. Spleen cells from all immunized mice were harvested after one week of last immunization for lymphocyte proliferation assay and cytotoxic T-lymphocyte assay.
RESULTS: PCR and Sequencing analysis showed the presence of the required gene fragment in pET21a(+)/ HBcAg(MIR)/MAGE-A3(EPI-1, or -2, or -3) recombinant plasmid. Purified rHBcAg(MIR)/MAGE-A3(EPI-1, or -2, or -3) could be probed specifically by McAb of 6×his-tag. ELISA analysis indicated that serum from immunized mice with rHBcAg(MIR)/MAGE-A3(EPI-1, -2, or -3) proteins could be discerned specifically by complete MAGE-A3 protein, and high level of antibodies in immune serum were obtained, and all antibody titers could reach above 1:1600. The splenocytes from groups of rHBcAg(MIR)/MAGE-A3(EPI-1,-2, or -3), stimulated respectively with corresponding peptides showed the higher proliferative responses comparing with control groups of HBcAg(MIR) or PBS (p<0.05, respectively). Splenocytes from mice immunized with rHBcAg(MIR)/MAGE-A3 (EPI-1, or -2, or -3) could killed target cells effectively, and there were significant difference of CTL activities compared with control groups of HBcAg(MIR), or PBS (p<0.05, respectively) at any ratio of effector : target.
CONCLUSION: Our results indicated MIR in HBcAg presenting platform could present MAGE-A3 multiepitopes efficiently and induced significant humoral or cellular immunity. The immune strategy based on multiepitopeimmunization could have potential for preventing or controlling MAGE-A3 associated malignant disease.

Van Tongelen A, Loriot A, De Smet C
Oncogenic roles of DNA hypomethylation through the activation of cancer-germline genes.
Cancer Lett. 2017; 396:130-137 [PubMed] Related Publications
Global loss of DNA methylation is frequently observed in the genome of human tumors. Although this epigenetic alteration is clearly associated with cancer progression, the way it exerts its pro-tumoral effect remains incompletely understood. A remarkable consequence of DNA hypomethylation in tumors is the aberrant activation of "cancer-germline" genes (also known as "cancer-testis" genes), which comprise a diverse group of germline-specific genes that use DNA methylation as a primary mechanism for repression in normal somatic tissues. Here we review the evidence that such cancer-germline genes contribute to key processes of tumor development. Notably, several cancer-germline genes were found to stimulate oncogenic pathways involved in cell proliferation (SSX, DDX43, MAEL, PIWIL1), angiogenesis (DDX53), immortality (BORIS/CTCFL), and metastasis (CT-GABRA3). Others appear to inhibit tumor suppressor pathways, including those controlling growth inhibition signals (MAGEA11, MAGEB2), apoptosis (MAGEA2, MAGEC2), and genome integrity (HORMAD1, NXF2). Cancer-germline genes were also implicated in the regulation of tumor metabolism (MAGEA3/MAGEA6). Together, our survey substantiates the concept that DNA hypomethylation promotes tumorigenesis via transcriptional activation of oncogenes. Importantly, considering their highly restricted pattern of expression, cancer-germline genes may represent valuable targets for the development of anti-cancer therapies with limited side effects.

Laban S, Giebel G, Klümper N, et al.
MAGE expression in head and neck squamous cell carcinoma primary tumors, lymph node metastases and respective recurrences-implications for immunotherapy.
Oncotarget. 2017; 8(9):14719-14735 [PubMed] Free Access to Full Article Related Publications
Melanoma associated antigens (MAGE) are potential targets for immunotherapy and have been associated with poor overall survival (OS) in head and neck squamous cell carcinoma (HNSCC). However, little is known about MAGE in lymph node metastases (LNM) and recurrent disease (RD) of HNSCC.To assess whether MAGE expression increases with metastasis or recurrence, a tissue microarray (TMA) of 552 primary tumors (PT), 219 LNM and 75 RD was evaluated by immunohistochemistry for MAGE antigens using three monoclonal antibodies to multiple MAGE family members. Mean expression intensity (MEI) was obtained from triplicates of each tumor specimen.The median MEI compared between PT, LNM and RD was significantly higher in LNM and RD. In paired samples, MEI was comparable in PT to respective LNM, but significantly different from RD. Up to 25% of patients were negative for pan-MAGE or MAGE-A3/A4 in PT, but positive in RD. The prognostic impact of MAGE expression was validated in the TMA cohort and also in TCGA data (mRNA). OS was significantly lower for patients expressing pan-MAGE or MAGE-A3/A4 in both independent cohorts.MAGE expression was confirmed as a prognostic marker in HNSCC and may be important for immunotherapeutic strategies as a shared antigen.

