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Biomedical subjects

E Tartour

Publications and source records attributed to E Tartour.

At least 37 records · Page 2Linked to original sources
PubMed1998

Gene therapy with cytokine-transfected xenogeneic cells in metastatic tumors.

On the basis of compelling preclinical data in cats and dogs we initiated a clinical gene therapy study in nine patients with advanced solid tumors using xenogeneic fibroblasts secreting human IL-2 (Vero-IL-2 cells). Cohorts of three successive patients with tumors accessible to CT- or ultrasound-guided injection were treated repeatedly with 5 x 10(5), 5 x 10(6), or 5 x 10(7) Vero-IL-2 cells. Endpoints of the study were feasibility, toxicity, and clinical and biological effects of this novel approach to immunotherapy of cancer. Histopathological, immunological and molecular analyses were performed on biopsy specimens of tumors and blood samples from before, during and after treatment. Low levels of serum antibodies to Vero cells developed in 2/9 patients. Analysis of tumor biopsies showed increased expression of CD3 mRNA and enhanced tumor infiltration with varying lymphocyte subpopulations after treatment. In addition, monoclonal alterations of the TCR repertoire of blood and tumor lymphocytes were observed. Treatment was well tolerated and toxicity consisted of transient fever in one patient and short-lived, mild itching and erythema in two others. One patient with soft tissue sarcoma showed a more than 90% and more than 50% reduction of the volume of two distant, non-injected metastases, respectively, lasting for 22+ months. Four other patients showed stabilization of their disease for three to nine months, among whom was a patient with melanoma who developed marked vitiligo. We conclude that repeated injection of up to 5 x 10(7) Vero-IL-2 cells was safe and showed biological and clinical activity in heavily pretreated patients with advanced solid tumors. Further evaluation of intratumoral application of Vero-IL-2 seems warranted.

Adult↗
PubMed1998

In vivo induction of functional Fc gammaRI (CD64) on neutrophils and modulation of blood cytokine mRNA levels in cancer patients treated with G-CSF (rMetHuG-CSF).

Neutrophils from 13 children who received G-CSF for the collection of peripheral blood progenitors while they were in haematological steady state were studied at various times after G-CSF injection for Fc gammaR expression (Fc gammaRI or CD64, Fc gammaRII or CD32, and Fc gammaRIII or CD16) and for their ability to exert antibody-dependent cell cytotoxicity (ADCC) through Fc gammaRI. Changes in IFNgamma, IL8, IL10, MCP1 and TNF alpha mRNA levels in peripheral blood cells were also studied 4 h and 24 h after the first G-CSF injection. Fc gammaRI expression increased strongly after 24 h and then remained at the same level throughout treatment. In contrast, Fc gammaRIII expression sharply decreased at day 1 and diminished even further thereafter. No change in Fc gammaRII was observed. ADCC exerted by neutrophils through Fc gammaRI started to increase after 24 h with the peak level at day 5. Cytokine mRNA analyses indicated a reproducible and strong increase of IL8 mRNA (11/13 children) after 24 h, whereas the changes in the mRNA levels of the other cytokines tested were more heterogenous (TFNgamma: three; IL10: six; MCP1: five: TNF alpha: four, of the 13 children). Therefore this study opens the way to an optimized therapeutic schedule for the combined use of G-CSF and monoclonal antibodies in adjuvant immuno-intervention.

Adolescent↗
PubMed1998

Cytokines and cancer.

The relationships between cytokines and cancer are multiple and bidirectional. On the one hand, cytokines may directly influence carcinogenesis and metastasis by modifying the tumor phenotype. On the other hand, during tumor progression, modifications of the cytokine expression in the tumor environment may be induced by the tumor cells, leading to a state of immunosuppression reflected by low cytokine expression in tumor stroma. Cytokines also play a role by stimulating the host immune system to generate anti-tumor specific responses. Finally, the use of cytokines as anti-tumor agents has led to objective clinical responses in about 15-25% of patients with metastatic melanoma or renal cell carcinoma, which presents the basis for the development of promising immunotherapeutic approaches for cancer therapy.

