Biomedical subjects

Fabrice André

Publications and source records attributed to Fabrice André.

13 recordsLinked to original sources

PubMed2006

DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy.

BACKGROUND: Adjuvant cisplatin-based chemotherapy improves survival among patients with completely resected non-small-cell lung cancer, but there is no validated clinical or biologic predictor of the benefit of chemotherapy. METHODS: We used immunohistochemical analysis to determine the expression of the excision repair cross-complementation group 1 (ERCC1) protein in operative specimens of non-small-cell lung cancer. The patients had been enrolled in the International Adjuvant Lung Cancer Trial, thereby allowing a comparison of the effect of adjuvant cisplatin-based chemotherapy on survival, according to ERCC1 expression. Overall survival was analyzed with a Cox model adjusted for clinical and pathological factors. RESULTS: Among 761 tumors, ERCC1 expression was positive in 335 (44%) and negative in 426 (56%). A benefit from cisplatin-based adjuvant chemotherapy was associated with the absence of ERCC1 (test for interaction, P=0.009). Adjuvant chemotherapy, as compared with observation, significantly prolonged survival among patients with ERCC1-negative tumors (adjusted hazard ratio for death, 0.65; 95% confidence interval [CI], 0.50 to 0.86; P=0.002) but not among patients with ERCC1-positive tumors (adjusted hazard ratio for death, 1.14; 95% CI, 0.84 to 1.55; P=0.40). Among patients who did not receive adjuvant chemotherapy, those with ERCC1-positive tumors survived longer than those with ERCC1-negative tumors (adjusted hazard ratio for death, 0.66; 95% CI, 0.49 to 0.90; P=0.009). CONCLUSIONS: Patients with completely resected non-small-cell lung cancer and ERCC1-negative tumors appear to benefit from adjuvant cisplatin-based chemotherapy, whereas patients with ERCC1-positive tumors do not.

Adult↗

PubMed2006

Dendritic cell derived-exosomes: biology and clinical implementations.

Exosomes are nanometer-sized membrane vesicles invaginating from multivesicular bodies and secreted from different cell types. They represent an "in vitro" discovery, but vesicles with the hallmarks of exosomes are present in vivo in germinal centers and biological fluids. Their protein and lipid composition is unique and could account for their expanding functions such as eradication of obsolete proteins, antigen presentation, or "Trojan horses" for viruses or prions. The potential of dendritic cell-derived exosomes (Dex) as cell-free cancer vaccines is addressed in this review. Lessons learned from the pioneering clinical trials allowed reassessment of the priming capacities of Dex in preclinical models, optimizing clinical protocols, and delineating novel, biological features of Dex in cancer patients.

Animals↗

PubMed2005

Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial.

BACKGROUND: DC derived-exosomes are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection. Here we report the feasability and safety of the first Phase I clinical trial using autologous exosomes pulsed with MAGE 3 peptides for the immunization of stage III/IV melanoma patients. Secondary endpoints were the monitoring of T cell responses and the clinical outcome. PATIENTS AND METHODS: Exosomes were purified from day 7 autologous monocyte derived-DC cultures. Fifteen patients fullfilling the inclusion criteria (stage IIIB and IV, HLA-A1+, or -B35+ and HLA-DPO4+ leukocyte phenotype, tumor expressing MAGE3 antigen) were enrolled from 2000 to 2002 and received four exosome vaccinations. Two dose levels of either MHC class II molecules (0.13 versus 0.40 x 1014 molecules) or peptides (10 versus 100 mug/ml) were tested. Evaluations were performed before and 2 weeks after immunization. A continuation treatment was performed in 4 cases of non progression. RESULTS: The GMP process allowed to harvest about 5 x 1014 exosomal MHC class II molecules allowing inclusion of all 15 patients. There was no grade II toxicity and the maximal tolerated dose was not achieved. One patient exhibited a partial response according to the RECIST criteria. This HLA-B35+/A2+ patient vaccinated with A1/B35 defined CTL epitopes developed halo of depigmentation around naevi, a MART1-specific HLA-A2 restricted T cell response in the tumor bed associated with progressive loss of HLA-A2 and HLA-BC molecules on tumor cells during therapy with exosomes. In addition, one minor, two stable and one mixed responses were observed in skin and lymph node sites. MAGE3 specific CD4+ and CD8+ T cell responses could not be detected in peripheral blood. CONCLUSION: The first exosome Phase I trial highlighted the feasibility of large scale exosome production and the safety of exosome administration.

Journal Article↗

PubMed2005

Chemoprevention of lung cancer.

