42 results on '"Sandrine Aspeslagh"'
Search Results
2. Isolated adrenocorticotropic hormone deficiency and sialadenitis associated with nivolumab: a case report
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Sylvain Raoul Simeni Njonnou, Sandrine Aspeslagh, Marie-Josiane Ntsama Essomba, Marie-Lucie Racu, Fernando Kemta Lekpa, and Frédéric Vandergheynst
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Sialadenitis ,Isolated adrenal insufficiency (IAD) ,Hypophysitis ,Brain methionine PET/MR ,Aquaporins ,Case report ,Medicine - Abstract
Abstract Background Immune checkpoint inhibition with anti-PD(L)1 and anti-CTLA4 antibodies has significantly changed cancer treatment during the last 10 years. Nevertheless, boosting the immune system with immune checkpoint inhibition can result in immune-related adverse events, affecting different organ systems, among which the endocrine system is the most affected. However, there are few descriptions of the association of immune-related adverse events, and the pathophysiology of some is still lacking. Case summary Here, we report a 70-year-old Caucasian patient treated with nivolumab (anti-PD1 monoclonal antibody) after resection of a unique relapse of melanoma in the neck region who presented with sicca syndrome, extreme fatigue, and weight loss 6 months after the start of anti-PD1 therapy. Blood tests revealed hypoglycemia and secondary hypocortisolism due to isolated adrenocorticotrophic hormone deficiency. Interestingly, brain methionine positron emission tomography/magnetic resonance revealed physiological metabolism of the pituitary gland, which was not increased in size, and no hypophyseal metastasis was detected. The sicca syndrome investigation revealed the absence of anti-SSA/SSB antibodies, while the labial salivary gland biopsy showed lymphoplasmatocytic infiltrates with a focus score of 1. To provide new insights into the physiopathology of the anti-PD1-related sialadenitis, we investigated the distribution of aquaporins 5 by immunostaining on the labial salivary gland acini, and compared this distribution with the one expressed in the primary Sjögren’s syndrome. Contrary to patients with primary Sjögren’s syndrome (in whom aquaporins 5 is mainly expressed at the basolateral side), but similar to the patients with no sialadenitis, we observed expression of aquaporins 5 at the apical pole. This new finding deserves to be confirmed in other patients with anti-PD1-related sialadenitis. Owing to these immune-related adverse events, anti-PD1 was stopped; nevertheless, the patient developed a new relapse 1 year later (March 2020) in the neck region, which was treated by radiotherapy. Since then, no relapse of melanoma was seen (1.5 years after radiotherapy), but the patient still requires hypophyseal replacement therapy. The sialoadenitis resolved partially. Conclusion We report a combination of sialoadenitis and hypophysitis explaining extreme fatigue in a patient who was treated in the adjuvant setting with anti-PD1 for a melanoma relapse.
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- 2022
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3. Durvalumab-induced thyroiditis in a patient with non-small cell lung carcinoma: a case report and review of pathogenic mechanisms
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Jeroen M. K. de Filette, Stéphanie André, Lynn De Mey, Sandrine Aspeslagh, Rafik Karmali, Bart J Van der Auwera, and Bert Bravenboer
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Durvalumab ,Thyroiditis ,Immune Checkpoint Inhibitors ,HLA ,Case Report ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Abstract Background Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 and its ligand (PD-1/PD-L1) have become the current standard-of-care for advanced cancers. This novel therapeutic approach comes with its costs in the form of immune-related adverse events (irAE), including endocrinopathy. Case presentation A 63-year-old woman was diagnosed with a non-small cell lung carcinoma of the right superior lobe, cT3N2M0. She developed thyrotoxicosis followed by hypothyroidism induced by consolidation immunotherapy with durvalumab (anti-PD-L1). Analysis of the human leukocyte antigen (HLA) region showed HLA-DR4 (susceptible) and DR13 (protective). The possible mechanisms are subsequently discussed in detail. Conclusions The case of a patient with thyroiditis associated with the PD-L1 inhibitor durvalumab is described, highlighting the need for proactive monitoring of thyroid hormone levels. Identifying biomarkers associated with an increased risk of ICI-induced side effects (such as HLA) is of interest for better patient selection, optimal management and improved understanding of the mechanisms involved.
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- 2022
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4. First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1)
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Stephane Champiat, Aurélien Marabelle, Anna Spreafico, Mehmet Altan, Todd M Bauer, Osama Rahma, Karen A Autio, Neeta Somaiah, Meredith McKean, Aaron R Hansen, Jan H M Schellens, Willeke Ros, F Stephen Hodi, Jeffrey S Weber, John V Heymach, Herbert Struemper, Sandrine Aspeslagh, Daniel C Cho, Jennifer K Litton, Axel Hoos, Vincent K Lam, Emmett V Schmidt, Sophie Postel-Vinay, Frans L Opdam, Elaine M Paul, Christoph M Ahlers, Helen Zhou, Shelby A Gorman, Maura Watmuff, Kaitlin M Yablonski, Niranjan Yanamandra, and Michael J Chisamore
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background The phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors.Methods GSK3174998 (0.003–10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity.Results 138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56–CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response.Conclusions GSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers.Trial registration number NCT02528357.
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- 2023
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5. COVID-19 and Cushing’s disease in a patient with ACTH-secreting pituitary carcinoma
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J M K de Filette, Bastiaan Sol, Gil Awada, Corina E Andreescu, David Unuane, Sandrine Aspeslagh, Jan Poelaert, and Bert Bravenboer
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Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
The pandemic caused by severe acute respiratory syndrome coronavirus 2 is of an unprecedented magnitude and has made it challenging to properly treat patients with urgent or rare endocrine disorders. Little is known about the risk of coronavirus disease 2019 (COVID-19) in patients with rare endocrine malignancies, such as pituitary carcinoma. We describe the case of a 43-year-old patient with adrenocorticotrophic hormone-secreting pituitary carcinoma who developed a severe COVID-19 infection. He had stabilized Cushing’s disease after multiple lines of treatment and was currently receiving maintenance immunotherapy with nivolumab (240 mg every 2 weeks) and steroidogenesis inhibition with ketoconazole (800 mg daily). On admission, he was urgently intubated for respiratory exhaustion. Supplementation of corticosteroid requirements consisted of high-dose dexamethasone, in analogy with the RECOVERY trial, followed by the reintroduction of ketoconazole under the coverage of a hydrocortisone stress regimen, which was continued at a dose depending on the current level of stress. He had a prolonged and complicated stay at the intensive care unit but was eventually discharged and able to continue his rehabilitation. The case points out that multiple risk factors for severe COVID-19 are present in patients with Cushing’s syndrome. ‘Block-replacement’ therapy with suppression of endogenous steroidogenesis and supplementation of corticosteroid requirements might be preferred in this patient population.
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- 2022
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6. A Late Dermatologic Presentation of Bullous Pemphigoid Induced by Anti-PD-1 Therapy and Associated with Unexplained Neurological Disorder
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Xiaoxiao Wang, Mariano Suppa, Pascal Bruderer, Nicolas Sirtaine, Sandrine Aspeslagh, and Joseph Kerger
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anti-pd-1 antibody ,anti-pd-l1 antibody ,bullous pemphigoid ,immunotherapy ,melanoma ,neurological disorder ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Immunotherapy has become the standard of care for various cancer types. The widespread use of immune checkpoints inhibitors confronts us with a whole range of novel immune-related adverse events. Skin toxicity is one of the most frequent adverse events. In this article, we report a case of anti-PD-1 induced late bullous pemphigoid (BP) with mucosal erosions and associated with a troublesome neurological disorder of undetermined origin in a patient with metastatic melanoma. Skin biopsy was essential to make the diagnosis and rapid initiation of systemic prednisolone played a role in favorable clinical outcome of BP. We will discuss the difficulty of early diagnosis of BP, its unusual association with neurological disorders, and the specific management of this particular dermatological entity.
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- 2021
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7. Pneumocystis Infection in Two Patients Treated with Both Immune Checkpoint Inhibitor and Corticoids
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Maroun Sadek, Angela Loizidou, Annie Drowart, Sigi Van den Wijngaert, Maria Gomez-Galdon, and Sandrine Aspeslagh
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immune-related adverse events ,immunotherapy ,ipilimumab ,nivolumab ,pembrolizumab ,pneumocystis pneumonia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The introduction of immune checkpoint inhibitor (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 and programmed cell death receptor 1 has dramatically improved clinical outcome for cancer patients. Nevertheless, this treatment can be associated with immune-related adverse events (irAEs) which sometimes need management with prolonged immune suppression. In order to analyze the risk of Pneumocystis jiroveci pneumonia (PJP) in this population, all PJP cases at our oncological hospital between 2004 and 2019 were searched. Only two cases were found in patients treated with ICI (480 patients received ICI during that period). The first was treated with both ipilimumab and nivolumab for metastatic melanoma and required long-term corticosteroids plus infliximab for immune-related colitis. The second received both pembrolizumab and brentuximab for Hodgkin's lymphoma and received corticosteroids for macrophage-activating syndrome. These two cases illustrate that PJP is rare but might be severe in the ICI population and should be differentiated from tumor progression or irAE.