Animals↗
PubMed1998

[Fas, fas ligand, immune tolerance, and cancer: implications in cancer of the colon].

Fas and Fas ligand (FasL) are implicated in programmed cell death or apoptosis. In the immunological field, they are particularly important in auto-immunity, graft rejection and anti-tumoral response. Fas ligand expression on thymocytes, activated T lymphocytes, and in sites of immune privilege, suggests the importance of Fas/FasL interactions in negative control of the immune response. The recent description of FasL expression by tumoral cells, represents a new mechanism of immune escape for different cancer, and has been well studied in colon adenocarcinoma.

Apoptosis↗
PubMed1997

Soluble interleukin-2 receptor serum level as a predictor of locoregional control and survival for patients with head and neck carcinoma: results of a multivariate prospective study.

BACKGROUND: The diagnosis and follow-up of head and neck carcinoma patients are based exclusively on clinical staging, which cannot always predict clinical outcome accurately. Because oral squamous cell carcinomas produce interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha and express IL-2 receptors, the authors assessed the prognostic value of the serum levels of these markers. METHODS: Serum levels of IL-6, TNF-alpha, soluble IL-2 receptors (s-IL-2-R), and acute phase proteins were measured at the time of diagnosis in a prospective study of 85 patients with primary squamous cell carcinoma of the head and neck. The influence of each clinical and laboratory parameter on locoregional control and survival was analyzed. RESULTS: At presentation, a relationship was observed between advanced tumor (T) classification and high serum levels of CRP (P = 0.0015) and s-IL-2-R (P < 0.05). A high lymph node (N) classification was significantly associated with elevated serum IL-6 (P = 0.01) and CRP levels (P = 0.0002). In the univariate analysis, T classification, N classification, performance status, Prognostic Inflammatory and Nutritional Index, and serum s-IL-2-R level were significantly correlated with both locoregional control and survival. Multivariate analysis showed that the only significant prognostic factors related independently to locoregional control were N classification (P = 0.02) and serum s-IL-2-R level (P = 0.02). In a Cox multivariate analysis, serum s-IL-2-R level was found to be the most predictive factor of survival (P = 0.0001). CONCLUSIONS: This study shows that serum s-IL-2-R level at the time of diagnosis represents a new independent prognostic variable for predicting the risk of locoregional recurrence and survival for patients with head and neck squamous cell carcinoma.

Adult↗
PubMed1997

Regulation of CD44 isoform expression and CD44-mediated signaling in human dendritic cells.

Dendritic cells (DCs) express CD44, a cell surface receptor for the extracellular matrix ligand hyaluronate, involved in cell-cell interactions and cell migration. Besides the "standard" form of CD44, a variety of splice variants contain an additional extracellular region encoded by 10 "variable" exons termed v1 to v10. The standard form of CD44 as well as variants containing exon v6 (CD44v6) are known to play important roles in the immune system, yet largely unexplored in the DC lineage. In this study, we examined the regulation of CD44 isoforms in human DCs derived from monocytes cultivated in the presence of GM-CSF and IL-4. We found that v3, v6 and v9 variants are all up-regulated upon TNF-alpha stimulation of DCs. In addition, we show that stimulation of DCs using anti-CD44 mAbs can induce DC agregation, up-regulation of accessory molecule expression and secretion of cytokines. A mAb directed against CD44v6 variants was shown to mediate some of these effects.

Antibodies, Monoclonal↗
PubMed1997

The use of cytokines in the treatment of solid tumours.

This manuscript reviews the clinical trials with cytokines in solid tumors. Starting with Interleukin 2 alone or in association with other cytokines and chemotherapy, the reviews opens the prospects of future direction for the use of cytokines as adjuvant therapy, for vaccination or to inhibit the growth activity of certain cytokines.