Chen X, Wang L, Yue D, et al.
Correlation between the high expression levels of cancer-germline genes with clinical characteristics in esophageal squamous cell carcinoma.
Histol Histopathol. 2017; 32(8):793-803 [PubMed] Related Publications
Antigens encoded by cancer-germline genes are attractive targets for cancer immunotherapy. In this study, we aimed to evaluate the mRNA expression of cancer-germline genes, expression of the encoded proteins in patients with esophageal squamous cell carcinoma (ESCC) and their correlations with clinical characteristics. In addition, the effects of downregulation cancer-germline genes on ESCC cells were assessed in vitro. Our results showed that cancer-germline genes were frequently expressed in ESCC samples. The positive rates of in ESCC samples were: 87% of MAGE-A3, 60% of MAGE-A4, 65% of MAGE-C2, and 20% of NY-ESO-1 at mRNA level. MAGE-A3 expression was associated with age, lymph node metastasis and tumor stage (all P<0.05), while MAGE-C2 expression was only associated with tumor stage (P<0.05). Furthermore, the MAGE-A3 expressing patients had a poorer overall survival (P<0.05). Multivariate analysis identified MAGE-A3 as an independent poor prognostic marker in ESCC. In vitro assay, ESCC cell lines treated with specific siRNAs to down-regulate MAGE-A3 and MAGE-C2 resulted in decreased colony-formation and migration ability (P<0.05). Epithelial marker E-cadherin was up-regulated in siRNA-MAGE-A3/C2 cells compared to controls, whereas mesenchymal markers Vimentin, N-cadherin and Slug were downregulated (all P<0.05), suggesting a role for MAGE-A3/C2 in ESCC metastasis through inducing epithelial-mesenchymal transition. The present study revealed that cancer-germline genes and their encoded proteins were frequently expressed in ESCC tumor samples and were related to poor prognosis. Thus, cancer-germline genes may serve as useful biomarkers and potential targets for ESCC patients.

Thongprasert S, Yang PC, Lee JS, et al.
The prevalence of expression of MAGE-A3 and PRAME tumor antigens in East and South East Asian non-small cell lung cancer patients.
Lung Cancer. 2016; 101:137-144 [PubMed] Related Publications
INTRODUCTION: Treatment of non-small cell lung cancer (NSCLC) is an important and often unmet medical need regardless of the disease stage at the time of first diagnosis. Antigen-specific immunotherapy may be a feasible therapeutic option if tumor associated antigens (TAAs) that can be targeted by the patient's immune system are identified. The study objective (NCT01837511) was to investigate the expression rates of MAGE-A3 and PRAME in tumors from East Asian NSCLC patients, and the associations between TAA expression and clinico-pathologic patient characteristics.
METHODS: Archived formalin-fixed paraffin-embedded tumor tissue specimens were tested for MAGE-A3 and PRAME expression by quantitative reverse transcription polymerase chain reaction. Exploratory analyses of the impact of patient and tumor characteristics on antigen expression were performed by multivariate logistic regression analyses.
RESULTS: A total of 377 specimens were tested and a valid expression result was obtained for 86.5% and 92.6% for MAGE-A3 and PRAME, respectively. Of the specimens with valid test results, 26.4% expressed MAGE-A3, 49.9% PRAME, 20.0% both and 57.5% expressed at least one TAA. The same pattern of associations between antigen expression and patient and tumor characteristics was found for both TAAs: higher rates of antigen-positive tumors were found in squamous cell carcinomas compared to adenocarcinomas, and for smokers compared to non-smokers.
CONCLUSIONS: Expression of MAGE-A3 and PRAME suggests an association with tumor histology and the patient's smoking status. The rates of TAA-positive tumors found in these East and South East Asian NSCLC patients indicate that both antigens may serve as targets for antigen-specific immunotherapies.

