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"Bonnefoy, Yves"
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Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial
Chemotherapy is the standard of care for advanced stages of non-small-cell lung cancer (NSCLC). TG4010 is a targeted immunotherapy based on a poxvirus (modified vaccinia virus Ankara) that codes for MUC1 tumour-associated antigen and interleukin 2. This study assessed TG4010 in combination with first-line chemotherapy in advanced NSCLC.
148 patients with advanced (stage IIIB [wet] or IV) NSCLC expressing MUC1 by immunohistochemistry, and with performance status 0 or 1, were enrolled in parallel groups in this open-label, phase 2B study. 74 patients were allocated to the combination therapy group, and received TG4010 (10
8 plaque forming units) plus cisplatin (75 mg/m
2 on day 1) and gemcitabine (1250 mg/m
2 on days 1 and 8) repeated every 3 weeks for up to six cycles. 74 patients allocated to the control group received the same chemotherapy alone. Patients were allocated using a dynamic minimisation procedure stratified by centre, performance status, and disease stage. The primary endpoint was 6-month progression-free survival (PFS), with a target rate of 40% or higher in the experimental group. Analyses were done on an intention-to-treat basis. This study is completed and is registered with
ClinicalTrials.gov, number
NCT00415818.
6-month PFS was 43·2% (32 of 74; 95% CI 33·4–53·5) in the TG4010 plus chemotherapy group, and 35·1% (26 of 74; 25·9–45·3) in the chemotherapy alone group. Fever, abdominal pain, and injection-site pain of any grade according to National Cancer Institute Common Toxicity Criteria were more common in the TG4010 group than in the chemotherapy alone group: 17 of 73 patients (23·3%) versus six of 72 (8·3%), 12 (16·4%) versus two (2·8%), and four (5·5%) versus zero (0%), respectively. The most common grade 3–4 adverse events were neutropenia (33 [45·2%] of patients in the TG4010 plus chemotherapy group
vs 31 [43·1%] in the chemotherapy alone group) and fatigue (18 [24·7%]
vs 13 [18·1%]); the only grade 3–4 events that differed significantly between groups were anorexia (three [4·1%]
vs 10 [13·9%]) and pleural effusion (none
vs four [5·6%]). 38 of 73 patients (52·1%) in the TG4010 plus chemotherapy group and 34 of 72 (47·2%) in the chemotherapy alone group had at least one serious adverse event.
This phase 2B study suggests that TG4010 enhances the effect of chemotherapy in advanced NSCLC. A confirmatory phase 2B–3 trial has been initiated.
Transgene SA, Advanced Diagnostics for New Therapeutic Approaches (ADNA)/OSEO.
Journal Article
Therapeutic Effects of Anti-CD115 Monoclonal Antibody in Mouse Cancer Models through Dual Inhibition of Tumor-Associated Macrophages and Osteoclasts
Tumor progression is promoted by Tumor-Associated Macrophages (TAMs) and metastasis-induced bone destruction by osteoclasts. Both myeloid cell types depend on the CD115-CSF-1 pathway for their differentiation and function. We used 3 different mouse cancer models to study the effects of targeting cancer host myeloid cells with a monoclonal antibody (mAb) capable of blocking CSF-1 binding to murine CD115. In mice bearing sub-cutaneous EL4 tumors, which are CD115-negative, the anti-CD115 mAb depleted F4/80(+) CD163(+) M2-type TAMs and reduced tumor growth, resulting in prolonged survival. In the MMTV-PyMT mouse model, the spontaneous appearance of palpable mammary tumors was delayed when the anti-CD115 mAb was administered before malignant transition and tumors became palpable only after termination of the immunotherapy. When administered to mice already bearing established PyMT tumors, anti-CD115 treatment prolonged their survival and potentiated the effect of chemotherapy with Paclitaxel. As shown by immunohistochemistry, this therapeutic effect correlated with the depletion of F4/80(+)CD163(+) M2-polarized TAMs. In a breast cancer model of bone metastasis, the anti-CD115 mAb potently blocked the differentiation of osteoclasts and their bone destruction activity. This resulted in the inhibition of cancer-induced weight loss. CD115 thus represents a promising target for cancer immunotherapy, since a specific blocking antibody may not only inhibit the growth of a primary tumor through TAM depletion, but also metastasis-induced bone destruction through osteoclast inhibition.
Journal Article
Optimizing Conductive Polymer Composites: The Role of Graphite Particle Size and Concentration in PVDF, PP, and PET Matrices
This study investigates the impact of graphite (GR) concentration and particle size on the performance of conductive polymer composites (CPCs) using polyvinylidene fluoride (PVDF), polypropylene (PP), and polyethylene terephthalate (PET) as matrix materials. Composites were prepared with GR concentrations ranging from 20 to 60 wt. % and particle sizes categorized as G1 (5.9 µm), G2 (17.8 µm), and G3 (561 µm), and evaluated for their electrical, thermal, and mechanical properties. The investigation of the effect of graphite particle size on composite properties represents the main originality of this work. Among all composites, PVDF containing 60 wt. % of medium-sized G2 particles exhibited the lowest electrical resistivity (0.77 ohm·cm through-plane and 0.69 ohm·cm in-plane), along with the highest residual ash content (72%). In PP and PET matrices, incorporating 60 wt. % G2 particles resulted in through-plane resistivities of 11.3 ohm·cm and 1.6 ohm·cm, and in-plane resistivities of 5 ohm·cm and 1.2 ohm·cm, respectively, with thermal decomposition temperatures of 374 °C and 401 °C. Regarding mechanical performance and thermal stability, composites with small-sized G1 particles demonstrated superior performance due to their larger surface area and stronger matrix interactions. The PVDF/G1 (40/60 wt. %) composite achieved the highest flexural modulus (6.8 GPa), flexural strength (38.6 MPa), compressive modulus (0.28 GPa), and decomposition temperature (445 °C), highlighting its exceptional properties. These CPCs show significant promise for energy and electronic applications, particularly in the fabrication of bipolar plates for proton exchange membrane fuel cells, as well as in shielding materials and thermoelectric devices.
Journal Article
Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis
Increasing evidence supports involvement of inflammation and immunity in atherogenesis. We report here that CD40 ligand (CD40L), an immunoregulatory signaling molecule heretofore considered largely restricted to recently activated CD4+ T lymphocytes, is expressed by human vascular endothelial cells (EC), smooth muscle cells (SMC), and human macrophages in vitro, and is coexpressed with its receptor CD40 on all three cell types in human atherosclerotic lesions in situ. Cultured human vascular EC, SMC, and human macrophages all constitutively expressed CD40L mRNA as well as protein. Stimulation with interleukin 1 beta, tumor necrosis factor alpha, or interferon gamma increased surface levels and de novo synthesis of CD40L on all three cell types. CD40L expressed on EC, SMC, and macrophages exhibited biological activity, as it induced B7.2 expression on B cells. Human vascular SMC also constitutively expressed CD40, the receptor for CD40L, and through CD40 signaling, human recombinant CD40L induced expression of proinflammatory cytokines in these cells, identifying SMC as a target for CD40L. Human atherosclerotic lesions (n = 8) showed expression of immunoreactive CD40L on EC, SMC, and macrophages, while normal arterial tissues (n = 5) contained no CD40L. In atheroma CD40L+ cells often also expressed CD40. These observations establish human vascular EC, SMC, and human macrophages as a novel source of CD40L, and point to T cell-independent CD40 signaling, and a broader function of this pathway in regulation of nonimmune cells, as illustrated here by potential autocrine and paracrine activation during atherogenesis.
Journal Article