Animals↗
PubMed1997

IL-6 is a survival prognostic factor in renal cell carcinoma.

It has been reported that a high plasmatic concentration of interleukin-6 (IL-6) is correlated to a lack of response to immunotherapy in several malignancies, suggesting that IL-6 was either a marker of tumour aggressiveness or had only a predictive value of response to immunotherapy. To discriminate between these two possibilities, a retrospective study was performed in a series of 19 patients with metastatic renal cell carcinoma who did not respond to IL-2/IFNalpha/5-FU treatment. Serum levels of IL-6, C-reactive Protein (CRP), soluble IL-2-receptor (sIL-2R), M-CSF and neopterin were assayed before treatment. IL-6 showed a significant correlation with patients median survival time (P < 0.016), suggesting that serum concentration of IL-6 before treatment is a marker of tumour aggressiveness rather than a predictive parameter for an immunological response.

Adult↗
PubMed1997

Characterization of soluble gp130 released by melanoma cell lines: A polyvalent antagonist of cytokines from the interleukin 6 family.

gp130 acts as a common transducing signal chain for all receptors belonging to the interleukin (IL)-6 receptor family. The IL-6-related cytokines [IL-6, IL-11, oncostatin M (OSM), leukemia inhibitory factor, ciliary neurotrophic factor, and cardiotrophin] often modulate tumor phenotype and control the proliferation of many tumor cell lines. We demonstrate that melanoma cell lines release, in vitro and in vivo (when transplanted in nude mice), soluble gp130 (sgp130), a potential antagonist of cytokines from the IL-6 family. Biochemical analysis revealed that sgp130 derived from melanoma patients' sera or from culture supernatants of melanoma cell lines is a Mr 104,000 protein that resolved after deglycosylation as a Mr 58,000 protein. PCR and Northern blot analysis only identified one gp130 membrane mRNA, suggesting that the soluble form of gp130 is generated by proteolytic cleavage. OSM reproducibly increases sgp130 released by melanoma cell lines, whereas leukemia inhibitory factor stimulates the production of sgp130 in only one of three cell lines tested. This tumor-derived sgp130 is functional because it binds in solution to the IL-6-soluble IL-6 receptor (gp80) complex. Recombinant sgp130 inhibits the growth inhibitory activity of the IL-6-soluble IL-6 receptor complex and OSM on some melanoma cell lines. Therefore, this soluble gp130 represents a natural antagonist of cytokines from the IL-6 family.

Animals↗
PubMed1996

[Immunotherapy in the treatment of cancers].

The recent discovery of the molecular structure of tumor antigens expressed by melanoma cells has contributed to the development of therapeutic strategies aimed at stimulating anti-tumor immunity. The first clinical trials in patients with cancer involved systemic administration of interleukin 2 alone or in combination with alpha-interferon or other chemotherapy agents. Objective clinical responses were observed in 15 to 25% of the patients with melanomas or renal cell cancer. In order to improve these encouraging early results, different clinical protocols are being evaluated with the goal of increasing intra-tumoral concentrations of the administered cytokines. Better optimization of methods for immunizing against specific tumor antigens naturally leads to the transition from non-specific stimulation of the human immune system to tumor antigen specific immunotherapy.

Animals↗
PubMed1996

Decreased frequency of HLA-DRB1 13 alleles in Frenchwomen with HPV-positive carcinoma of the cervix.

