Immunisation of metastatic cancer patients with MAGE-3 protein combined with adjuvant SBAS-2: a clinical report

Marchand, Marie; Punt, Cornelis J.A.; Aamdal, Steinar; Escudier, Bernard; Kruit, Wim; Keilholz, Ulrich; Håkansson, Leif; Baren, Nicolas van; Humblet, Yves; Mulders, Peter F.A.; Avril, Marie-Françoise; Eggermont, Alexander M.M.; Scheibenbogen, Carmen; Uiters, John; Wanders, J.; Delire, M; Boon, Thierry; Stoter, G.

doi:10.1016/s0959-8049(02)00479-3

Cited by 154 publications

(114 citation statements)

References 16 publications

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“…One dose of the MAGE-A3 Cancer Immunotherapeutic consisted of 300 μg recombinant MAGE-A3 antigen (recMAGE-A3) produced and purified from Escherichia coli as previously described (Marchand et al, 2003), formulated in a fixed dose of the AS15 immunostimulant, containing 3-O-desacyl-4′-monophosphoryl lipid A (GlaxoSmithKline Vaccines), QS-21 (Quillaja saponaria Molina, fraction 21; Antigenics Inc., a wholly owned subsidiary of Agenus Inc., Lexington, MA, USA), CpG 7909 synthetic oligodeoxynucleotides containing unmethylated CpG motifs, and liposome (50 μg 3-O-desacyl-4′-monophosphoryl lipid A, 50 μg QS-21 and 420 μg CpG 7909).…”

Section: Test Itemsmentioning

confidence: 99%

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: Test Itemsmentioning

confidence: 99%

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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“…MAGE-A3 is a non-mutated cancer-testis TAA frequently expressed by tumors of different histology [23,24], and is currently utilized as target antigen in different cancer immunotherapy protocols [25,[26][27][28][29]. To study MAGE-A3-specific CD4 1 T-cell responses, we have generated empty HLA-DR Ã 1101 tetramers, one of the most frequent allele in the Caucasian population, which can be loaded with the desired peptides to stain specific T cells [12].…”

Section: T Cells In Anti-tumor Immune Response; Nevertheless Little Ismentioning

confidence: 99%

The CD4⁺ T‐cell epitope‐binding register is a critical parameter when generating functional HLA‐DR tetramers with promiscuous peptides

et al. 2010

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Detection of CD4 1 T cells specific for tumor-associated antigens is critical to investigate the spontaneous tumor immunosurveillance and to monitor immunotherapy protocols in patients. We investigated the ability of HLA-DR*1101 multimers to detect CD4 1 T cells specific for three highly promiscuous MAGE-A3 derived peptides: (p39), MAGE-A3 281-295 (p57) and MAGE-A3 286-300 (p58). Tetramers stained specific CD4 1 T cells only when loaded with p39, although all peptides activated the specific T cells when presented by plasticbound HLA-DR*1101 monomers. This suggested that tetramer staining ability was determined by the mode rather than the affinity of peptide binding to HLA-DR*1101. We hypothesized that peptides should bear a single P1 anchor residue to bind all arms of the multimer in a homogeneous register to generate peptide-HLA-DR conformers with maximal avidity. Bioinformatics analysis indicated that p39 contained one putative P1 anchor residue, whereas the other two peptides contained multiple ones. Designing p57 and p58 analogues containing a single anchor residue generated HLA-DR*1101 tetramers that stained specific CD4 1 T cells. Producing HLA-DR*1101 monomers linked with the optimized MAGE-A3 analogues, but not with the original epitopes, further improved tetramer efficiency. Optimization of CD4 1 T-cell epitope-binding registers is thus critical to generate functional HLA-DR tetramers.Key words: Anchor residues . HLA-DR Ã 1101 . MAGE-A3 . MHC tetramers . Tumor antigens Supporting Information available online IntroductionAnimal studies have clearly shown the critical role for CD4 1 T cells in anti-tumor immune response; nevertheless, little is known as yet about spontaneous tumor-specific CD4 1 T-cell responses in patients [1,2]. This knowledge would be instrumental to the definition of the mechanisms underlying tumor immunosurveillance and, possibly, tumor escape, as well as for the correct design of optimal vaccination strategies.CD4 1 T-cell responses specific for tumor associated antigens (TAA) can be investigated at the single cell level by using soluble [3][4][5][6]. The identification of primary antigen-specific CD4 1 T cells by peptide-pulsed MHC class II tetramers seems, however, less straightforward than that of CD8 1 T cells by peptide-loaded MHC class I tetramers [7,8]. Several biological and structural characteristics of the CD4 1 T-cell response that differ from those displayed by the CD8 1 one seem to affect the capacity of MHC class II tetramers to optimally stain specific CD4 1 T cells ex vivo: (i) the lower frequency of peptide-specific CD4 1 T cells, (ii) their apparent lower affinity for the peptide-MHC class II complexes [9][10][11][12][13], and (iii) the requirement for an activation-induced TCR reorganization to bind with sufficient avidity cognate peptide-MHC class II tetramers [12,14,15].Furthermore, the open structure of the MHC class II molecules allows peptides as long as 20 aa to extend out of the binding groove at both ends [16][17][18]. It is thus possible that a peptide,...