Tarnowski M, Czerewaty M, Deskur A, et al.
Expression of Cancer Testis Antigens in Colorectal Cancer: New Prognostic and Therapeutic Implications.
Dis Markers. 2016; 2016:1987505 [PubMed] Free Access to Full Article Related Publications
Background. While cancer/testis antigens (CTAs) are restricted in postnatal tissues to testes and germ line-derived cells, their role in cancer development and the clinical significance of their expression still remain to be better defined. Objective. The aim of this study was to investigate the level of CTA expression in colon samples from patients with colorectal cancer (CRC) in relation to patient clinical status. Methods. Forty-five patients with newly diagnosed colorectal cancer were included in the study. We selected a panel of 18 CTAs that were previously detected in CRC as well as some new gene candidates, and their expression was detected at the mRNA level by employing RQ-PCR. Additionally, we evaluated CTA expression in three colon cancer cell lines (CL-188, HTB-39, and HTB-37) after exposure to the DNA methylation-modifying drug 5-azacytidine. Results. We report that 6 out of 18 (33%) CTAs tested (MAGEA3, OIP5, TTK, PLU1, DKKL1, and FBXO39) were significantly (p < 0.05) overexpressed in tumor tissue compared with healthy colon samples isolated from the same patients. Conclusions. Moreover, we found that MAGEA3, PLU-1, and DKKL expression positively correlated with disease progression, evaluated according to the Dukes staging system. Finally, 5-azacytidine exposure significantly upregulated expression of CTAs on CRC cells, which indicates that this demethylation agent could be employed therapeutically to enhance the immune response against tumor cells.

Vanderstraeten A, Tuyaerts S, Everaert T, et al.
In Vitro Assessment of the Expression and T Cell Immunogenicity of the Tumor-Associated Antigens BORIS, MUC1, hTERT, MAGE-A3 and Sp17 in Uterine Cancer.
Int J Mol Sci. 2016; 17(9) [PubMed] Free Access to Full Article Related Publications
BACKGROUND: While immunotherapy moved to the forefront of treatment of various cancers, it remains underexplored for uterine cancer. This might be due to the small patient population with advanced endometrial carcinoma and uterine sarcoma. Data about immunotherapeutic targets are scarce in endometrial carcinoma and lacking in uterine sarcoma.
METHODS: Expression of five tumor-associated antigens (TAA) (BORIS, MUC1, hTERT, MAGE-A3 and Sp17) was validated in uterine tumor samples by immunohistochemistry (IHC) and/or quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). TAA immunogenicity was analyzed by determining spontaneous T cell responses towards overlapping peptide pools covering the whole TAA in patient blood.
RESULTS: At mRNA level, MAGE-A3 and Sp17 were overexpressed in a minority of patients and BORIS was moderately overexpressed (26% in endometrial carcinoma and 62% in uterine sarcoma). hTERT was overexpressed in the vast majority of tumors. On protein level, MUC1 was upregulated in primary, recurrent and metastatic EMCAR and in metastatic US tumors. hTERT protein was highly expressed in both normal and malignant tissue. Spontaneous TAA-specific T cell responses were detected in a minority of patients, except for hTERT to which T cell responses occurred more frequently.
CONCLUSIONS: These data point to MUC1 and hTERT as most suitable targets based on expression levels and T cell immunogenicity for use in immunotherapeutic regimens.