Specific types of human papillomaviruses (HPV) are associated with most cases of pre-invasive and invasive neoplasia of the uterine cervix. HLA phenotype influences susceptibility and resistance to viral infections and may therefore influence the course of HPV-associated tumors. Some data suggest that specific HLA class-II alleles may be associated with protection from or susceptibility to papillomavirus-associated lesions, but these results are still controversial. Using molecular probes, we looked for associations between specific DQA1, DQB1, DRB1 HLA class-II alleles, HPV types and cervical cancer. The analysis was performed on a population of 126 patients with invasive cervical cancer. For HLA typing, 165 healthy individuals were taken as controls. The DRB1 1301/02 allele frequency significantly decreased in patients (11%) as compared to controls (29%). This difference in frequency was dependent on the HPV-positive status of tumors and was no longer significant in the group of HPV-negative lesions. The same trends were observed with the DRB1 1301/02-DQA1 0103-DQB1 0603 haplotype frequency. An increase in the frequency of the DRB1 1401/07 and DRB1 03 alleles was observed in patients under 40. Contrary to what has been reported in the literature, no increase in the DRB1 15 allele frequency was observed in our series and only a slight increase in the DQB1 03 frequency was found in patients (70%) compared to controls (58%). In our study, no positive correlations between cervical cancer in Frenchwomen and specific HLA DR-DQ haplotypes has been found. In contrast, a negative correlation between DRB1 1301/ 02 alleles and HPV-positive tumors has been observed. This may suggest a protective effect of DR13 against HPV-associated lesions of the cervix.

Adult↗
PubMed1996

Macrophage inflammatory protein-1alpha is induced by human immunodeficiency virus infection of monocyte-derived macrophages.

Disparate findings have been reported as to whether human immunodeficiency virus (HIV) affects cytokine production by macrophages (MA). We investigated production of different cytokines and of macrophage inflammatory protein (MIP)-1alpha by HIV-1Ba-L- or HIV-1Ada-infected blood-derived MA. Relative to controls, only MIP-1alpha levels increased twofold to > 10-fold in supernatants 2 to 3 weeks postinfection (PI), at the time of maximum virus production; levels of the other chemokines (RANTES, interleukin (IL)-8) and cytokines (IL-1alpha, IL-3, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1) investigated were not affected. MIP-1alpha mRNA signal assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) was, however, only occasionally greater in cells from infected cultures relative to controls. MIP-1alpha levels in supernatants remained in the same range as in control cultures when more than 10 mmol/L Zidovudine was added 24 hours PI, which indicates involvement of virus replication in the effect. Anti-MIP-1alpha antibody labeling identified a 10% to 25% subset of MA, strongly expressing HLA-DR and CD4, and also stained by anti-IL-6 and anti-TNF-alpha antibodies. Two weeks PI, dual staining showed that the majority of the 5% to 20% cells that were p24+ belonged to the MIP-1alpha+ population, which may define a MA subset capable to better sustain HIV replication. MIP-1alpha induced by HIV replication in MA might play a role in the pathophysiology of HIV infection; in impaired hematopoiesis; or as a CD4+ and CD8+ lymphocyte chemoattractant, by recruiting either or both HIV-susceptible and cytotoxic T lymphocytes to virus replication sites.

Antiviral Agents↗
PubMed1996

Phenotypic and functional characterisation of tumour-infiltrating lymphocytes derived from thyroid tumours.

The natural history of thyroid tumours and the hyper-reactivity of the immune system in patients with thyroid cancer suggest that immune surveillance may play a role in the control of this disease. A study was therefore undertaken to analyse the phenotypic and functional features of tumour-infiltrating lymphocytes (TILs) derived from thyroid tumours. In a series of experiments, it was found that, in contrast to TILs derived from patients with melanoma or renal cell carcinoma, thyroid TILs could be efficiently expanded in vitro only in the presence of allogeneic EBV transformed B (B. EBV) cells. Indeed, only one of the seven thyroid-derived TILs grew in vitro without feeder cells, whereas all 16 thyroid-derived TILs could be expanded in the presence of allogeneic B. EBV feeder cells. Phenotypic analysis of these TILs revealed a frequent in vitro expansion of an unusual T cell population that expressed both the CD4 and CD8 markers. Indeed, it was demonstrated that in five of 14 TILs in short-term culture (< day 23) and four of 11 TILs in long-term culture (> day 40), a lymphocyte population that coexpressed CD4 and CD8 antigen accounted for more than 15% of the total TIL population. This double-positive T cell population was not observed in TILs derived from melanoma or renal cell carcinoma. Thyroid-derived TILs also displayed an intense cytolytic activity against NK-sensitive tumour targets with 10 of 11 TILs exhibiting significant cytotoxicity towards the NK-sensitive K562 cell line. Six of 11 TILs were also cytotoxic towards autologous tumour, but when cold target inhibition with K562 was performed with three cultures, unlabelled K562 completely inhibited lysis of autologous tumour cells. A significant expansion of CD3+CD56+ T cells in the different TIL populations may explain this high level of NK-like cytotoxicity. In conclusion, TILs derived from thyroid tumours could be efficiently expanded in vitro under certain culture conditions. Different strategies must be explored to enhance their specific tumour autologous specificity, however, before they can be used in immunotherapy protocols.