Lung cancer remains a major cause of mortality worldwide, despite advances in surgery, radiotherapy and chemotherapy. Most patients present with advanced disease, and early detection approaches are still experimental. Chemoprevention strategies are therefore essential. Chemoprevention can be defined as the use of specific natural or synthetic chemical agents to reverse, suppress or prevent progression to invasive cancer. The present review will provide an update on lung cancer clinical chemoprevention trials as well as the molecular basis of lung carcinogenesis. A better knowledge of lung carcinogenesis is obviously fundamental to improve chemoprevention strategies. Identification of molecular defects involved in premalignant lesions and/or invasive cancer could lead to clinical studies with new molecular-targeted agents (mainly tyrosine kinase inhibitors, farnesyl-transferase inhibitors and/or antiangiogenic molecules) and the development of surrogate biomarkers. Such biomarkers would be essential to detect high-risk patients, select adequate chemoprevention strategies and monitor drug efficacy. New chemoprevention trials are planned with collaborative efforts of researchers involved in fundamental or clinical studies.

Anticarcinogenic Agents↗

PubMed2005

The potential of exosomes in immunotherapy.

In 1996, B cell-derived exosome immunogenicity was first reported. In 1998, dendritic cell-derived exosomes were also shown to have immunogenic properties in mice, leading to tumour eradication. These observations showed for the first time that exosomes were bioactive vesicles with immuno-regulatory roles and potent antitumour effects. Exosomes are secreted vesicles formed in late endocytic compartments (multivesicular bodies). Vesicles exocytosed from multivesicular bodies into the extracellular medium are referred to as 'exosomes' and should not be confused with the more recently described 'ribonuclease complex' also named exosome. Exosomes are vesicles of 50-100 nm in diameter, formed by inward budding of the endosomal membrane in a process that sequesters particular proteins and lipids. This review will describe the biogenesis, the protein and lipid compositions, and the biological functions of exosomes; this review will also present their immunostimulatory functions in mice and humans, and will discuss their possible use as cancer vaccines.

Animals↗

PubMed2004

[Expression of chemokine receptors by cancer cells].

Chemokine receptors are involved in the trafficking of leucocytes. It has been shown recently that chemokine receptors (CXCR4, CCR7...) are expressed by breast cancer cells and could be involved in the metastasis phenomenon. Since this discovery, new data have been generated in this topic. These data confirm that chemokine receptors are involved in the occurrence of metastases, suggest that their expression is regulated by genes involved in the carcinogenesis and/or angiogenesis (VHL...) and that inhibitors could be of interest in the treatment of breast cancer. In this paper, we will review all these data and will discuss the perspectives that opens this new concept.

Breast Neoplasms↗

PubMed2004

Breast-conserving surgery after neoadjuvant anthracycline-based chemotherapy for large breast tumors.

BACKGROUND: Randomized trials comparing neoadjuvant versus adjuvant chemotherapy show that primary chemotherapy allows more frequent breast-preserving surgery even though no survival advantage has been demonstrated. The aim of the current study was to determine the predicting factors and the survival impact of breast conservation in patients with large breast tumors treated with neoadjuvant chemotherapy. METHODS: Between January 1987 and December 2001, 594 patients with invasive T2-3 breast carcinoma who were ineligible for breast-conserving surgery (the mean initial tumor diameter was 49 mm) were treated with 3 or 4 courses of an anthracycline-based primary chemotherapy, surgery, and radiotherapy. Various clinicopathologic factors were tested as possible predicting factors of breast-preserving surgery. Survival analyses were performed to determine the implications of breast-conserving surgery on outcome. RESULTS: After primary chemotherapy, 287 (48%) patients were eligible for breast-conserving surgery and 307 patients underwent a mastectomy. Initial tumor diameter > 5 cm, low histologic grade, lobular histology, and multicentricity were independent predicting factors of breast conservation ineligibility in the multivariate analysis (logistic regression). In the univariate survival analysis, a failure of breast-preserving surgery was associated with a poor outcome. Local disease recurrence-free survival rates were similar in patients treated with lumpectomy and mastectomy. CONCLUSIONS: The results reported in the current study suggested that initial diameter, histologic type and grade, and multicentricity are potential prechemotherapy predicting factors of breast conservation. When carefully selected, patients treated with breast conservation had a risk of local disease recurrence similar to the risk of chest wall disease recurrence after mastectomy.

Adult↗

PubMed2004

Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells.

Current immunization protocols in cancer patients involve CTL-defined tumor peptides. Mature dendritic cells (DC) are the most potent APCs for the priming of naive CD8(+) T cells, eventually leading to tumor eradication. Because DC can secrete MHC class I-bearing exosomes, we addressed whether exosomes pulsed with synthetic peptides could subserve the DC function consisting in MHC class I-restricted, peptide-specific CTL priming in vitro and in vivo. The priming of CTL restricted by HLA-A2 molecules and specific for melanoma peptides was performed: 1) using in vitro stimulations of total blood lymphocytes with autologous DC pulsed with GMP-manufactured autologous exosomes in a series of normal volunteers; 2) in HLA-A2 transgenic mice (HHD2) using exosomes harboring functional HLA-A2/Mart1 peptide complexes. In this study, we show that: 1). DC release abundant MHC class I/peptide complexes transferred within exosomes to other naive DC for efficient CD8(+) T cell priming in vitro; 2). exosomes require nature's adjuvants (mature DC) to efficiently promote the differentiation of melanoma-specific effector T lymphocytes producing IFN-gamma (Tc1) effector lymphocytes in HLA-A2 transgenic mice (HHD2). These data imply that exosomes might be a transfer mechanism of functional MHC class I/peptide complexes to DC for efficient CTL activation in vivo.