Li B, Severson E, Pignon JC, et al.
Comprehensive analyses of tumor immunity: implications for cancer immunotherapy.
Genome Biol. 2016; 17(1):174 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Understanding the interactions between tumor and the host immune system is critical to finding prognostic biomarkers, reducing drug resistance, and developing new therapies. Novel computational methods are needed to estimate tumor-infiltrating immune cells and understand tumor-immune interactions in cancers.
RESULTS: We analyze tumor-infiltrating immune cells in over 10,000 RNA-seq samples across 23 cancer types from The Cancer Genome Atlas (TCGA). Our computationally inferred immune infiltrates associate much more strongly with patient clinical features, viral infection status, and cancer genetic alterations than other computational approaches. Analysis of cancer/testis antigen expression and CD8 T-cell abundance suggests that MAGEA3 is a potential immune target in melanoma, but not in non-small cell lung cancer, and implicates SPAG5 as an alternative cancer vaccine target in multiple cancers. We find that melanomas expressing high levels of CTLA4 separate into two distinct groups with respect to CD8 T-cell infiltration, which might influence clinical responses to anti-CTLA4 agents. We observe similar dichotomy of TIM3 expression with respect to CD8 T cells in kidney cancer and validate it experimentally. The abundance of immune infiltration, together with our downstream analyses and findings, are accessible through TIMER, a public resource at .
CONCLUSIONS: We develop a computational approach to study tumor-infiltrating immune cells and their interactions with cancer cells. Our resource of immune-infiltrate levels, clinical associations, as well as predicted therapeutic markers may inform effective cancer vaccine and checkpoint blockade therapies.

Pan SH, Su KY, Spiessens B, et al.
Gene expression of MAGE-A3 and PRAME tumor antigens and EGFR mutational status in Taiwanese non-small cell lung cancer patients.
Asia Pac J Clin Oncol. 2017; 13(5):e212-e223 [PubMed] Related Publications
AIM: To determine the frequency of expression of the tumor-associated antigens (TAAs) melanoma-associated antigen A3 (MAGE-A3) and preferentially expressed antigen of melanoma (PRAME) and the rate of EGFR mutations in a Taiwanese non-small cell lung cancer (NSCLC) population including only adenocarcinomas and squamous cell carcinomas. Furthermore, to investigate associations between TAA expression and EGFR mutations and to evaluate these TAAs as prognostic markers for overall survival. The occurrence of single nucleotide polymorphisms in MAGEA3 and PRAME was also assessed.
METHODS: Archival fresh-frozen tumor tissue specimens were tested by quantitative reverse transcription polymerase chain reaction assays to detect MAGE-A3 and PRAME expression. EGFR mutations were detected by mass spectroscopy and single nucleotide polymorphisms by gene sequencing.
RESULTS: Of the 156 adenocarcinomas examined, 3.3% expressed MAGE-A3, 32.2% expressed PRAME and 62.8% had EGFR mutations. Of the 128 squamous cell carcinomas, 29.8% expressed MAGE-A3, 59.2% expressed PRAME and 20.5% harbored EGFR mutations. TAA expression was similar across subgroups determined by patient or tumor characteristics. There was no association between TAA expression and EGFR mutation status and TAA expression was found not to be a prognostic marker for survival. Single nucleotide polymorphisms were identified, one of which with a possible impact on MAGE-A3 expression.
CONCLUSIONS: In this NSCLC population, expression of MAGE-A3 and PRAME was more frequent in squamous cell carcinomas than in adenocarcinomas tumors. EGFR mutations were not associated with TAA expression for either histology and were three times more frequent in adenocarcinomas than in squamous cell carcinomas tumors.

Saiag P, Gutzmer R, Ascierto PA, et al.
Prospective assessment of a gene signature potentially predictive of clinical benefit in metastatic melanoma patients following MAGE-A3 immunotherapeutic (PREDICT).
Ann Oncol. 2016; 27(10):1947-53 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Genomic profiling of tumor tissue may aid in identifying predictive or prognostic gene signatures (GS) in some cancers. Retrospective gene expression profiling of melanoma and non-small-cell lung cancer led to the characterization of a GS associated with clinical benefit, including improved overall survival (OS), following immunization with the MAGE-A3 immunotherapeutic. The goal of the present study was to prospectively evaluate the predictive value of the previously characterized GS.
PATIENTS AND METHODS: An open-label prospective phase II trial ('PREDICT') in patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma.
RESULTS: Of 123 subjects who received the MAGE-A3 immunotherapeutic, 71 (58.7%) displayed the predictive GS (GS+). The 1-year OS rate was 83.1%/83.3% in the GS+/GS- populations. The rate of progression-free survival at 12 months was 5.8%/4.1% in GS+/GS- patients. The median time-to-treatment failure was 2.7/2.4 months (GS+/GS-). There was one complete response (GS-) and two partial responses (GS+). The MAGE-A3 immunotherapeutic was similarly immunogenic in both populations and had a clinically acceptable safety profile.
CONCLUSION: Treatment of patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma with the MAGE-A3 immunotherapeutic demonstrated an overall 1-year OS rate of 83.5%. GS- and GS+ patients had similar 1-year OS rates, indicating that in this study, GS was not predictive of outcome. Unexpectedly, the objective response rate was lower in this study than in other studies carried out in the same setting with the MAGE-A3 immunotherapeutic. Investigation of a GS to predict clinical benefit to adjuvant MAGE-A3 immunotherapeutic treatment is ongoing in another melanoma study.This study is registered at NCT00942162.