Adult↗
PubMed1996

Soluble CD16 (sCD16), a marker of malignancy in individuals with monoclonal gammopathy of undetermined significance (MGUS).

There are no well-defined host markers to determine which patients with a diagnosis of monoclonal gammopathy of undetermined significance (MGUS) will progress to multiple myeloma (MM). In this preliminary study we measured plasmatic soluble Fe gamma receptor type III (sFe gamma RIII or sCD16) in 54 individuals with MGUS. 35 patients with multiple myeloma (MM) and 29 healthy controls. We confirmed, through receiver operating characteristic (ROC) curve analysis, that a low level of sCD16 discriminates MM patients from controls. Indeed, for a sCD16 value of 1.3 micrograms/ml, the sensitivity, as well as the specificity, of this discrimination were both equal to 83%, i.e. 83% of MM patients had a plasmatic sCD16 value < 1.3 micrograms/ml compared with only 17% of controls. Moreover, ROC curve analysis showed that a low sCD16 level also identifies among MGUS patients a subgroup of patients who rapidly progress towards multiple myeloma: in this comparison, for a sCD16 level of 1.3 micrograms/ml. sensitivity and specificity were 70% and 79% respectively. Therefore a low sCD16 level in MGUS indicated a high likelihood of rapid evolution of MM. In contrast to sCD16, soluble IL-6R did not appear to be discriminant in this study.

Adult↗
PubMed1996

Predictors of clinical response to interleukin-2--based immunotherapy in melanoma patients: a French multiinstitutional study.

PURPOSE: Various parameters have been reported to be correlated with response to interleukin-2 (IL-2) therapy. A multiinstitutional study was performed to assess by multivariate analysis the predictive value of known clinical and biologic melanoma prognostic markers recorded before the onset of IL-2 therapy on the likelihood of objective clinical response. PATIENTS AND METHODS: Serum C-reactive protein (CRP), IL-6, and lactate dehydrogenase (LDH) levels were measured in 81 metastatic melanoma patients included in different IL-2-based regimens before the starting of IL-2-therapy. Clinically defined prognostic groups, i.e., patients with superficial or visceral metastases, were also analyzed for response correlates. Patients were evaluated for response to treatment 4 to 6 weeks after completion of one course of therapy. RESULTS: On univariate analysis, the pretreatment values of CRP (P = .001), IL-6 (P = .007), and LDH (P = .02) and site of metastases (P = .0004) were correlated with clinical response. However, only CRP (P < .007) and clinically defined group (P < .004) were independent predictors on multifactorial analysis. Indeed, when adjusted to CRP, IL-6 tended to improve patient selection, but did not reach statistical significance (P = .07). Furthermore, using multivariate survival analysis based on the Cox proportional hazards model, only CRP was found to be an independent prognostic factor for survival (P < .0001). CONCLUSION: In this study, patients with high serum levels of CRP and/or visceral organ involvement before therapy were unlikely to respond to IL-2 therapy. Therefore, clinical classification based on the site of metastases and serum CRP determination before the start of IL-2 therapy may help to improve selection of melanoma patients who may benefit from IL-2 and could prevent unnecessary morbidity.

Adult↗