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- 2020
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8. Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study
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Guillaume Manson, Alexandre Thibault Jacques Maria, Florence Poizeau, François-Xavier Danlos, Marie Kostine, Solenn Brosseau, Sandrine Aspeslagh, Pauline Du Rusquec, Maxime Roger, Maud Pallix-Guyot, Marc Ruivard, Léa Dousset, Laurianne Grignou, Dimitri Psimaras, Johan Pluvy, Gilles Quéré, Franck Grados, Fanny Duval, Frederic Bourdain, Gwenola Maigne, Julie Perrin, Benoit Godbert, Beatris Irina Taifas, Alexandra Forestier, Anne-Laure Voisin, Patricia Martin-Romano, Capucine Baldini, Aurélien Marabelle, Christophe Massard, Jérôme Honnorat, Olivier Lambotte, and Jean-Marie Michot
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Paraneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy. Methods We included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively. Findings Of the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45–88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1–2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1. Interpretation Our results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS.
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- 2019
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9. Eosinophilic Fasciitis in a Patient Treated by Atezolizumab for Metastatic Triple-Negative Breast Cancer
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Yacine Wissam, Laila Belcaid, Ruth Wittoek, Vanessa Smith, Amber Vanhaecke, Sofie De Schepper, Lennart Jans, Daphné t’Kint de Roodenbeke, Andrea Gombos, and Sandrine Aspeslagh
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atezolizumab ,breast cancer ,eosinophilic fasciitis ,immunotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Immune checkpoint inhibition has revolutionized the treatment for numerous cancer patients; however, the spectrum of immune-related adverse events (irAEs) remains to be fully uncovered. We report a 48-year-old woman who was treated in the Phase III IMpassion130 study (atezolizumab and nanoparticle albumin-bound [nab]-paclitaxel) for metastatic triple-negative breast cancer. She experienced a partial response after 3 months. Nevertheless, the patient presented with thickening of the skin and muscle fatigue in the distal extremities together with blood eosinophilia after 15 months. Skin biopsy and magnetic resonance imaging were diagnostic of eosinophilic fasciitis (EF). Symptoms clearly improved upon stopping atezolizumab, while tumor response is still ongoing after discontinuing treatment. We identified five other cases of EF during immunotherapy, all occurring after about 1 year and in contrast to our case, mostly accompanied by other irAEs. This highlights that even if EF is a rare irAE, timely recognition and management remains important.
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- 2019
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10. PRIMMO study protocol: a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer
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Sandra Tuyaerts, An M. T. Van Nuffel, Eline Naert, Peter A. Van Dam, Peter Vuylsteke, Alex De Caluwé, Sandrine Aspeslagh, Piet Dirix, Lien Lippens, Emiel De Jaeghere, Frédéric Amant, Katrien Vandecasteele, and Hannelore Denys
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PD-1 blockade ,Radiation ,Immune modulation ,Tumor microenvironment ,Cervical carcinoma ,Endometrial carcinoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Immunotherapeutic approaches have revolutionized oncological practice but are less evaluated in gynecological malignancies. PD-1/PD-L1 blockade in gynecological cancers showed objective responses in 13–17% of patients. This could be due to immunosuppressive effects exerted by gynecological tumors on the microenvironment and an altered tumor vasculature. In other malignancies, combining checkpoint blockade with radiation delivers benefit that is believed to be due to the abscopal effect. Addition of immune modulation agents has also shown to enhance immune checkpoint blockade efficacy. Therefore we designed a regimen consisting of PD-1 blockade combined with radiation, and different immune/environmental-targeting compounds: repurposed drugs, metronomic chemotherapy and a food supplement. We hypothesize that these will synergistically modulate the tumor microenvironment and induce and sustain an anti-tumor immune response, resulting in tumor regression. Methods PRIMMO is a multi-center, open-label, non-randomized, 3-cohort phase 2 study with safety run-in in patients with recurrent/refractory cervical carcinoma, endometrial carcinoma or uterine sarcoma. Treatment consists of daily intake of vitamin D, lansoprazole, aspirin, cyclophosphamide and curcumin, starting 2 weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6 cycles. Radiation (3 × 8 Gy) is given on days 1, 3 and 5 of the first pembrolizumab dose. The safety run-in consists of 6 patients. In total, 18 and 25 evaluable patients for cervical and endometrial carcinoma respectively are foreseen to enroll. No sample size is determined for uterine sarcoma due to its rarity. The primary objective is objective response rate at week 26 according to immune-related response criteria. Secondary objectives include safety, objective response rate at week 26 according to RECIST v1.1, best overall response, progression-free survival, overall survival and quality of life. Exploratory, translational research aims to evaluate immune biomarkers, extracellular vesicles, cell death biomarkers and the gut microbiome. Discussion In this study, a combination of PD-1 blockade, radiation and immune/environmental-targeting compounds is tested, aiming to tackle the tumor microenvironment and induce anti-tumor immunity. Translational research is performed to discover biomarkers related to the mode of action of the combination. Trial registration EU Clinical Trials Register: EudraCT 2016-001569-97, registered on 19-6-2017. Clinicaltrials.gov: NCT03192059, registered on 19-6-2017.
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- 2019
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11. Impact of solid cancer on in-hospital mortality overall and among different subgroups of patients with COVID-19: a nationwide, population-based analysis
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Mariana Brandão, Sylvie Rottey, Evandro de Azambuja, Annouschka Laenen, Hans Wildiers, Peter Vuylsteke, Annemie Rutten, Sandrine Aspeslagh, Christel Fontaine, Joelle Collignon, Willem Lybaert, Jolanda Verheezen, Jean-Charles Goeminne, Wim Demey, Dominique Van Beckhoven, Jessika Deblonde, Tatjana Geukens, Kevin Punie, Kristof Bafort, Leïla Belkhir, Nathalie Bossuyt, Vincent Colombie, Christine Daubresse, Nicolas Dauby, Paul De Munter, Didier Delmarcelle, Mélanie Delvallee, Rémy Demeester, Quentin Delefortrie, Thierry Dugernier, Xavier Holemans, Ingrid Louviaux, Pierre Yves Machurot, Philippe Minette, Saphia Mokrane, Catherine Nachtergal, Séverine Noirhomme, Denis Piérard, Camelia Rossi, Carole Schirvel, Erica Sermijn, Frank Staelens, Filip Triest, Nina Van Goethem, Jens Van Praet, Anke Vanhoenacker, Roeland Verstraete, Elise Willems, and Chloé Wyndham-Thomas
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Cancer seems to have an independent adverse prognostic effect on COVID-19-related mortality, but uncertainty exists regarding its effect across different patient subgroups. We report a population-based analysis of patients hospitalised with COVID-19 with prior or current solid cancer versus those without cancer.Methods We analysed data of adult patients registered until 24 May 2020 in the Belgian nationwide database of Sciensano. The primary objective was in-hospital mortality within 30 days of COVID-19 diagnosis among patients with solid cancer versus patients without cancer. Severe event occurrence, a composite of intensive care unit admission, invasive ventilation and/or death, was a secondary objective. These endpoints were analysed across different patient subgroups. Multivariable logistic regression models were used to analyse the association between cancer and clinical characteristics (baseline analysis) and the effect of cancer on in-hospital mortality and on severe event occurrence, adjusting for clinical characteristics (in-hospital analysis).Results A total of 13 594 patients (of whom 1187 with solid cancer (8.7%)) were evaluable for the baseline analysis and 10 486 (892 with solid cancer (8.5%)) for the in-hospital analysis. Patients with cancer were older and presented with less symptoms/signs and lung imaging alterations. The 30-day in-hospital mortality was higher in patients with solid cancer compared with patients without cancer (31.7% vs 20.0%, respectively; adjusted OR (aOR) 1.34; 95% CI 1.13 to 1.58). The aOR was 3.84 (95% CI 1.94 to 7.59) among younger patients (
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- 2020
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12. An in silico approach for modelling T-helper polarizing iNKT cell agonists.
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Anton De Spiegeleer, Evelien Wynendaele, Matthias Vandekerckhove, Sofie Stalmans, Maxime Boucart, Nele Van Den Noortgate, Koen Venken, Serge Van Calenbergh, Sandrine Aspeslagh, and Dirk Elewaut
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Medicine ,Science - Abstract
Many analogues of the glycolipid alpha-galactosylceramide (α-GalCer) are known to activate iNKT cells through their interaction with CD1d-expressing antigen-presenting cells, inducing the release of Th1 and Th2 cytokines. Because of iNKT cell involvement and associated Th1/Th2 cytokine changes in a broad spectrum of human diseases, the design of iNKT cell ligands with selective Th1 and Th2 properties has been the subject of extensive research. This search for novel iNKT cell ligands requires refined structural insights. Here we will visualize the chemical space of 333 currently known iNKT cell activators, including several newly tested analogues, by more than 3000 chemical descriptors which were calculated for each individual analogue. To evaluate the immunological responses we analyzed five different cytokines in five different test-systems. We linked the chemical space to the immunological space using a system biology computational approach resulting in highly sensitive and specific predictive models. Moreover, these models correspond with the current insights of iNKT cell activation by α-GalCer analogues, explaining the Th1 and Th2 biased responses, downstream of iNKT cell activation. We anticipate that such models will be of great value for the future design of iNKT cell agonists.