Theodoraki MN, Lorenz KJ, Schneider J, et al.
Influence of Photodynamic Therapy on the Expression of Cancer/Testis Antigens in Squamous Cell Carcinoma of the Head and Neck.
Anticancer Res. 2016; 36(8):3973-82 [PubMed] Related Publications
BACKGROUND: Photodynamic therapy (PDT) represents a palliative treatment resulting in induction of inflammatory reactions with importance for the development of an antitumor immunity. Cancer/testis antigens (CTAs) have been associated with poor prognosis in different types of cancer, including head and neck squamous cell carcinoma (HNSCC).
MATERIALS AND METHODS: Tumor tissue samples before and after PDT were evaluated for the expression of four different CTAs by immunohistochemistry. Expression intensity and subcellular expression pattern were assessed.
RESULTS: Before PDT, expression of any CTA was detectable in 91%. Comparing the overall expression of CTAs, a decreased expression of all melanoma-associated antigens (MAGEs) post-treatment and a slightly increased expression of New York esophageal squamous cell carcinoma 1 (NY-ESO-1) was visible. The simultaneous cytoplasmic and nuclear expression of pan-MAGE or MAGE-A3/A4 correlated with reduced treatment-failure-free-survival (TFFS).
CONCLUSION: This study investigated the impact of PDT on CTA expression in HNSCC, detecting modified expression patterns after PDT. These changes may have been caused by immunological pressure or epigenetic regulation of CTA expression.

Dong L, Lin W, Qi P, et al.
Circulating Long RNAs in Serum Extracellular Vesicles: Their Characterization and Potential Application as Biomarkers for Diagnosis of Colorectal Cancer.
Cancer Epidemiol Biomarkers Prev. 2016; 25(7):1158-66 [PubMed] Related Publications
BACKGROUND: Long noncoding RNA (lncRNA) and mRNAs are long RNAs (≥200 nucleotides) compared with miRNAs. In blood, long RNAs may be protected by serum extracellular vesicles, such as apoptotic bodies (AB), microvesicles (MV), and exosomes (EXO). They are potential biomarkers for identifying cancer.
METHODS: Sera from 76 preoperative colorectal cancer patients, 76 age- and sex-matched healthy subjects, and 20 colorectal adenoma patients without colorectal cancer were collected. We investigated the distribution of long RNAs into the three vesicles. Seventy-nine cancer-related long RNAs were chosen and detected using qPCR.
RESULTS: The quantity of long RNA has varying distribution among three subtypes of extracellular vesicles in serum. Most mRNA and lncRNA genes had higher quantity in EXOs than that in ABs and MVs, whereas MVs contain lowest quantity. We investigated 79 long RNAs chosen from The Cancer Genome Atlas and the LncRNADisease database in the sera of healthy patients, and those with colorectal cancer. In the training and test sets, the AUCs were 0.936 and 0.877, respectively. The AUC of total serum RNA was lower (0.857) than that of exosomal RNA in the same samples (0.936).
CONCLUSION: The present study shows that exosomal mRNAs and lncRNAs in serum could be used as biomarkers to detect colorectal cancer.
IMPACT: Among three types of vesicles in sera, EXOs were the richest reservoir for almost all measured long RNAs. The combination of two mRNAs, KRTAP5-4 and MAGEA3, and one lncRNA, BCAR4, could be potential candidates to detect colorectal cancer. Cancer Epidemiol Biomarkers Prev; 25(7); 1158-66. ©2016 AACR.