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“…Different strategies to achieve this are being explored, including vaccination with peptides, 22,31,39 -42 naked DNA encoding part of or whole TA, [43][44][45][46][47] recombinant virus, 48 -51 recombinant protein, 52,53 peptide coated dendritic cells (DCs) 54 -62 or peripheral blood mononuclear cells (PBMC) 63 and TA mRNA loaded DCs. 64,65 In spite of the big endeavour put in DC-based therapies, evidence supporting their clinical efficiency still remains scant.…”

Section: Vaccination Strategiesmentioning

confidence: 99%

“…Besides the well-known proinflammatory Incomplete Freund's Adjuvant (IFA) and coadministration of cytokines such as IL-2, 32 IL-12 63 or GM-CSF, 40 the potent immunostimulatory properties of toll-like receptor (TLR) agonists are rapidly becoming apparent. Thus, TLR-4 ligands including monophosphoryl lipid A (MPL), a chemically modified derivative of lipopolisaccharide (LPS) that exhibits similar immune activation potential, but reduced toxicity compared to LPS, 77 alone or in combination with QS21 (saponin), 52 as well as the synthetic lipid A mimetic Ribi 529, an aminoalkyl glucosaminide 4-phosphate, 77 and the TLR-9 agonist CpG-oligonucleotide 78 were shown to enhance antigen-specific immunity by providing activatory signals to DCs. A novel TLR-2 ligand is the outer membrane protein A of gram-negative bacteria, which has been shown to enhance the induction of specific CTL when mixed with peptide vaccines in mice.…”

Section: Vaccination Strategiesmentioning

confidence: 99%

Recent advances in tumour antigen‐specific therapy: In vivo veritas

Mahnke

Speiser

Luescher

et al. 2004

Intl Journal of Cancer

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Modern cancer therapies should strive not only to eliminate malignant tissues but also to preserve healthy tissues and the patient's quality of life. Antigen-specific immunotherapy approaches are promising for either aspect since they are designed to only act against tissues expressing 1 or more specified tumour antigens. In order to develop successful vaccine and adoptive transfer protocols, longitudinal monitoring of cancer patients taking part in clinical trials is mandatory. Here, in vivo expansion of antigenspecific cells, as well as their ex vivo functional status represent important parameters to be analysed. To obtain results that most closely reflect the cells' in vivo status, functional assays must be carried out with as little in vitro culturing as possible. The present minireview discusses recent advances in these domains. Key words: cancer vaccines; T cell monitoring; tetramers; immunotherapy Tumour antigensRapid advances in the identification of MHC class I-restricted tumour antigens (TA) and their antigenic peptides 1 took place at the end of the 20th century, engendering antigen (Ag)-specific immunotherapy approaches to cancer treatment. [2][3][4] In contrast, progress in the molecular identification of MHC class II restricted peptides of TA has been much slower. Although tumour-specific CD8 ϩ T-cell responses have been documented upon vaccination with MHC class I-restricted peptides, it could be shown in murine tumour models that the generation of potent and long-lasting anti-tumour immunity is improved when both MHC class I-and class II-restricted T-cell epitopes are included in tumour vaccines. [5][6][7] These observations fostered the search for TA-derived peptides that are presented by class II molecules in cancer patients and lead to the isolation of diverse CD4 ϩ T-cell clones specific for given TA, though the precise epitopes have not yet been identified in all cases. 8,9 The high number of human MHC class II alleles severely limits the applicability of many of the antigenic peptides identified thus far. An exception is the HLA-DP4 molecule. Indeed, 2 highly prevalent alleles encode its ␤ chain and their combined frequency reaches approximately 60% of the population world-wide. Two HLA-DP4-restricted tumour associated antigenic peptides have been identified thus far. 10,11 Moreover, detailed analysis of HLA-DP4 peptide binding may facilitate future searches of novel tumour antigenic peptides restricted by this frequently occurring class II MHC allele. 12 Another favourable trait is the "degenerate" DR binding of certain antigenic peptides, i.e., various TA-derived antigenic peptides have been reported to bind to diverse HLA-DR molecules. 13,14 The identification of TA-derived epitopes presented by MHC class II molecules is complicated by the lack of effective screening methods. Recently, by combination of a computer-based algorithm for MHC-binding with T-cell functional analyses, a class II-restricted epitope of carcinoembryonic Ag (CEA, aa 116 -140) was identified that is naturally proce...

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Immunisation of metastatic cancer patients with MAGE-3 protein combined with adjuvant SBAS-2: a clinical report

Cited by 154 publications

References 16 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

The CD4⁺ T‐cell epitope‐binding register is a critical parameter when generating functional HLA‐DR tetramers with promiscuous peptides

Recent advances in tumour antigen‐specific therapy: In vivo veritas

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Immunisation of metastatic cancer patients with MAGE-3 protein combined with adjuvant SBAS-2: a clinical report

Cited by 154 publications

References 16 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

The CD4+ T‐cell epitope‐binding register is a critical parameter when generating functional HLA‐DR tetramers with promiscuous peptides

Recent advances in tumour antigen‐specific therapy: In vivo veritas

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The CD4⁺ T‐cell epitope‐binding register is a critical parameter when generating functional HLA‐DR tetramers with promiscuous peptides