Lausanne, Switzerland
Lausanne, Switzerland

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Jebahi S.,CNRS Chemistry Institute of Rennes | Jebahi S.,University of Sfax | Saoudi M.,University of Sfax | Farhat L.,Service of Medical Oncology | And 5 more authors.
Cell Biochemistry and Function | Year: 2015

Radiation therapy contributes to a significant increase in bone osteoporosis and skin loss. Various natural health products might be beneficial to reduce bone and skin alterations. Curcumin (CUR) medicines derived from natural plants have played an important role in health care. This study aims at synthesizing and evaluating the performance therapy of CUR-encapsulated bioglass-chitosan (CUR-BG-CH). In vitro, the antioxidant assay was evaluated by using 1,1-diphenyl-2-picrylhydrazyl free-radical (DPPH) scavenging and the nitroblue tetrazolium reduction. The CUR-BG-CH antimicrobial effects were tested in liquid media. In vivo, after rat 60Co γ-radiation, the tissue wound-healing process was studied by grafting CUR and CUR-BG-CH in femoral condyle and dorsal skin rat tissue. The antioxidant studies indicated that CUR-BG-CH quenches free radicals more efficiently than unmodified CUR and had effective DPPH (91%) and superoxide anion (51%) radical scavenging activities. The CUR-BG-CH biomaterial exhibited an important antimicrobial activity against Staphylococcus aureus. The histomorphometric parameters showed amelioration in CUR-BG-CH-treated rats. An improved mechanical property was noticed (33.16±5.0HV) when compared with that of unmodified CUR group (23.15±4.9 HV). A significant decrease in tumour necrosis factor-α cytokine production was noted in the CUR-BG-CH rats (90pg/ml) as compared with that of unmodified CUR group (240pg/ml). The total amount of hydroxyproline was significantly enhanced (33.5%) in CUR-BG-CH group as compared with that of control. Our findings suggested that CUR-BG-CH might have promising potential applications for wound healing. © 2015 John Wiley & Sons, Ltd.


PubMed | Laboratory of Tumor Immunobiology, University of Lausanne, Service of Medical Oncology, University of Athens Medical School and University of Tübingen
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Enhancing immune responses with immune-modulatory monoclonal antibodies directed to inhibitory immune receptors is a promising modality in cancer therapy. Clinical efficacy has been demonstrated with antibodies blocking inhibitory immune checkpoints such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) or PD-1/PD-L1. Treatment with ipilimumab, a fully human CTLA-4-specific mAb, showed durable clinical efficacy in metastatic melanoma; its mechanism of action is, however, only partially understood. This is a study of 29 patients with advanced cutaneous melanoma treated with ipilimumab. We analyzed peripheral blood mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients responding and 14 not responding to ipilimumab by multicolor flow cytometry, antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and immunohistochemistry. PBMCs and matched tumor biopsies were collected 24 h before (i.e., baseline) and up to 4 wk after ipilimumab. Our findings show, to our knowledge for the first time, that ipilimumab can engage ex vivo FcRIIIA (CD16)-expressing, nonclassical monocytes resulting in ADCC-mediated lysis of regulatory T cells (Tregs). In contrast, classical CD14(++)CD16(-) monocytes are unable to do so. Moreover, we show that patients responding to ipilimumab display significantly higher baseline peripheral frequencies of nonclassical monocytes compared with nonresponder patients. In the tumor microenvironment, responders have higher CD68(+)/CD163(+) macrophage ratios at baseline and show decreased Treg infiltration after treatment. Together, our results suggest that anti-CTLA-4 therapy may target Tregs in vivo. Larger translational studies are, however, warranted to substantiate this mechanism of action of ipilimumab in patients.


Trape J.,Service of Laboratory Medicine | Molina R.,Hospital Clinic Of Barcelona | Sant F.,Service of Pathology | Montesinos J.,Service of Medical Oncology | And 11 more authors.
Tumor Biology | Year: 2012

The utility of tumour markers (TM) in the differential diagnosis of cancer in serous effusion (fluid effusion (FE)) has been the subject of controversy. The aim of this study was to prospectively validate our previous study and to assess whether the addition of adenosine deaminase (ADA), C-reactive protein (CRP) or percentage of polymorphonuclear cells (%PN) allows the identification of false positives. In this study, carcinoembryonic antigen, cancer antigen 15-3, cancer antigen 19-9, ADA, CRP and %PN in FE were determined in 347 patients with 391 effusions. Effusions were considered as malignant effusion when at least one TM in serum exceeded the cutoff and the ratio FE/S was higher than 1.2. Also, cases with values of ADA, CRP and %PN above the established cutoffs in serous effusion were considered as potential false positives. The combined sensitivity and specificity of the three TM was 76.2 % (95 % confidence intervals (CI) 67.8-83.3 %) and 97.0 % (95 % CI 94.1-98.7), respectively. Subanalysis of the 318 cases with previous criteria and negative ADA, CRP and %PN obtained sensitivities of 78.4 % (95 % CI 69.4-85.6) and a specificity of 100 % (95 % CI 98.2-100). The results obtained validate our previous study and are improved with the addition of ADA, CRP and %PN. TM in serous effusions and serum could be useful for the diagnostic assessment of patients with serous effusions. © 2012 International Society of Oncology and BioMarkers (ISOBM).