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- 2014
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13. Preclinical evaluation of invariant natural killer T cells in the 5T33 multiple myeloma model.
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Haneen Nur, Karel Fostier, Sandrine Aspeslagh, Wim Renmans, Elisabeth Bertrand, Xavier Leleu, Mérédis Favreau, Karine Breckpot, Rik Schots, Marc De Waele, Els Van Valckenborgh, Elke De Bruyne, Thierry Facon, Dirk Elewaut, Karin Vanderkerken, and Eline Menu
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Medicine ,Science - Abstract
Immunomodulators have been used in recent years to reactivate host anti-tumor immunity in several hematological malignancies. This report describes the effect of activating natural killer T (NKT) cells by α-Galactosylceramide (α-GalCer) in the 5T33MM model of multiple myeloma (MM). NKT cells are T lymphocytes, co-expressing T and NK receptors, while invariant NKT cells (iNKTs) also express a unique semi-invariant TCR α-chain. We followed iNKT numbers during the development of the disease in both 5T33MM mice and MM patients and found that their numbers dropped dramatically at the end stage of the disease, leading to a loss of total IFN-γ secretion. We furthermore observed that α-GalCer treatment significantly increased the survival of 5T33MM diseased mice. Taken together, our data demonstrate for the first time the possibility of using a preclinical murine MM model to study the effects of α-GalCer and show promising results of α-GalCer treatment in a low tumor burden setting.
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- 2013
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14. Activated iNKT cells promote memory CD8+ T cell differentiation during viral infection.
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Emma C Reilly, Elizabeth A Thompson, Sandrine Aspeslagh, Jack R Wands, Dirk Elewaut, and Laurent Brossay
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Medicine ,Science - Abstract
α-Galactosylceramide (α-GalCer) is the prototypical lipid ligand for invariant NKT cells. Recent studies have proposed that α-GalCer is an effective adjuvant in vaccination against a range of immune challenges, however its mechanism of action has not been completely elucidated. A variety of delivery methods have been examined including pulsing dendritic cells with α-GalCer to optimize the potential of α-GalCer. These methods are currently being used in a variety of clinical trials in patients with advanced cancer but cannot be used in the context of vaccine development against pathogens due to their complexity. Using a simple delivery method, we evaluated α-GalCer adjuvant properties, using the mouse model for cytomegalovirus (MCMV). We measured several key parameters of the immune response to MCMV, including inflammation, effector, and central memory CD8(+) T cell responses. We found that α-GalCer injection at the time of the infection decreases viral titers, alters the kinetics of the inflammatory response, and promotes both increased frequencies and numbers of virus-specific memory CD8(+) T cells. Overall, our data suggest that iNKT cell activation by α-GalCer promotes the development of long-term protective immunity through increased fitness of central memory CD8(+) T cells, as a consequence of reduced inflammation.
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- 2012
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15. Pembrolizumab, radiotherapy, and an immunomodulatory five-drug cocktail in pretreated patients with persistent, recurrent, or metastatic cervical or endometrial carcinoma: Results of the phase II PRIMMO study
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Emiel A. De Jaeghere, Sandra Tuyaerts, An M. T. Van Nuffel, Ann Belmans, Kris Bogaerts, Regina Baiden-Amissah, Lien Lippens, Peter Vuylsteke, Stéphanie Henry, Xuan Bich Trinh, Peter A. van Dam, Sandrine Aspeslagh, Alex De Caluwé, Eline Naert, Diether Lambrechts, An Hendrix, Olivier De Wever, Koen K. Van de Vijver, Frédéric Amant, Katrien Vandecasteele, Hannelore G. Denys, Obstetrics and Gynaecology, CCA - Cancer Treatment and Quality of Life, CCA - Cancer biology and immunology, ARD - Amsterdam Reproduction and Development, Clinical sciences, Medical Oncology, Physiology, Faculty of Physical Education and Physical Therapy, and Laboratory for Medical and Molecular Oncology
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combination ,Cancer Research ,Science & Technology ,Immunology ,Drug therapy, combination ,Gynecologic neoplasms ,CANCER-PATIENTS ,Radioimmunotherapy ,CELL CARCINOMA ,CHEMOTHERAPY ,EFFICACY ,SOLID TUMORS ,Immunomodulation ,Oncology ,Tumor microenvironment ,CEMIPLIMAB ,RADIATION-THERAPY ,SAFETY ,CYCLOPHOSPHAMIDE ,Medicine and Health Sciences ,Immunology and Allergy ,Human medicine ,Drug therapy ,Life Sciences & Biomedicine - Abstract
A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0–31.0) in cervical cancer and 12.0% (90% CI 3.4–28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1–25.7) in cervical cancer and 3.6 weeks (95% CI 3.6–15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0–67.0) and 37.4 weeks (95% CI 19.0–50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders (p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity.Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97).
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- 2023
16. Isolated adrenocorticotropic hormone deficiency and sialadenitis associated with nivolumab
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Sylvain Raoul Simeni Njonnou, Sandrine Aspeslagh, Marie-Josiane Ntsama Essomba, Marie-Lucie Racu, Fernando Kemta Lekpa, Frédéric Vandergheynst, Brussels Heritage Lab, Laboratory of Molecular and Medical Oncology, Clinical sciences, and Medical Oncology
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immune checkpoint inhibitors ,Sjogren's Syndrome ,Adrenocorticotropic Hormone ,oncology ,Humans ,Melanoma/drug therapy ,General Medicine ,Neoplasm Recurrence, Local ,Nivolumab/adverse effects ,Tomography, X-Ray Computed ,Aged - Abstract
Background Immune checkpoint inhibition with anti-PD(L)1 and anti-CTLA4 antibodies has significantly changed cancer treatment during the last 10 years. Nevertheless, boosting the immune system with immune checkpoint inhibition can result in immune-related adverse events, affecting different organ systems, among which the endocrine system is the most affected. However, there are few descriptions of the association of immune-related adverse events, and the pathophysiology of some is still lacking. Case summary Here, we report a 70-year-old Caucasian patient treated with nivolumab (anti-PD1 monoclonal antibody) after resection of a unique relapse of melanoma in the neck region who presented with sicca syndrome, extreme fatigue, and weight loss 6 months after the start of anti-PD1 therapy. Blood tests revealed hypoglycemia and secondary hypocortisolism due to isolated adrenocorticotrophic hormone deficiency. Interestingly, brain methionine positron emission tomography/magnetic resonance revealed physiological metabolism of the pituitary gland, which was not increased in size, and no hypophyseal metastasis was detected. The sicca syndrome investigation revealed the absence of anti-SSA/SSB antibodies, while the labial salivary gland biopsy showed lymphoplasmatocytic infiltrates with a focus score of 1. To provide new insights into the physiopathology of the anti-PD1-related sialadenitis, we investigated the distribution of aquaporins 5 by immunostaining on the labial salivary gland acini, and compared this distribution with the one expressed in the primary Sjögren’s syndrome. Contrary to patients with primary Sjögren’s syndrome (in whom aquaporins 5 is mainly expressed at the basolateral side), but similar to the patients with no sialadenitis, we observed expression of aquaporins 5 at the apical pole. This new finding deserves to be confirmed in other patients with anti-PD1-related sialadenitis. Owing to these immune-related adverse events, anti-PD1 was stopped; nevertheless, the patient developed a new relapse 1 year later (March 2020) in the neck region, which was treated by radiotherapy. Since then, no relapse of melanoma was seen (1.5 years after radiotherapy), but the patient still requires hypophyseal replacement therapy. The sialoadenitis resolved partially. Conclusion We report a combination of sialoadenitis and hypophysitis explaining extreme fatigue in a patient who was treated in the adjuvant setting with anti-PD1 for a melanoma relapse.
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- 2022
17. Severe treatment-induced inflammatory polyarthritis in advanced melanoma patients
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Justine Lauwyck, Max Schreuer, Laurent Meric de Bellefon, Joanna Van Erps, Bart Neyns, Sandrine Aspeslagh, Faculty of Medicine and Pharmacy, Medical Oncology, Clinical sciences, and Laboratory of Molecular and Medical Oncology
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Cancer Research ,advanced melanoma patients ,Skin Neoplasms ,Arthritis ,Case Report ,Dermatology ,DMARDs ,immune checkpoint inhibitors ,Mice ,Antirheumatic Agents ,csDMARDs ,oncology ,Quality of Life ,Animals ,Humans ,bDMARDs ,Melanoma ,Glucocorticoids ,Severe treatment-induced inflammatory polyarthritis ,Retrospective Studies - Abstract
Immune checkpoint inhibitors (ICI) and targeted therapies form the therapeutic mainstay for v-Raf murine sarcoma viral oncogene homolog B V600-mutated metastatic melanoma. Both treatment regimens can cause inflammatory arthritis. The reported incidence of treatment-induced inflammatory arthritis is low, though presumably underestimated due to lack of awareness, clear definitions and uniform grading systems. Nevertheless, recognition is important as inflammatory arthritis can become chronic and thus affect the quality of life beyond treatment. In this short communication, we present two patients with metastatic melanoma treated with ICI and targeted therapies who develop severe polyarthritis. Based on their clinical discourse we describe standard inflammatory arthritis treatment modalities and more advanced immunomodulatory treatment options with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologic DMARDs (bDMARDs). Long-term immunosuppressive treatment with glucocorticoids or DMARDs in this setting raises concerns about antitumour response and potential carcinogenic risk. Current literature on this topic is scarce, heterogeneous and retrospective. Prospective analysis of cancer patients treated with DMARDs is needed to clearly address these concerns.