Animals↗

PubMed2004

Exosomes as potent cell-free peptide-based vaccine. II. Exosomes in CpG adjuvants efficiently prime naive Tc1 lymphocytes leading to tumor rejection.

Ideal vaccines should be stable, safe, molecularly defined, and out-of-shelf reagents efficient at triggering effector and memory Ag-specific T cell-based immune responses. Dendritic cell-derived exosomes could be considered as novel peptide-based vaccines because exosomes harbor a discrete set of proteins, bear functional MHC class I and II molecules that can be loaded with synthetic peptides of choice, and are stable reagents that were safely used in pioneering phase I studies. However, we showed in part I that exosomes are efficient to promote primary MHC class I-restricted effector CD8(+) T cell responses only when transferred onto mature DC in vivo. In this work, we bring evidence that among the clinically available reagents, Toll-like receptor 3 and 9 ligands are elective adjuvants capable of triggering efficient MHC-restricted CD8(+) T cell responses when combined to exosomes. Exosome immunogenicity across species allowed to verify the efficacy of good manufactory procedures-manufactured human exosomes admixed with CpG oligonucleotides in prophylactic and therapeutic settings of melanoma in HLA-A2 transgenic mice. CpG adjuvants appear to be ideal adjuvants for exosome-based cancer vaccines.

Adjuvants, Immunologic↗

PubMed2004

Exosome-based immunotherapy.

Exosomes are small membrane vesicles originating from late endosomes and secreted by hematopoietic and epithelial cells in culture. Exosome proteic and lipid composition is unique and might shed some light into exosome biogenesis and function. Exosomes secreted from professional antigen-presenting cells (i.e., B lymphocytes and dendritic cells) are enriched in MHC class I and II complexes, costimulatory molecules, and hsp70-90 chaperones, and have therefore been more extensively studied for their immunomodulatory capacities in vitro and in vivo. This review will present the main biological features pertaining to tumor or DC-derived exosomes, will emphasize their immunostimulatory function, and will discuss their implementation in cancer immunotherapy.

Antigen Presentation↗

PubMed2004

[Adjuvant chemotherapy in non-small cell lung cancer].

Lung cancer is the leading cause of cancer death in France. Nearly 80% of lung tumors are non-small cell lung cancers (NSCLC). Surgery is the best curative approach, but it only concerns 30% of NSCLC, since the diagnosis is frequently made in patients with locally advanced or metastatic disease. Even when surgery is performed relapse occurs in up to 50% of patients. Several adjuvant trials have been led in the late 90's after an individual data-based meta-analysis suggested a 5% survival benefit at 5 years. Among those, the IALT study, with 1 867 patients included, confirms the benefit of post-operative chemotherapy in resected NSCLC. In this article, the current status of adjuvant chemotherapy is reviewed, and future prospects are discussed.

Antineoplastic Agents↗

PubMed2002

From the antigen-presenting cell to the antigen-presenting vesicle: the exosomes.

Exosomes are membrane vesicles of 30 to 100 nm in diameter, of endocytic origin, and are produced and secreted in vitro by living cells of diverse origin. In vivo and in vitro experiments suggest, from their particular proteomic composition, that exosomes are involved in the transfer of tumor antigens to antigen presenting cells, and in the stimulation of a specific immune response. In this review, we provide a molecular characterization of exosomes. The hypotheses accounting for exosome biogenesis will be outlined. Finally, we will describe their bioactivities and discuss their potential relevance and clinical implementation for cancer immunotherapy.

Animals↗

PubMedDate not supplied

The potential of exosomes in immunotherapy of cancer.

Dendritic-cell-derived exosomes (DEX) secreted after dendritic cell loading with tumor peptides were found to mediate tumor rejection in mice. This observation prompted us to demonstrate that MHC class I/peptide complexes harbored onto exosomal membranes were capable of priming cytotoxic T cells and to mediate rejection of tumors expressing the relevant antigens. Moreover, DEX also promote NK cell activation in immunocompetent mice and NK cell-dependent antitumor effects. The first Phase I trial using DEX to immunize melanoma patients revealed the feasibility of DEX production in stage IV melanoma, their safety in long-term follow up and their bioactivity in vivo.

Animals↗