Yao X, Lu YC, Parker LL, et al.
Isolation and Characterization of an HLA-DPB1*04: 01-restricted MAGE-A3 T-Cell Receptor for Cancer Immunotherapy.
J Immunother. 2016; 39(5):191-201 [PubMed] Free Access to Full Article Related Publications
Long-term tumor regressions have been observed in patients following the adoptive transfer of autologous tumor-infiltrating lymphocytes or genetically modified T cells expressing MHC class I-restricted T-cell receptors (TCRs), but clinical trials have not evaluated responses to genetically modified T cells expressing antitumor MHC class II-restricted TCRs. As studies carried out in a murine tumor model system have demonstrated that the adoptive transfer of CD4 T cells could lead to the regression of established tumors, we plan to test the hypothesis that CD4 T cells can also induce tumor regressions in cancer patients. In this study, 2 MAGE-A3-specific TCRs were isolated from a regulatory T-cell clone (6F9) and an effector clone (R12C9), generated from the peripheral blood of 2 melanoma patients after MAGE-A3 vaccination. The results indicated that T cells transduced with 6F9 TCR mediated stronger effector functions than R12C9 TCR. The 6F9 TCR specifically recognized MAGE-A3 and the closely related MAGE-A6 gene product, but not other members of the MAGE-A family in the context of HLA-DPB1*04:01. To test the feasibility of a potential clinical trial using this TCR, a clinical-scale procedure was developed to obtain a large number of purified CD4 T cells transduced with 6F9 TCR. Because HLA-DPB1*04:01 is present in ∼60% of the Caucasian population and MAGE-A3 is frequently expressed in a variety of cancer types, this TCR immunotherapy could potentially be applicable for a significant portion of cancer patients.

Vansteenkiste JF, Cho BC, Vanakesa T, et al.
Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet Oncol. 2016; 17(6):822-835 [PubMed] Related Publications
BACKGROUND: Fewer than half of the patients with completely resected non-small-cell lung cancer (NSCLC) are cured. Since the introduction of adjuvant chemotherapy in 2004, no substantial progress has been made in adjuvant treatment. We aimed to assess the efficacy of the MAGE-A3 cancer immunotherapeutic in surgically resected NSCLC.
METHODS: In this randomised, double-blind, placebo-controlled trial, we recruited patients aged at least 18 years with completely resected stage IB, II, and IIIA MAGE-A3-positive NSCLC who did or did not receive adjuvant chemotherapy from 443 centres in 34 countries (Europe, the Americas, and Asia Pacific). Patients were randomly assigned (2:1) to receive 13 intramuscular injections of recMAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic) or placebo during 27 months. Randomisation and treatment allocation at the investigator site was done centrally via internet with stratification for chemotherapy versus no chemotherapy. Participants, investigators, and those assessing outcomes were masked to group assignment. A minimisation algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. The final analyses included the total treated population (all patients who had received at least one treatment dose). This trial is registered with, number NCT00480025.
FINDINGS: Between Oct 18, 2007, and July 17, 2012, we screened 13 849 patients for MAGE-A3 expression; 12 820 had a valid sample and of these, 4210 (33%) had a MAGE-A3-positive tumour. 2312 of these patients met all eligibility criteria and were randomly assigned to treatment: 1515 received MAGE-A3 and 757 received placebo and 40 were randomly assigned but never started treatment. 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. Median follow-up was 38·1 months (IQR 27·9-48·4) in the MAGE-A3 group and 39·5 months (27·9-50·4) in the placebo group. In the overall population, median disease-free survival was 60·5 months (95% CI 57·2-not reached) for the MAGE-A3 immunotherapeutic group and 57·9 months (55·7-not reached) for the placebo group (hazard ratio [HR] 1·02, 95% CI 0·89-1·18; p=0·74). Of the patients who did not receive chemotherapy, median disease-free survival was 58·0 months (95% CI 56·6-not reached) in those in the MAGE-A3 group and 56·9 months (44·4-not reached) in the placebo group (HR 0·97, 95% CI 0·80-1·18; p=0·76). Because of the absence of treatment effect, we could not identify a gene signature predictive of clinical benefit to MAGE-A3 immunotherapeutic. The frequency of grade 3 or worse adverse events was similar between treatment groups (246 [16%] of 1515 patients in the MAGE-A3 group and 122 [16%] of 757 in the placebo group). The most frequently reported grade 3 or higher adverse events were infections and infestations (37 [2%] in the MAGE-A3 group and 19 [3%] in the placebo group), vascular disorders (30 [2%] vs 17 [3%]), and neoplasm (benign, malignant, and unspecified (29 [2%] vs 16 [2%]).
INTERPRETATION: Adjuvant treatment with the MAGE-A3 immunotherapeutic did not increase disease-free survival compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC. Based on our results, further development of the MAGE-A3 immunotherapeutic for use in NSCLC has been stopped.
FUNDING: GlaxoSmithKline Biologicals SA.

