A Phase I Trial of an HLA-A1 Restricted MAGE-3 Epitope Peptide with Incomplete Freundʼs Adjuvant in Patients with Resected High-Risk Melanoma

The use of synthetic peptides as vaccines aimed at the induction of therapeutic CD8-positive T-cell responses against tumor cells initially experienced great enthusiasm, mostly because of advances in vaccine technology, including design, synthesis, and delivery. However, despite impressive results in animal models, the application of such vaccines in humans has met with only limited success. The therapeutic activity of vaccine-stimulated, tumor-specific, CD8-positive T cells can be hampered through the physical burden of the tumor, tolerance mechanisms, and local factors within the tumor microenvironment. Recently, accumulating evidence has suggested that combining a peptide-based therapeutic vaccination with conventional chemotherapy can uncover the full potential of the antitumor immune response, increasing the success of immunotherapy. In addition, therapeutic vaccination in the preventive setting has been extremely effective in eliciting antitumor responses in preclinical tumor models and has demonstrated good promise clinically in patients with minimal residual disease. The rationale behind preventive vaccination is that patients with minimal tumor burden still have a fully competent immune system capable of developing robust antitumor responses. Finally, therapeutic CD8-positive T-cell peptide vaccines have been improved by coimmunization with T-helper epitopes expressed on long peptides.

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“…36,37 Although those studies demonstrated the capacity of PADRE to induce potent responses to PADRE itself, this did not increase CTL activity.…”

Section: Clinical Trials Using Polyepitope Long-peptide Vaccinesmentioning

confidence: 90%

A new era in anticancer peptide vaccines

Perez

Hofe

Kallinteris

et al. 2010

Cancer

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“…1,2 A number of them are presently being evaluated in clinical immunization trials. [3][4][5][6][7] In this study, we applied TMA technology to the analysis of MAGE-A4 expression in bladder cancers. Our results show that this TAA is expressed in tumors of different histologic types and most frequently in squamous cell carcinomas.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Capitalizing on this background, clinical immunization trials are currently being implemented, showing promising preliminary results. [3][4][5][6][7] Concomitantly, the potential relevance of these proteins as tumor markers is also emerging. Clinical studies suggest that MAGE TAA expression is prevailingly detectable in highly aggressive, poorly differentiated tumors, 8 -10 thereby increasing their interest as therapeutic targets.…”

mentioning

confidence: 99%

Prognostic relevance of MAGE‐A4 tumor antigen expression in transitional cell carcinoma of the urinary bladder: A tissue microarray study

