Phase 1/2 study of subcutaneous and intradermal immunization with a recombinant MAGE-3 protein in patients with detectable metastatic melanoma

Kruit, Wim; Ojik, Heidi H. van; Brichard, Vincent G.; Escudier, Bernard; Dorval, Thierry; Dréno, Brigitte; Patel, Poulam M.; Baren, Nicolas van; Avril, Marie-Françoise; Piperno, Sophie; Khammari, Amir; Stas, Marguerite; Ritter, Gerd; Bernard, Loris; Godelaine, Danièle; Brasseur, Francis; Zhang, Yi; Bruggen, Pierre van der; Boon, Thierry; Eggermont, Alexander M.M.; Marchand, Marie

doi:10.1002/ijc.21264

Cited by 145 publications

(89 citation statements)

References 21 publications

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“…Although the percentage of cytokine-producing CD4 + T cells was low in our study, it was detectable by an ex vivo assay without an in vitro stimulation of the peripheral blood mononuclear cells. The low percentage of CD4 + T cells observed in our non-clinical study and in previous clinical studies (Kruit et al, 2005(Kruit et al, , 2013 could be explained by the low frequency of MAGE-A3-specific T-cell precursors, which is well documented in humans (Chaux et al, 1998). No CD8 + T cells producing IL-2, TNF-α or IFN-γ cytokines were detected, in line with the results of a phase II study in patients with melanoma (Kruit et al, 2013).…”

Section: Discussionsupporting

confidence: 91%

Non‐clinical safety evaluation of single and repeated intramuscular administrations of MAGE‐A3 Cancer Immunotherapeutic in rabbits and cynomolgus monkeys

Destexhe

Grosdidier

Baudson

et al. 2014

J of Applied Toxicology

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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.

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Section: Discussionsupporting

confidence: 91%

Non‐clinical safety evaluation of single and repeated intramuscular administrations of MAGE‐A3 Cancer Immunotherapeutic in rabbits and cynomolgus monkeys

Destexhe

Grosdidier

Baudson

et al. 2014

J of Applied Toxicology

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“…2 Owing to their high sequence homology MAGE-A proteins have been considered functionally redundant, and have been largely exploited in the immunotherapy field through cancer vaccine development or as tumor markers. [3][4][5] Only during the last few years, their biological function has begun to be investigated. A growing body of evidence indicates that MAGE-A proteins could confer advantages to cancer cells by different mechanisms and with a certain degree of specificity.…”

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confidence: 99%

MageA2 restrains cellular senescence by targeting the function of PMLIV/p53 axis at the PML-NBs

et al. 2011

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MAGE-A genes are a subfamily of the melanoma antigen genes (MAGEs), whose expression is restricted to tumor cells of different origin and normal tissues of the human germline. Although the specific function of individual MAGE-A proteins is being currently explored, compelling evidence suggest their involvement in the regulation of different pathways during tumor progression. We have previously reported that MageA2 binds histone deacetylase (HDAC)3 and represses p53-dependent apoptosis in response to chemotherapeutic drugs. The promyelocytic leukemia (PML) tumor suppressor is a regulator of p53 acetylation and function in cellular senescence. Here, we demonstrate that MageA2 interferes with p53 acetylation at PMLnuclear bodies (NBs) and with PMLIV-dependent activation of p53. Moreover, a fraction of MageA2 colocalizes with PML-NBs through direct association with PML, and decreases PMLIV sumoylation through an HDAC-dependent mechanism. This reduction in PML post-translational modification promotes defects in PML-NBs formation. Remarkably, we show that in human fibroblasts expressing RasV12 oncogene, MageA2 expression decreases cellular senescence and increases proliferation. These results correlate with a reduction in NBs number and an impaired p53 response. All these data suggest that MageA2, in addition to its anti-apoptotic effect, could have a novel role in the early progression to malignancy by interfering with PML/p53 function, thereby blocking the senescence program, a critical barrier against cell transformation.

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“…This combination of restricted normal tissue expression, spontaneous immunogenicity and frequent tumor expression has pushed MAGE and NY-ESO-1 to the forefront of tumor immunotherapy as attractive targets for cancer vaccines, 1,8 and multiple clinical trials using these 2 antigens have been carried out, with promising results observed in some studies. [9][10][11][12][13][14][15][16][17] Following the initial identification of MAGE and NY-ESO-1 families, more than 80 gene or gene families have been described as CT or CT candidate genes in the literature. These genes have been organized and annotated into a CT database by the Ludwig Institute for Cancer Research (http://www.cancerimmunity.org/ Ctdatabase/ and http://www.cta.lncc.br).…”

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confidence: 99%

Cancer/testis antigen CT45: Analysis of mRNA and protein expression in human cancer

Chen

Hsu

Lee

et al. 2009

Intl Journal of Cancer

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CT45 is a cancer/testis gene that we previously identified by massively parallel signature sequencing. Encoded by a multigene family on chromosome X, CT45 showed restricted mRNA expression to normal testis and various cancers. In this study, monoclonal antibodies were generated against recombinant CT45 protein, and CT45 protein expression in normal and tumor tissues was evaluated by immunohistochemical analysis. In adult normal tissue, CT45 expression was restricted to testicular germ cells, detected as a nuclear protein mainly at the stage of primary spermatocytes. In tumors, CT45 protein expression correlated with the mRNA levels detected by quantitative RT-PCR, and most lung cancer and ovarian cancers with CT45 mRNA at levels >1% of testicular expression were CT45 protein-positive. In positive cases, CT45 showed expression patterns that ranged from diffuse strong staining to heterogeneous and patchy expression. In lung cancer, CT45 expression was least frequent in adenocarcinoma, more frequent in squamous cell carcinoma and neuroendocrine tumors. Using tissue microarrays, 376 lung cancer, 219 ovarian cancer and 155 breast cancer were evaluated for CT45 protein expression. The expression frequency was highest in ovarian cancer (37%), followed by lung cancer (13%) and lowest in breast cancer (<5%). Given the focal nature of CT45 expression in many cases, these numbers represented the minimal frequency of expression in these tumor types. In summary, the expression frequency and characteristics of CT45 expression are similar to other CT cancer vaccine targets currently in clinical trials, e.g., NY-ESO-1 and MAGE-A, suggesting CT45 as a potentially useful cancer target. ' 2009 UICC

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Phase 1/2 study of subcutaneous and intradermal immunization with a recombinant MAGE-3 protein in patients with detectable metastatic melanoma

Cited by 145 publications

References 21 publications

Non‐clinical safety evaluation of single and repeated intramuscular administrations of MAGE‐A3 Cancer Immunotherapeutic in rabbits and cynomolgus monkeys

Non‐clinical safety evaluation of single and repeated intramuscular administrations of MAGE‐A3 Cancer Immunotherapeutic in rabbits and cynomolgus monkeys

MageA2 restrains cellular senescence by targeting the function of PMLIV/p53 axis at the PML-NBs

Cancer/testis antigen CT45: Analysis of mRNA and protein expression in human cancer

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