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- 2022
18. A Late Dermatologic Presentation of Bullous Pemphigoid Induced by Anti-PD-1 Therapy and Associated with Unexplained Neurological Disorder
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Joseph Kerger, Sandrine Aspeslagh, Xiaoxiao Wang, Pascal Bruderer, Nicolas Sirtaine, Mariano Suppa, Laboratory of Molecular and Medical Oncology, Clinical sciences, and Medical Oncology
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medicine.medical_specialty ,medicine.medical_treatment ,Case Report ,Neurological disorder ,medicine ,melanoma ,neurological disorder ,Adverse effect ,RC254-282 ,medicine.diagnostic_test ,business.industry ,Bullous pemphigoid ,Melanoma ,Anti-PD-1 antibody ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunotherapy ,medicine.disease ,Dermatology ,Skin biopsy ,oncology ,Prednisolone ,Anti-PD-L1 antibody ,immunotherapy ,business ,medicine.drug - Abstract
Immunotherapy has become the standard of care for various cancer types. The widespread use of immune checkpoints inhibitors confronts us with a whole range of novel immune-related adverse events. Skin toxicity is one of the most frequent adverse events. In this article, we report a case of anti-PD-1 induced late bullous pemphigoid (BP) with mucosal erosions and associated with a troublesome neurological disorder of undetermined origin in a patient with metastatic melanoma. Skin biopsy was essential to make the diagnosis and rapid initiation of systemic prednisolone played a role in favorable clinical outcome of BP. We will discuss the difficulty of early diagnosis of BP, its unusual association with neurological disorders, and the specific management of this particular dermatological entity.
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- 2021
19. Bilateral Corneal Perforation in a Patient Under Anti-PD1 Therapy
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Marcel Ten Tusscher, Karolien Termote, Camille Van Mierlo, Pieter-Paul Schauwvlieghe, Nele De Brucker, Sandrine Aspeslagh, Anaïs Ramaekers, Ophtalmology - Eye surgery, Faculty of Medicine and Pharmacy, Clinical sciences, Medical Oncology, Surgical clinical sciences, and Neuroprotection & Neuromodulation
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Male ,Serum ,medicine.medical_specialty ,Lung Neoplasms ,genetic structures ,Contact Lenses ,Programmed Cell Death 1 Receptor ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Bilateral Corneal Perforation ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Carcinoma ,Humans ,Adverse effect ,Corneal Ulcer ,Aged ,Cancer ,business.industry ,Corneal Perforation ,Corneal perforation ,corneal ulcer ,medicine.disease ,Bandages ,Immune checkpoint ,eye diseases ,Surgery ,Ophthalmology ,Monoclonal ,030221 ophthalmology & optometry ,Tissue Adhesives ,sense organs ,Anti-PD1 Therapy ,business ,030217 neurology & neurosurgery ,Keratoplasty, Penetrating - Abstract
Immune checkpoint inhibition has improved the clinical outcomes for numerous patients with cancer. However, the downside is a whole new spectrum of immune-related adverse events. We report a 68-year-old man with a history of nonsmall cell lung cancer presenting with a spontaneous corneal perforation in the right eye after 22 cycles of pembrolizumab. In addition, a chronic central nonhealing epithelial defect developed after performing a penetrating keratoplasty. Treatment with autologous serum drops resulted in complete healing of the corneal ulcer, where other conventional therapies had no effect. One month after reinitiating pembrolizumab therapy, our patient presented again with a corneal perforation in the fellow eye. This case describes relapsing sterile ulcerations associated with pembrolizumab use and presents an unexpected cure.
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- 2021
20. Delayed immune-related adverse events with anti-PD1-based immunotherapy in melanoma
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N. Thompson, Christian U. Blank, Adnan Khattak, Alice Labianca, A. Arance, T. Quah, Wen Xu, Clara Allayous, C. Martínez-Vila, Ryan J. Sullivan, Roslyn Wallace, P.A. Ascierto, Sarah J. Welsh, Carina N. Owen, Shahneen Sandhu, Prachi Bhave, V. Vanella, Xue Bai, Jennifer L. McQuade, Céleste Lebbé, Bart Neyns, Matteo S. Carlino, Irene L.M. Reijers, J. Mangana, Serigne Lo, Sophia Callaghan, Mario Mandalà, Sandrine Aspeslagh, Olivier Michielin, Camille L. Gerard, Paul Lorigan, Douglas B. Johnson, Andrew Haydon, Lisa Zimmer, Georgina V. Long, A.M. Menzies, Faculty of Sciences and Bioengineering Sciences, Laboratory for Medical and Molecular Oncology, Clinical sciences, Medical Oncology, Faculty of Psychology and Educational Sciences, and Physics
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0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,delayed ,medicine.medical_treatment ,Medizin ,03 medical and health sciences ,0302 clinical medicine ,irAE ,medicine ,melanoma ,Humans ,Immunologic Factors ,anti-PD1 ,Adverse effect ,Pneumonitis ,Retrospective Studies ,Manchester Cancer Research Centre ,business.industry ,Melanoma ,Incidence (epidemiology) ,ResearchInstitutes_Networks_Beacons/mcrc ,toxicity ,Hematology ,Immunotherapy ,Pneumonia ,medicine.disease ,Rash ,Anti-PD-1 ,Confidence interval ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,anti-PD-1 ,immunotherapy ,medicine.symptom ,business ,Encephalitis - Abstract
BACKGROUND: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy.PATIENTS AND METHODS: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined.RESULTS: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were 3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (CONCLUSIONS: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.
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- 2021
21. Impact of solid cancer on in-hospital mortality overall and among different subgroups of patients with COVID-19
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Chloé Wyndham-Thomas, Vincent Colombie, Anke Vanhoenacker, Sylvie Rottey, Rémy Demeester, Nina Van Goethem, Kristof Bafort, Dominique Van Beckhoven, Thierry Dugernier, Roeland Verstraete, Quentin Delefortrie, Hans Wildiers, Elise Willems, Joëlle Collignon, Leila Belkhir, Mélanie Delvallee, Jean-Charles Goeminne, Séverine Noirhomme, Filip Triest, Annouschka Laenen, Erica Sermijn, Kevin Punie, Peter Vuylsteke, Jens Van Praet, Frank Staelens, Christine Daubresse, Tatjana Geukens, Catherine Nachtergal, Camelia Rossi, Xavier Holemans, Philippe Minette, Willem Lybaert, Saphia Mokrane, Nathalie Bossuyt, Christel Fontaine, Sandrine Aspeslagh, Carole Schirvel, Jolanda Verheezen, Annemie Rutten, Didier Delmarcelle, Ingrid Louviaux, Mariana Brandão, Wim Demey, Jessika Deblonde, Evandro de Azambuja, PierreYves Machurot, Paul De Munter, Denis Pierard, Nicolas Dauby, Medical Oncology, Laboratory for Medical and Molecular Oncology, UCL - (MGD) Service d'oncologie médicale, and UCL - SSS/IREC/MONT - Pôle Mont Godinne
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Male ,Cancer Research ,Comorbidity ,Logistic regression ,law.invention ,Belgium ,Adrenal Cortex Hormones ,Risk Factors ,law ,Neoplasms ,Medicine and Health Sciences ,Medicine ,Hospital Mortality ,Lung ,Original Research ,Cancer ,Aged, 80 and over ,education.field_of_study ,health policy ,Middle Aged ,Sciences bio-médicales et agricoles ,Prognosis ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Intensive care unit ,Health policy ,Hospitalization ,Intensive Care Units ,oncology ,Female ,Coronavirus Infections ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Solid cancer ,Pneumonia, Viral ,Population ,lcsh:RC254-282 ,Betacoronavirus ,Internal medicine ,Humans ,cancer ,Mortality ,Adverse effect ,education ,Pandemics ,Aged ,In hospital mortality ,Pandemic ,SARS-CoV-2 ,business.industry ,pandemic ,COVID-19 ,medicine.disease ,Respiration, Artificial ,mortality ,business - Abstract
BACKGROUND: Cancer seems to have an independent adverse prognostic effect on COVID-19-related mortality, but uncertainty exists regarding its effect across different patient subgroups. We report a population-based analysis of patients hospitalised with COVID-19 with prior or current solid cancer versus those without cancer. METHODS: We analysed data of adult patients registered until 24 May 2020 in the Belgian nationwide database of Sciensano. The primary objective was in-hospital mortality within 30 days of COVID-19 diagnosis among patients with solid cancer versus patients without cancer. Severe event occurrence, a composite of intensive care unit admission, invasive ventilation and/or death, was a secondary objective. These endpoints were analysed across different patient subgroups. Multivariable logistic regression models were used to analyse the association between cancer and clinical characteristics (baseline analysis) and the effect of cancer on in-hospital mortality and on severe event occurrence, adjusting for clinical characteristics (in-hospital analysis). RESULTS: A total of 13 594 patients (of whom 1187 with solid cancer (8.7%)) were evaluable for the baseline analysis and 10 486 (892 with solid cancer (8.5%)) for the in-hospital analysis. Patients with cancer were older and presented with less symptoms/signs and lung imaging alterations. The 30-day in-hospital mortality was higher in patients with solid cancer compared with patients without cancer (31.7% vs 20.0%, respectively; adjusted OR (aOR) 1.34; 95% CI 1.13 to 1.58). The aOR was 3.84 (95% CI 1.94 to 7.59) among younger patients (
- Published
- 2020
22. Interim safety and efficacy results of a phase II clinical trial on trametinib and low-dose dabrafenib in patients with advanced BRAFV600 wild-type melanoma