Köcher

Zheng

Bolli

et al. 2002

Intl Journal of Cancer

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TAAs of the MAGE family are mostly studied as targets of specific immune responses. Their potential relevance as tumor markers has also been underlined. We used a MAb, 57B, recognizing MAGE-A4 protein in paraffin-embedded sections, to evaluate its expression in bladder cancers by employing TMA including 2,317 samples from 1,849 patients. In 2,090/2,317 cases (90.2%), immunostaining yielded interpretable results. Since for some patients more than 1 sample was available, only interpretable first biopsies (n ‫؍‬ 1,628) were considered. MAGE-A4 protein was expressed at significantly (p < 0.001) higher frequency in squamous (25/55, 45.5%) than in adeno (4/15, 26.7%), sarcomatoid (4/14, 28.6%), small cell (5/20, 25%) or transitional cell (281/1,522, 18.5%) carcinomas. In TCCs, overall MAGE-A4 positivity was significantly correlated with invasive phenotype (p < 0.001) and high tumor grade (p < 0.0001). Clinical data from 908 TCC patients were retrospectively evaluated, revealing that strong 57B staining was highly significantly associated with decreased tumorspecific survival (p < 0.0001). These data suggest that evaluation of MAGE-A4 protein expression is useful in the identification of groups of TCCs characterized by severe prognosis, thus possibly providing indications for early MAGE TAA-targeted immunotherapy. © 2002 Wiley-Liss, Inc. Key words: bladder cancer; 57B MAb; MAGE-A4; tissue microarray; tumor-specific survivalHuman TAAs of the MAGE family are recognized by CTLs from tumor patients. 1,2 Capitalizing on this background, clinical immunization trials are currently being implemented, showing promising preliminary results. [3][4][5][6][7] Concomitantly, the potential relevance of these proteins as tumor markers is also emerging. Clinical studies suggest that MAGE TAA expression is prevailingly detectable in highly aggressive, poorly differentiated tumors, 8 -10 thereby increasing their interest as therapeutic targets.In particular, MAGE gene expression has also been described in urinary bladder cancers, 8 but the number of cases was too low to allow evaluation of clinicopathologic or prognostic correlations.TMA technology offers the unique possibility to rapidly analyze large numbers of tumors. 11 Minute tissue cylinders (diameter 0.6 mm) are taken from hundreds of different primary tumor blocks and subsequently brought into 1 empty recipient paraffin block. Sections from such array blocks can then be used for simultaneous in situ analysis of hundreds or thousands of tumors at the DNA, RNA or protein level.In this study, we used a bladder cancer TMA containing 2,317 specimens to evaluate the frequency of MAGE-A4 protein expression as detected by a specific MAb (57B) and to assess its correlation with tumor phenotype and clinical outcome. MATERIAL AND METHODS MAb 57BReagent 57B was generated by our group using as immunogen recombinant MAGE-A3 protein. 12 Immunohistochemic studies carried out in different laboratories have emphasized that, although 57B identifies multiple MAGE gene products in transfected cells, ...

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“…The MHC class I peptides confer MUC1 specificity leading to the induction of CTL-mediated anti-tumor responses; the Hepatitis B core antigen-derived MHC class II pan T helper peptide was included to boost CD8 + anti-tumor responses [30,31]; CpG-ODN was included to promote DC activation via its interaction with Toll-like receptor (TLR)-9 [32,33] to enhance CTL responses, expansion and survival [33][34][35][36][37]. GM-CSF promotes antigen presentation and DC recruitment to vaccine sites [38][39][40][41] and is commonly used as a biological adjuvant in preclinical and clinical immunotherapy studies [42,43].…”

Section: Effect Of Peptide Vaccination On Adenoma Formation In Muc1tmentioning

confidence: 99%

Characterization of the MUC1.Tg/MIN transgenic mouse as a model for studying antigen-specific immunotherapy of adenomas

Akporiaye

Bradley-Dunlop

Gendler

et al. 2007

Vaccine

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A bigenic MUC1.Tg/MIN mouse model was developed by crossing Apc/ MIN/+ (MIN) mice with human MUC1 transgenic mice to evaluate MUC1 antigen-specific immunotherapy of intestinal adenomas. The MUC1.Tg/MIN mice developed adenomas at a rate comparable to that of MIN mice and had similar levels of serum MUC1 antigen. A MUC1-based vaccine consisting of MHC class I-restricted MUC1 peptides, a MHC class II-restricted pan-helper peptide, unmethylated CpG oligodeoxynucleotide and GM-CSF caused flattening of adenomas and significantly reduced the number of large adenomas. Immunization was successful in generating a MUC1-directed immune response evidenced by increased MUC1 peptide-specific anti-tumor cytotoxicity and IFN-γ secretion by lymphocytes.

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A Phase I Trial of an HLA-A1 Restricted MAGE-3 Epitope Peptide with Incomplete Freundʼs Adjuvant in Patients with Resected High-Risk Melanoma

Cited by 111 publications

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A new era in anticancer peptide vaccines

A new era in anticancer peptide vaccines

Prognostic relevance of MAGE‐A4 tumor antigen expression in transitional cell carcinoma of the urinary bladder: A tissue microarray study

Characterization of the MUC1.Tg/MIN transgenic mouse as a model for studying antigen-specific immunotherapy of adenomas

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