Miyauchi K, Tsuchikawa T, Wada M, et al.
Clinical relevance of antigen spreading pattern induced by CHP-MAGE-A4 cancer vaccination.
Immunotherapy. 2016; 8(5):527-40 [PubMed] Related Publications
AIM: To investigate the antigen spreading pattern in the CHP-MAGE-A4-vaccinated patients and analyze the clinical relevance of antigen spreading pattern as a surrogate marker of patient survival.
MATERIALS & METHODS: 12 patients who had been injected with 300 μg of CHP-MAGE-A4 and 0.5 Klinische Einheit of OK-432 in more than five vaccinations were analyzed.
RESULTS: Increases in the anti-MAGE-A4-specific antibody response were observed in eight patients (66.7%), compared with six patients (50%) for anti-NY-ESO-1 and five patients (41.7%) for anti-MAGE-A3 after five vaccinations. We identified frequent antigen spreading following MAGE-A4 vaccinations without associations with the clinical response or patient prognosis.
CONCLUSION: Antigen spreading pattern might reflect tumor shrinkage as a response to treatment and treatment history (clinical trial registration number: UMIN000001999).

Srivastava P, Paluch BE, Matsuzaki J, et al.
Induction of cancer testis antigen expression in circulating acute myeloid leukemia blasts following hypomethylating agent monotherapy.
Oncotarget. 2016; 7(11):12840-56 [PubMed] Free Access to Full Article Related Publications
Cancer testis antigens (CTAs) are promising cancer associated antigens in solid tumors, but in acute myeloid leukemia, dense promoter methylation silences their expression. Leukemia cell lines exposed to HMAs induce expression of CTAs. We hypothesized that AML patients treated with standard of care decitabine (20mg/m2 per day for 10 days) would demonstrate induced expression of CTAs. Peripheral blood blasts serially isolated from AML patients treated with decitabine were evaluated for CTA gene expression and demethylation. Induction of NY-ESO-1 and MAGEA3/A6, were observed following decitabine. Re-expression of NY-ESO-1 and MAGEA3/A6 was associated with both promoter specific and global (LINE-1) hypomethylation. NY-ESO-1 and MAGEA3/A6 mRNA levels were increased irrespective of clinical response, suggesting that these antigens might be applicable even in patients who are not responsive to HMA therapy. Circulating blasts harvested after decitabine demonstrate induced NY-ESO-1 expression sufficient to activate NY-ESO-1 specific CD8+ T-cells. Induction of CTA expression sufficient for recognition by T-cells occurs in AML patients receiving decitabine. Vaccination against NY-ESO-1 in this patient population is feasible.