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Gil Awada, Julia Katharina Schwarze, Eva Reijmen, Cleo Goyvaerts, Giuseppe Fasolino, sandrine aspeslagh, Bart Neyns, Clinical sciences, Faculty of Medicine and Pharmacy, Internal medicine - endocrinology, Basic (bio-) Medical Sciences, Laboratory of Molecullar and Cellular Therapy, Ophtalmology - Eye surgery, Medical Oncology, Laboratory of Molecular and Medical Oncology, Internal Medicine, and Laboratory for Medical and Molecular Oncology
- Abstract
Background: Preclinical and clinical data suggest MEK-inhibition (MEKi) to be effective in NRAS-mutant (mt) and NRAS wild-type (wt) melanoma. However, MEKi causes considerable cutaneous treatment-related adverse events (TRAE) which are less present if MEKi is combined with BRAFi. Methods: This open-label, dual-stratum, single-center phase 2 clinical trial investi- gated trametinib (T; 2 mg QD) in patients (pts) with advanced BRAFV600 wt, NRASQ61R/ K/L mt/wt melanoma who had progressed following or were ineligible for immune checkpoint inhibitors. In case of T-related cutaneous TRAE, low-dose dabrafenib (ld-D; 50 mg BID) was added to prevent further skin TRAE. The trial was amended in June 2019 to administer ld-D upfront with T. The primary endpoint was the confirmed objective response rate (ORR; per RECIST 1.1); secondary endpoints were progression- free and overall survival and safety. Results: Between Jan and Dec 2019, 9 pts initiated T monotherapy and 8 pts initiated T þ ld-D. TRAE were seen in 15 pts (29%G3-4; 29% SAE). One pt permanently interrupted T due to G3 pneumonitis. All 9 pts who initiated T monotherapy devel- oped G1-2 acneiform rash which resolved (to G0: 6 pts; to G1: 3 pts) with temporary interruption of T, local metronidazole therapy and subsequent addition of ld-D to T. One pt had a G1 recurrence of acneiform rash that was managed with local therapy. Of 8 pts who initiated T þ ld-D upfront, 1 developed G1 acneiform rash that resolved with local therapy only. Other TRAE are shown in the table. T dose was reduced in 4 pts for TRAE (1 pt with left ventricular ejection fraction decrease; 1 with central serous retinopathy; 1 with AST/ALT increase; 1 with hyponatremia and syncope). The unconfirmed ORR is 4/15 and the disease control rate is 7/15 evaluable pts. Conclusions: No unexpected toxicities were seen with T or T + ld-D. ld-D is able to prevent T-related skin toxicity. Thus, combining ld-D with T is a safe approach to in- crease tolerance of and optimize exposure to T. Clinical trial identification: NCT04059224; EudraCT 2018-004003-39. Legal entity responsible for the study: Universitair Ziekenhuis Brussel. Funding: Novartis, Stichting tegen Kanker. Disclosure: G. Awada: Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Astellas; Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (institution): Novartis. J.K. Schwarze: Travel/ Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: Merck Sharp & Dohme. S. Aspeslagh: Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advi- sory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Advisory/Consultancy, Speaker Bureau/Expert testimony: Sanofi; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis. B. Neyns: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: EtheRNA; Advi- sory/Consultancy, Speaker Bureau/Expert testimony: CryoStorage; Research grant/Funding (institu- tion): Pfizer; Research grant/Funding (institution): Merck Serono. All other authors have declared no conflicts of interest. https://doi.org/10.1016/j.annonc.2020.01.039
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- 2020
23. Persistent anti-tumor response in cancer patients experiencing pneumonitis related to immune checkpoint blockade
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Laila Belcaid, Sideris Spyridon, Soizic Garaud, Joseph Kerger, Sandrine Aspeslagh, Medical Oncology, and Laboratory of Molecular and Medical Oncology
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Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Adverse effect ,Immune Checkpoint Inhibitors ,Pneumonitis ,business.industry ,Melanoma ,Cancer ,Pneumonia ,General Medicine ,Immunotherapy ,medicine.disease ,Immune checkpoint ,Blockade ,Discontinuation ,030220 oncology & carcinogenesis ,business - Abstract
Background: Immunotherapy in the form of immune checkpoint inhibition (ICI) is now well established as acornerstone for treating many advanced malignancies. Nevertheless, as the number of indications for checkpoint inhibitors increases, so does the risk of immune-related adverse events (irAEs). Methods: We report two patient cases who, after being treated by an anti-programmed cell death 1 (PD-1), presented with grade III dyspnea due to pneumonitis. Discussion: Immunotherapy was discontinued and the patients required treatment with systemic corticosteroids. At the time of writing, both patients are still in complete response (CR), more than 1year beyond immunotherapy discontinuation. We discuss our cases with regard to recent literature reports on immune-related pneumonitis and persistence of response beyond discontinuation.
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- 2019
24. PRIMMO study protocol
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Emiel De Jaeghere, Hannelore Denys, Katrien Vandecasteele, Sandra Tuyaerts, Peter Vuylsteke, Sandrine Aspeslagh, Frédéric Amant, Peter van Dam, Lien Lippens, Eline Naert, Alex De Caluwé, An M. T. Van Nuffel, Piet Dirix, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service d'oncologie médicale, Physiology, Faculty of Medicine and Pharmacy, Medical Oncology, Laboratory for Medical and Molecular Oncology, Faculty of Physical Education and Physical Therapy, ARD - Amsterdam Reproduction and Development, CCA - Cancer Treatment and Quality of Life, CCA - Cancer biology and immunology, and AII - Cancer immunology
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_treatment ,Immune modulation ,Drug repurposing ,PD-1 blockade ,Uterine Cervical Neoplasms ,MICROENVIRONMENT ,Pembrolizumab ,THERAPY ,Cyclophosphamide/administration & dosage ,Uterine sarcoma ,Study Protocol ,0302 clinical medicine ,Medicine and Health Sciences ,Medicine ,Lansoprazole/administration & dosage ,Vitamin D ,Radiation ,Neoplasm Recurrence, Local/therapy ,Abscopal effect ,Sarcoma ,Chemoradiotherapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,D-3 TREATMENT ,Vitamin D/administration & dosage ,Antineoplastic Agents/administration & dosage ,Treatment Outcome ,Tumor microenvironment ,030220 oncology & carcinogenesis ,Female ,Immunotherapy ,Endometrial Neoplasms/therapy ,Biologie ,Antibodies, Monoclonal, Humanized/administration & dosage ,RADIOTHERAPY ,medicine.medical_specialty ,Curcumin ,Curcumin/administration & dosage ,Antineoplastic Agents ,Endometrial carcinoma ,Antibodies, Monoclonal, Humanized ,lcsh:RC254-282 ,Financial toxicity ,03 medical and health sciences ,Uterine cancer ,Internal medicine ,Genetics ,Humans ,Sarcoma/therapy ,Lansoprazole ,HEAD ,IMMUNOTHERAPY ,Aspirin/administration & dosage ,PEMBROLIZUMAB ,Cyclophosphamide ,Cervical carcinoma ,Aspirin ,business.industry ,Metronomic chemotherapy ,Drug Repositioning ,medicine.disease ,Metronomic Chemotherapy ,Survival Analysis ,Immune checkpoint ,Blockade ,Endometrial Neoplasms ,Cancérologie ,030104 developmental biology ,CELLS ,Human medicine ,Neoplasm Recurrence, Local ,business ,Uterine Cervical Neoplasms/therapy ,RESISTANCE ,RESPONSES - Abstract
Background: Immunotherapeutic approaches have revolutionized oncological practice but are less evaluated in gynecological malignancies. PD-1/PD-L1 blockade in gynecological cancers showed objective responses in 13-17% of patients. This could be due to immunosuppressive effects exerted by gynecological tumors on the microenvironment and an altered tumor vasculature. In other malignancies, combining checkpoint blockade with radiation delivers benefit that is believed to be due to the abscopal effect. Addition of immune modulation agents has also shown to enhance immune checkpoint blockade efficacy. Therefore we designed a regimen consisting of PD-1 blockade combined with radiation, and different immune/environmental-targeting compounds: repurposed drugs, metronomic chemotherapy and a food supplement. We hypothesize that these will synergistically modulate the tumor microenvironment and induce and sustain an anti-tumor immune response, resulting in tumor regression. Methods: PRIMMO is a multi-center, open-label, non-randomized, 3-cohort phase 2 study with safety run-in in patients with recurrent/refractory cervical carcinoma, endometrial carcinoma or uterine sarcoma. Treatment consists of daily intake of vitamin D, lansoprazole, aspirin, cyclophosphamide and curcumin, starting 2 weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6 cycles. Radiation (3 × 8 Gy) is given on days 1, 3 and 5 of the first pembrolizumab dose. The safety run-in consists of 6 patients. In total, 18 and 25 evaluable patients for cervical and endometrial carcinoma respectively are foreseen to enroll. No sample size is determined for uterine sarcoma due to its rarity. The primary objective is objective response rate at week 26 according to immune-related response criteria. Secondary objectives include safety, objective response rate at week 26 according to RECIST v1.1, best overall response, progression-free survival, overall survival and quality of life. Exploratory, translational research aims to evaluate immune biomarkers, extracellular vesicles, cell death biomarkers and the gut microbiome. Discussion: In this study, a combination of PD-1 blockade, radiation and immune/environmental-targeting compounds is tested, aiming to tackle the tumor microenvironment and induce anti-tumor immunity. Translational research is performed to discover biomarkers related to the mode of action of the combination. Trial registration: EU Clinical Trials Register: EudraCT 2016-001569-97, registered on 19-6-2017. Clinicaltrials.gov: NCT03192059, registered on 19-6-2017., SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2019