Gaba L.,Service of Medical Oncology | Mellado B.,Service of Medical Oncology | Ribalta T.,Service of Pathology
Journal of the Neurological Sciences | Year: 2012

Paraneoplastic cerebellar degeneration (PCD) is characterized by a subacute, severe pancerebellar syndrome, which is related to an underlying tumor. The presence of CSF or serum onconeural antibodies confirms the diagnosis and indicates the underlying tumor type. However, the association between PCD and extragonadal germ cell tumors with the absence of an onconeural antibody has rarely been described. We present a 55-year-old man who developed a pancerebellar syndrome, which made him unable to walk alone after 10 months. Routine blood analysis, brain MRI and CSF examination were normal. Despite onconeural antibodies were negative, a whole body PET-CT scan showed a hypermetabolic nodule in the thymus, which was removed, and a hypometabolic presacral mass. The pathologic study revealed a germinoma surrounded by a pronounced inflammatory infiltrate. Shortly after, the patient clearly improved his symptoms, before receiving chemotherapy and prednisone. The cerebellar ataxia worsened when steroids were reduced below 30 mg/day. Testicular sonography showed a suspicious lesion in one testicle, but no malignancy was found after orchiectomy. The presacral mass was removed after chemotherapy disclosing a mature teratoma. Our patient emphasizes that despite the absence of onconeural antibodies, studies to rule out an underlying tumor are mandatory in patients with subacute cerebellar ataxia. © 2012 Elsevier B.V.


Romano E.,Service of Medical Oncology | Romano E.,University of Lausanne | Michielin O.,Service of Medical Oncology | Michielin O.,University of Lausanne | And 10 more authors.
Journal of Translational Medicine | Year: 2014

Background: Immunotherapy offers a promising novel approach for the treatment of cancer and both adoptive T-cell transfer and immune modulation lead to regression of advanced melanoma. However, the potential synergy between these two strategies remains unclear.Methods: We investigated in 12 patients with advanced stage IV melanoma the effect of multiple MART-1 analog peptide vaccinations with (n = 6) or without (n = 6) IMP321 (LAG-3Ig fusion protein) as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs at day (D) 0 (Trial registration No: NCT00324623). All patients were selected on the basis of ex vivo detectable MART-1-specific CD8 T-cell responses and immunized at D0, 8, 15, 22, 28, 52, and 74 post-reinfusion.Results: After immunization, a significant expansion of MART-1-specific CD8 T cells was measured in 83% (n = 5/6) and 17% (n = 1/6) of patients from the IMP321 and control groups, respectively (P < 0.02). Compared to the control group, the mean fold increase of MART-1-specific CD8 T cells in the IMP321 group was respectively >2-, >4- and >6-fold higher at D15, D30 and D60 (P < 0.02). Long-lasting MART-1-specific CD8 T-cell responses were significantly associated with IMP321 (P < 0.02). At the peak of the response, MART-1-specific CD8 T cells contained higher proportions of effector (CCR7- CD45RA+/-) cells in the IMP321 group (P < 0.02) and showed no sign of exhaustion (i.e. were mostly PD1-CD160-TIM3-LAG3-2B4+/-). Moreover, IMP321 was associated with a significantly reduced expansion of regulatory T cells (P < 0.04); consistently, we observed a negative correlation between the relative expansion of MART-1-specific CD8 T cells and of regulatory T cells. Finally, although there were no confirmed responses as per RECIST criteria, a transient, 30-day partial response was observed in a patient from the IMP321 group.Conclusions: Vaccination with IMP321 as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs induced more robust and durable cellular antitumor immune responses, supporting further development of IMP321 as an adjuvant for future immunotherapeutic strategies. © 2014 Romano et al.; licensee BioMed Central Ltd.


PubMed | Service of Medical Oncology
Type: | Journal: Journal of translational medicine | Year: 2014

Immunotherapy offers a promising novel approach for the treatment of cancer and both adoptive T-cell transfer and immune modulation lead to regression of advanced melanoma. However, the potential synergy between these two strategies remains unclear.We investigated in 12 patients with advanced stage IV melanoma the effect of multiple MART-1 analog peptide vaccinations with (n=6) or without (n=6) IMP321 (LAG-3Ig fusion protein) as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs at day (D) 0 (Trial registration No: NCT00324623). All patients were selected on the basis of ex vivo detectable MART-1-specific CD8 T-cell responses and immunized at D0, 8, 15, 22, 28, 52, and 74 post-reinfusion.After immunization, a significant expansion of MART-1-specific CD8 T cells was measured in 83% (n=5/6) and 17% (n=1/6) of patients from the IMP321 and control groups, respectively (P<0.02). Compared to the control group, the mean fold increase of MART-1-specific CD8 T cells in the IMP321 group was respectively >2-, >4- and >6-fold higher at D15, D30 and D60 (P<0.02). Long-lasting MART-1-specific CD8 T-cell responses were significantly associated with IMP321 (P<0.02). At the peak of the response, MART-1-specific CD8 T cells contained higher proportions of effector (CCR7 CD45RA/) cells in the IMP321 group (P<0.02) and showed no sign of exhaustion (i.e. were mostly PD1CD160TIM3LAG32B4/). Moreover, IMP321 was associated with a significantly reduced expansion of regulatory T cells (P<0.04); consistently, we observed a negative correlation between the relative expansion of MART-1-specific CD8 T cells and of regulatory T cells. Finally, although there were no confirmed responses as per RECIST criteria, a transient, 30-day partial response was observed in a patient from the IMP321 group.Vaccination with IMP321 as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs induced more robust and durable cellular antitumor immune responses, supporting further development of IMP321 as an adjuvant for future immunotherapeutic strategies.

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