Xie C, Subhash VV, Datta A, et al.
Melanoma associated antigen (MAGE)-A3 promotes cell proliferation and chemotherapeutic drug resistance in gastric cancer.
Cell Oncol (Dordr). 2016; 39(2):175-86 [PubMed] Related Publications
BACKGROUND: Melanoma-associated antigen (MAGE)-A3 is a member of the family of cancer-testis antigens and has been found to be epigenetically regulated and aberrantly expressed in various cancer types. It has also been found that MAGE-A3 expression may correlate with an aggressive clinical course and with chemo-resistance. The objectives of this study were to assess the relationship between MAGE-A3 promoter methylation and expression and (1) gastric cancer patient survival and (2) its functional consequences in gastric cancer-derived cells.
METHODS: Samples from two independent gastric cancer cohorts (including matched non-malignant gastric samples) were included in this study. MAGE-A3 methylation and mRNA expression levels were determined by methylation-specific PCR (MSP) and quantitative real-time PCR (qPCR), respectively. MAGE-A3 expression was knocked down in MKN1 gastric cancer-derived cells using miRNAs. In addition, in vitro cell proliferation, colony formation, apoptosis, cell cycle, drug treatment, immunohistochemistry and Western blot assays were performed.
RESULTS: Clinical analysis of 223 primary patient-derived samples (ntumor = 161, nnormal = 62) showed a significant inverse correlation between MAGE-A3 promoter methylation and expression in the cancer samples (R = -0.63, p = 5.99e-19). A lower MAGE-A3 methylation level was found to be associated with a worse patient survival (HR: 1.5, 95 % CI: 1.02-2.37, p = 0.04). In addition, we found that miRNA-mediated knockdown of MAGE-A3 expression in MKN1 cells caused a reduction in its proliferation and colony forming capacities, respectively. Under stress conditions MAGE-A3 was found to regulate the expression of Bax and p21. MAGE-A3 knock down also led to an increase in Puma and Noxa expression, thus contributing to an enhanced docetaxel sensitivity in the gastric cancer-derived cells.
CONCLUSIONS: From our results we conclude that MAGE-A3 expression is regulated epigenetically by promoter methylation, and that its expression contributes to gastric cell proliferation and drug sensitivity. This study underscores the potential implications of MAGE-A3 as a therapeutic target and prognostic marker in gastric cancer patients.

Jin J, Liu BZ, Wu ZM
Evaluation of melanoma antigen gene A3 expression in drug resistance of epidermal growth factor receptor-tyrosine kinase inhibitors in advanced nonsmall cell lung cancer treatment.
J Cancer Res Ther. 2015; 11 Suppl:C271-4 [PubMed] Related Publications
OBJECTIVE: To investigate the correlation between melanoma antigen gene A3 (MAGE-A3) expression and progression-free survival (PFS) of nonsmall cell lung cancer (NSCLC) patients with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) therapy, aiming to provide a basis for research and treatment of EGFR-TKIs resistance.
RESEARCH AND METHODS: Retrospective analysis is conducted of PFS of 359 NSCLC patients who have been tested positive for EGFR, and experienced drug resistance during oral treatment of icotinib. MAGE-A3 expression is tested using immunology and histology chemistry methods, and T790M and c-MeT expression are tested using mutation-enriched polymerase chain reaction.
RESULTS: (1) MAGE-A3 expression in targeted treatment of NSCLC patients shows a positive rate of 33.98%. The comparative difference between MAGE-A3 expression and T790M, c-MeT and other resistance genes was not statistically significant (P > 0.05). (2) MAGE-A3 expression was higher in patients with NSCLC targeted therapy of primary drug resistance of positive rate than acquired resistance; meanwhile the expression level differences in three modes of acquired resistance are statistically significant (P < 0.05). (3) PFS of MAGE-A3 positive expression in the targeted treatment of acquired drug resistance in patients with NSCLC is shorter than the PFS of MAGE-A3 negative expression (P = 0.01); the comparative PFS differences in the three kinds of acquired drug resistance pattern have statistical significance (P = 0.02). (4) PFS and levels of MAGE-A3 expression in NSCLC patients with the three modes of acquired resistance are negatively correlated (P < 0.01), and MAGE-A3 expression has no correlation with age, gender, pathological type or PS score (P > 0.05).
CONCLUSION: MAGE-A3 expression in EGFR-TKIs target therapy in NSCLC patient suggests that there might be EGFR-TKIs drug resistance, and the higher the level of expression, the shorter the time of acquired drug resistance.

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