25. Immune checkpoint blockade for organ transplant patients with advanced cancer: how far can we go?
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Pauline De Bruyn, Véronique Del Marmol, Alain Le Moine, Piet Ost, Arnaud Devresse, Dirk Van Gestel, Sandrine Aspeslagh, Lieve Brochez, Vibeke Kruse, Hans Van Vlierberghe, Medical Oncology, Laboratory for Medical and Molecular Oncology, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, and UCL - (SLuc) Service de néphrologie
- Subjects
Graft Rejection ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Programmed Cell Death 1 Receptor ,MEDLINE ,Organ transplantation ,Liver Neoplasms/drug therapy ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Antineoplastic Agents, Immunological/administration & dosage ,Internal medicine ,medicine ,Humans ,CTLA-4 Antigen ,Immunosuppressive Agents/administration & dosage ,business.industry ,Kidney Transplantation/methods ,Liver Neoplasms ,Programmed Cell Death 1 Receptor/antagonists & inhibitors ,Graft Rejection/immunology ,Sciences bio-médicales et agricoles ,Kidney Transplantation ,CTLA-4 Antigen/antagonists & inhibitors ,Advanced cancer ,Immune checkpoint ,Blockade ,Cancérologie ,030104 developmental biology ,surgical procedures, operative ,Allograft rejection ,030220 oncology & carcinogenesis ,business ,Immunosuppressive Agents - Abstract
Checkpoint inhibitors (CPIs) provide impressive response rates among immunocompetent patients with various solid tumors. So far, organ transplant recipients have been excluded from clinical studies due to the putative risk of allograft rejection however 48 cases of liver and renal transplant patients treated with CPI were already described in literature., SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2019
26. Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study
- Author
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Julie Perrin, Florence Poizeau, Johan Pluvy, Alexandra Forestier, Franck Grados, Capucine Baldini, Maud Pallix-Guyot, Dimitri Psimaras, Solenn Brosseau, Laurianne Grignou, Jean-Marie Michot, Alexandre Thibault Jacques Maria, Guillaume Manson, Aurélien Marabelle, Olivier Lambotte, Benoit Godbert, Jérôme Honnorat, Fanny Duval, Maxime Roger, Pauline Du Rusquec, Frederic Bourdain, G. Maigné, Léa Dousset, Marie Kostine, Christophe Massard, Anne-Laure Voisin, Gilles Quere, Sandrine Aspeslagh, François-Xavier Danlos, Marc Ruivard, Beatris Irina Taifas, Patricia Martin-Romano, Salvy-Córdoba, Nathalie, CHU Pontchaillou [Rennes], Institut Gustave Roussy (IGR), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de rhumatologie, CHU Bordeaux [Bordeaux], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre d'Energétique et de Thermique de Lyon (CETHIL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie générale [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier Régional d'Orléans (CHRO), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Université de Bordeaux (UB), Université de Brest (UBO), Service de Neuroradiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Oncologie Thoracique (BREST - ICH), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Amiens-Picardie, Laboratoire de Génie des Procédés et Matériaux - EA 4038 (LGPM), CentraleSupélec, Service de Neurologie, Hôpital Foch [Suresnes], Hôpital de Bayonne, CH de la Côte Basque, Service de médecine interne [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Robert Schuman, Service de Pneumologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire de Technologie - Clermont-Ferrand (IUT Clermont-Ferrand), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut NeuroMyoGène (INMG), Université de Lyon, Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier de la Côte Basque (CHCB), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Normandie Université (NU)-Centre hospitalier universitaire de Rouen, Université Lille Nord de France (COMUE)-UNICANCER, Laboratoire d'Imagerie Biomédicale (LIB), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Medical Oncology, and Laboratory for Medical and Molecular Oncology
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Male ,Cancer Research ,Paraneoplastic Syndromes ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Severity of Illness Index ,B7-H1 Antigen ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Neoplasms ,Immunology and Allergy ,Aged, 80 and over ,Melanoma ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,Oncology ,030220 oncology & carcinogenesis ,Cohort ,Molecular Medicine ,Female ,France ,Symptom Assessment ,Encephalitis ,Research Article ,medicine.medical_specialty ,animal structures ,Immunology ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,lcsh:RC254-282 ,Autoimmune Diseases ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Internal medicine ,Pharmacovigilance ,Severity of illness ,medicine ,Humans ,Lung cancer ,Aged ,Pharmacology ,business.industry ,anti-PD-L1 immunotherapy ,Cancer ,Immunotherapy ,Paraneoplastic syndromes (PNS) ,medicine.disease ,nervous system ,business ,030217 neurology & neurosurgery - Abstract
International audience; BACKGROUND:Paraneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy.METHODS:We included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively.FINDINGS:Of the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45-88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1-2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1.INTERPRETATION:Our results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS.
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- 2019
27. Immuno-oncology-101
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Cinzia Solinas, John Stagg, Bertrand Allard, Christos Sotiriou, Laurence Buisseret, Soizic Garaud, Sandrine Aspeslagh, Bertrand Routy, Marleen Kok, Floriane Dupont, Medical Oncology, Laboratory for Medical and Molecular Oncology, Faculty of Psychology and Educational Sciences, and Faculty of Physical Education and Physical Therapy
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0301 basic medicine ,Cancer Research ,Medical Oncology/methods ,medicine.medical_treatment ,Antigen presentation ,Bioinformatics ,Medical Oncology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cancer immunotherapy ,Antigens, Neoplasm ,Neoplasms ,Neoplasms/immunology ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Tumor Microenvironment/immunology ,Antigen Presentation/immunology ,Tumor Escape/immunology ,Antigens, Neoplasm/immunology ,Tumor microenvironment ,Antigen Presentation ,cancer immunotherapy ,business.industry ,Immunotherapy ,Immune checkpoint ,Tumor antigen ,030104 developmental biology ,Tumor Escape ,030220 oncology & carcinogenesis ,Immunotherapy/methods ,Anti-tumor immunity ,Tumor-immune escape ,business - Abstract
Cancer immunotherapy is demonstrating impressive clinical benefit in different malignancies and clinical oncologists are increasingly turning their attention to immune-oncology. It is now well recognized that innate and adaptive immune cells infiltrating tumors are associated with clinical outcomes and responses to treatments, and can be harnessed to patients' benefit. Considerable advances have also been made in understanding how cancers escape from immune attack. Targeting of immunological escape processes regulated by the expression of immune checkpoint receptors and ligands and the down-modulation of tumor antigen presentation is the basis of immuno-oncology treatments. Despite recent achievements, there remain a number of unresolved issues in order to successfully implement cancer immunotherapy in many cancers. Importantly, clinical biomarkers are still needed for better optimization of emerging combination immunotherapies and better treatment tailoring. In this review, we summarize the function of innate and adaptive immune cells in anti-tumor immunity and the general mechanisms exploited by tumor cells to escape and inhibit immune responses as well as therapeutic strategies developed to overcome these mechanisms and discuss emerging biomarkers in immuno-oncology.
- Published
- 2018
28. Importance of choice of materials and methods in PD-L1 and TIL assessment in oropharyngeal squamous cell carcinoma
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Sylvie Rottey, Liesbeth Ferdinande, Philippe Deron, Fréderic Duprez, Sandrine Aspeslagh, Jo Van Dorpe, David Creytens, Astrid De Meulenaere, Tijl Vermassen, Medical Oncology, and Laboratory of Molecular and Medical Oncology
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0301 basic medicine ,Oncology ,Male ,B7-H1 Antigen ,Lymphocytes, Tumor-Infiltrating/pathology ,0302 clinical medicine ,Immunohistochemistry/methods ,Oropharyngeal squamous cell carcinoma ,tumour-infiltrating lymphocytes ,Observer Variation ,biology ,medicine.diagnostic_test ,Squamous Cell Carcinoma of Head and Neck/pathology ,hemic and immune systems ,methodology ,General Medicine ,Middle Aged ,Immunohistochemistry ,Oropharyngeal Neoplasms ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,biomarker ,Female ,Adult ,PD-L1 ,medicine.medical_specialty ,B7-H1 Antigen/analysis ,Histology ,chemical and pharmacologic phenomena ,Oropharyngeal Neoplasms/pathology ,Resection ,Pathology and Forensic Medicine ,Biomarkers, Tumor/analysis ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,Internal medicine ,Biopsy ,medicine ,Biomarkers, Tumor ,Humans ,Lung cancer ,Aged ,Tumor-infiltrating lymphocytes ,business.industry ,Squamous Cell Carcinoma of Head and Neck ,medicine.disease ,030104 developmental biology ,biology.protein ,oropharyngeal squamous cell carcinoma ,business - Abstract
Aims: A great deal of research is being conducted into PD-L1 immunohistochemistry (IHC) and tumour-infiltrating lymphocytes (TILs) as predictive or prognostic biomarkers for immunotherapy, although several practical issues exist concerning their assessment. The aim of this research was therefore to assess the importance of choice of materials and methods in PD-L1 and TILs scoring in oropharyngeal squamous cell carcinoma (OSCC). Methods and results: IHC for PD-L1 (SP142 and 22C3 clone) and TILs subtyping was performed on formalin-fixed paraffin-embedded tissue slides (biopsy, resection and/or lymph nodes specimens) of 99 patients with OSCC. A comparative analysis of PD-L1 and TILs scoring was made between different types of tissue specimens, between different PD-L1 clones, between TILs and different subsets of TILs and between the quantitative and semiquantitative assessments. PD-L1 scoring resulted in fair to moderate agreement for 22C3 and SP142 between various tissue specimens, with higher agreement at higher cut-off values, and in moderate agreement for 22C3 versus SP142. Evaluation by four independent observers proved substantial inter-rater agreement for both clones with high consistency in their ratings. Moderate agreement was observed for TILs and TILs subsets for the comparison between biopsy and resection. Lastly, strong correlations were found between quantitative and semiquantitative assessment for all PD-L1 and TILs scores. Conclusions: Our results highlight the challenges associated with the evaluation of PD-L1 and TILs in OSCC. Further research is warranted to evaluate the use of these biomarkers in order to allow implementation of PD-L1 and TILs infiltrate as biomarkers in daily clinical practice.
- Published
- 2018
29. Immunotherapy phase I trials in patients Older than 70 years with advanced solid tumours
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Sandrine Aspeslagh, Jean-Charles Soria, Olivier Mir, S. Postel Vinay, Eduardo Castanon, Antoine Hollebecque, Capucine Baldini, Valérie Dyevre, Andreea Varga, Jean-Marie Michot, Christophe Massard, H. Herin, Anas Gazzah, Rastislav Bahleda, Vincent Ribrag, Aurélien Marabelle, Medical Oncology, and Laboratory of Molecular and Medical Oncology
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0301 basic medicine ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Case-control studies ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Internal medicine ,medicine ,Clinical Trials, Phase I as Topic/statistics & numerical data ,Humans ,Cumulative incidence ,Young adult ,Age of Onset ,Aged ,Retrospective Studies ,Clinical Trials, Phase I as Topic ,business.industry ,Case-control study ,Age Factors ,Retrospective cohort study ,Immunosenescence ,Immunotherapy ,Middle Aged ,Immune checkpoint ,030104 developmental biology ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Disease Progression ,Immunotherapy/methods ,young adult ,Female ,Age of onset ,business ,aged, 80 and over ,Neoplasms/epidemiology - Abstract
Background: The development of immune checkpoint blocker development brings new hope in older patients (OPs) because of clinical efficacy and low toxicity. Clinical indications are rising steadily, but very few data are available in the geriatric population where comorbidities, reduced functional reserve and immunosenescence may affect efficacy and tolerance. Methods: All cases of patients enrolled in immunotherapy phase I trials between January 2012 and December 2016 in the Drug Development Department (DITEP) at Gustave Roussy were retrospectively reviewed. Case–control analysis was performed in OPs (patients ≥ 70 years) matched to younger patients (YPs) (patients < 70 years) by trial and treatment dose. We compared cumulative incidence, grade and type of immune-related adverse events (IrAEs) and survival outcomes. Results: Among the 46 OPs and the 174 YPs enrolled in 14 phase I/II trials, 10 (22%) and 23 (13%) patients experienced grade III–IV IrAEs. Cumulative incidence of grade I–II IrAEs was significantly higher in OPs than YPs (p < 0.05). No significant difference was observed between the two groups for grade III–IV IrAEs (p = 0.50). Older age was not associated with lower dose intensity of treatment (p = 0.14). No significant difference was observed between OPs and YPs in median progression-free survival (hazards ratio 1.41, 95% confidence interval [CI] [0.94–2.11] p = 0.09) or median overall survival (HR 0.92, 95% CI [0.61–1.39] p = 0.77). Conclusion: Immune checkpoint blockade appears to be an acceptable treatment option for OPs in the setting of phase I trials.
- Published
- 2018
30. In the immuno-oncology era, is anti-PD-1 or anti-PD-L1 immunotherapy modifying the sensitivity to conventional cancer therapies?
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Sandrine Aspeslagh, Laurent Dercle, Jean-Charles Soria, Margarida Matias, Sophie Postel-Vinay, Emilie Lanoy, Virginia Palomar, and Medical Oncology
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,Time Factors ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,B7-H1 Antigen ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Neoplasms ,Signal Transduction/drug effects ,Antineoplastic Combined Chemotherapy Protocols ,Antineoplastic Agents, Immunological/therapeutic use ,biology ,Programmed Cell Death 1 Receptor/antagonists & inhibitors ,Middle Aged ,Treatment Outcome ,030220 oncology & carcinogenesis ,Immunotherapy/methods ,Immunogenic cell death ,young adult ,Female ,Immunotherapy ,Antibody ,TUMOR MICROENVIRONMENT ,Signal Transduction ,Adult ,medicine.medical_specialty ,Cancer therapy ,B7-H1 Antigen/antagonists & inhibitors ,Subgroup analysis ,Disease-Free Survival ,03 medical and health sciences ,McNemar's test ,Internal medicine ,medicine ,Humans ,Aged ,Retrospective Studies ,business.industry ,Anti pd 1 ,Cancer ,medicine.disease ,Neoplasms/drug therapy ,030104 developmental biology ,Drug Resistance, Neoplasm ,biology.protein ,Antineoplastic Combined Chemotherapy Protocols/therapeutic use ,business - Abstract
Introduction The advent of anti-programmed death receptor-1/ligand-1 antibodies (anti-PD(L)1) is profoundly changing the therapeutic strategy of oncology. As anti-PD(L)1 modulate tumour microenvironment, it might impact sensitivity to conventional cancer therapy (CCT). Therefore, we explored whether sensitivity to CCT was different before and after anti-PD(L)1 therapy. Methods Patients who started anti-PD(L)1 treatment at Gustave Roussy Cancer Centre between February 2012 and December 2015, and who received at least one line of CCT immediately before and immediately after anti-PD(L)1, were eligible. We analysed progression-free survival (PFS) and overall response rate (ORR) of the CCT line immediately before (PFSpre/ORRpre) and after (PFSpost/ORRpost) anti-PD(L)1. PFS and ORR were compared using Wilcoxon signed rank and McNemar tests in a paired data subset for patients having received identical class of CCT pre and post anti-PD(L)1 therapy. Results Among 118 eligible patients, 65% received anti-PD1 and 35% anti-PD-L1 agents. Median PFSpre versus PFSpost was 4.7 versus 3.5 months (p = 0.011), respectively; it was 5.7 versus 6.8 months (NS) for patients who derived clinical benefit from immunotherapy and 3.9 versus 3.0 months (p = 0.012) for patients who were primary resistant to anti-PD(L)1 therapy. Subgroup analysis did not reveal any significant difference in PFS or ORR before versus after anti-PD(L)1 therapy according to CCT class or to its ability to induce immunogenic cell death. Conclusion Patients who derive benefit from immune therapies tend to have better PFS on conventional therapies after having received the anti-PD(L)1 agent. Further studies on larger data sets are warranted to confirm these findings.
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- 2017
31. RECIST response and variation of circulating tumour cells in phase 1 trials
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Françoise Farace, François-Clément Bidard, Charles Ferté, Christophe Massard, Sandrine Aspeslagh, Ludovic Lacroix, Jean-Philippe Spano, Christophe Le Tourneau, Jean-Charles Soria, Jean-Yves Pierga, Isabelle Borget, Paul Hofman, Véronique Diéras, Marie-Cécile Le Deley, and Medical Oncology
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0301 basic medicine ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Tumour response ,Gastroenterology ,Sensitivity and Specificity ,03 medical and health sciences ,0302 clinical medicine ,Stable Disease ,Predictive Value of Tests ,Neoplasms ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Prospective Studies ,cell count ,Response Evaluation Criteria in Solid Tumors ,Whole blood ,Aged ,Neoplastic Cells, Circulating/pathology ,Lung ,Clinical Trials, Phase I as Topic ,business.industry ,Cancer ,Phase i trials ,Middle Aged ,Neoplastic Cells, Circulating ,medicine.disease ,Survival Analysis ,Surgery ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Biomarkers, Tumor/blood ,030220 oncology & carcinogenesis ,Neoplasms/blood ,Biomarker (medicine) ,young adult ,Female ,business ,Progressive disease - Abstract
Background Circulating tumour cell (CTC) counting could be a new biomarker for better evaluation of tumour response to molecules tested in phase I trials. Patients and methods Consenting patients with advanced metastatic cancer referred to various phase I units were enrolled prospectively in this study. CTCs from 7.5 ml of whole blood drawn at baseline and after starting experimental therapy were counted using the CellSearch system, and tumour response was assessed using RECIST 1.1 criteria at baseline and 2 months after treatment initiation. Results Between March 2010 and May 2013, a total of 326 patients were enrolled, among whom 214 were evaluable (49% male, median age = 56; main cancer types: lung [28], colon [53], ovarian [18], breast [28]). At baseline, we detected ≥1 CTC/7.5 ml in 113/214 patients (53%), and at day 30, we observed ≥1 CTC/7.5 ml in 103/214 patients (48%). Two months after treatment initiation, 11 (5%) of the 214 patients were classified as having a partial response, with no CTCs in 9 of them or a decrease in the CTC count after therapy. In contrast, among the 104 patients (49%) classified as having progressive disease, 38 patients had a higher CTC count. The remaining 99 patients (49%), 33 of whom (33%) had a lower CTC count, were classified as having stable disease. The sensitivity and specificity of CTC variation for predicting progressive disease were 41% (32–51%) and 80% (73–88%) respectively. Conclusion An early CTC change following therapy does not correlate with RECIST response in patients with advanced cancer enrolled in phase I trials.
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- 2017
32. Phase I dose-escalation study of milciclib in combination with gemcitabine in patients with refractory solid tumors
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Andrea Varga, Antoine Hollebecque, Rastilav Bahleda, Anas Gazzah, Christophe Massard, Sandrine Aspeslagh, Jean-Charles Soria, Anna Spreafico, Michele Reni, Kunwar Shailubhai, and Medical Oncology
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,Lung Neoplasms ,Antimetabolites, Antineoplastic/administration & dosage ,Carcinoma, Non-Small-Cell Lung/drug therapy ,Toxicology ,Deoxycytidine ,Gastroenterology ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,Pharmacology (medical) ,Drug Interactions ,Middle Aged ,Cyclin-Dependent Kinases ,Treatment Outcome ,Tolerability ,030220 oncology & carcinogenesis ,Peritoneal mesothelioma ,Female ,medicine.drug ,Antimetabolites, Antineoplastic ,medicine.medical_specialty ,Maximum Tolerated Dose ,Neutropenia ,Cyclin-Dependent Kinases/antagonists & inhibitors ,03 medical and health sciences ,Refractory ,Pharmacokinetics ,Internal medicine ,medicine ,Humans ,Lung Neoplasms/drug therapy ,Deoxycytidine/administration & dosage ,Aged ,Pharmacology ,business.industry ,Antineoplastic Combined Chemotherapy Protocols/adverse effects ,medicine.disease ,Pyrazoles/administration & dosage ,Gemcitabine ,Quinazolines/administration & dosage ,Neoplasms/drug therapy ,Regimen ,030104 developmental biology ,Drug Resistance, Neoplasm ,Concomitant ,Quinazolines ,Pyrazoles ,business - Abstract
BACKGROUND: This phase I trial evaluated the safety and tolerability of milciclib, an inhibitor of multiple cyclin-dependent kinases and tropomycin receptor kinase A, in combination with gemcitabine in patients with refractory solid tumors. DESIGN: Sixteen patients were enrolled and treated with milciclib at three dose levels (45 mg/m2/day, n = 3; 60 mg/m2/day, n = 3; and 80 mg/m2/day, n = 10) with a fixed dose of gemcitabine (1000 mg/m2/day). Milciclib was administered orally once daily for 7 days on/7 days off in a 4-week cycle, and gemcitabine was administered intravenously on days 1, 8 and 15 in a 4-week cycle. RESULTS: All 16 enrolled patients were evaluable for safety and toxicity. Dose-limiting toxicities, which occurred in only one out of nine patients treated at the maximum dose tested (milciclib 80 mg/m2/day and gemcitabine 1000 mg/m2/day), consisted of Grade 4 thrombocytopenia, Grade 3 ataxia and Grade 2 tremors in the same patient. Most frequent treatment-related AEs were neutropenia and thrombocytopenia. Among 14 evaluable patients, one NSCLC patient showed partial response and 4 patients (one each with thyroid, prostatic, pancreatic carcinoma and peritoneal mesothelioma) showed long-term disease stabilization (>6-14 months). Pharmacokinetics of the orally administered milciclib (~t1/2 33 h) was not altered by concomitant treatment with gemcitabine. CONCLUSION: The combination treatment was well tolerated with manageable toxicities. The recommended phase II dose was 80 mg/m2/day for milciclib and 1000 mg/m2/day for gemcitabine. This combination treatment regimen showed encouraging clinical benefit in ~36% patients, including gemcitabine refractory patients. These results support further development of combination therapies with milciclib in advanced cancer patients.
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- 2017
33. 3D waterfall plots
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E. Castanon Alvarez, Sandrine Aspeslagh, J-C. Soria, and Medical Oncology
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Medical Oncology/methods ,MEDLINE ,Waterfall ,Medical Oncology ,computer.software_genre ,Tumor response ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Medicine ,Humans ,Clinical Trials as Topic/methods ,Clinical Trials as Topic ,geography ,Data display ,geography.geographical_feature_category ,business.industry ,Representation (systemics) ,Neoplasms therapy ,Hematology ,Neoplasms/drug therapy ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Data Display ,Artificial intelligence ,business ,computer ,Natural language processing - Published
- 2017
34. JAK Mutations as Escape Mechanisms to Anti-PD-1 Therapy
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Sandrine Aspeslagh, Sophie Postel-Vinay, Jean-Charles Soria, Aurélien Marabelle, and Medical Oncology
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0301 basic medicine ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,medicine.disease_cause ,B7-H1 Antigen ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,B7-H1 Antigen/genetics ,Mutation ,Janus kinase 1 ,business.industry ,Anti pd 1 ,Cancer ,Immunotherapy ,Janus Kinase 1 ,medicine.disease ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Immunology ,immunotherapy ,mutation ,business - Abstract
Loss of function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned they may also be involved in primary resistance to anti-PD-1 therapy. JAK1/2 inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to lack of PD-L1 expression upon interferon gamma exposure mediated by inability to signal through the interferon gamma receptor pathway. JAK1/2 loss-of-function alterations in TCGA confer adverse outcomes in patients. We propose that JAK1/2 loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy.
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- 2017
35. NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients
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Serge Leyvraz, Katrin S. Reiners, Christos Christidis, Jean-Yves Blay, Jonathan M. Pitt, Marion Lambert, Aurélien Marabelle, Frédéric Vély, Alexandre Ivagnes, Jean-François Emile, Christian Auclair, Benedita Rocha, Axel Le Cesne, Loic Chaigneau, Christelle Piperoglou, Kariman Chaba, Philippe Terrier, Eric Vivier, Nicolas Isambert, Julien Adam, Sylvie Rusakiewicz, Pierre Validire, Bruno Landi, Thierry Perniceni, Laurence Zitvogel, Sarah Jegou, Sylvie Bonvalot, Michaela Semeraro, Sophie Caillat-Zucman, David Enot, Sandrine Aspeslagh, Aurélie Perier, Christophe Borg, Vichnou Poirier-Colame, Anne Berger, Alexander M.M. Eggermont, Antoine Toubert, Niels Halama, Joachim Koch, Elke Pogge von Strandmann, Olivier Mir, Julien Domont, Anne Caignard, Jean-Michel Coindre, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Institut Gustave Roussy (IGR), Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Saclay, Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION )-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Service d'Immunologie [AP-HM], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Microorganismes, Molécules Bioactives et Physiopathologie Intestinale (LBM-E4), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] (DHU i2B ), CHU Saint-Antoine [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Departement d'Anatomopathologie, Institut Mutualiste de Montsouris (IMM), Hellenic Open University [Patras], Département de chirurgie digestive, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Centre Jean-bernard, Département de biologie et pathologie médicales [Gustave Roussy], Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Service de Pathologie, Institut Bergonié, Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et physiologie des lymphocytes T (U1020), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Virologie et Immunologie Moléculaires, Université Francois Rabelais [Tours], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'immunologie, AP-HP Hôpital universitaire Robert-Debré [Paris], Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Equipe 11, Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de médecine oncologique [Gustave Roussy], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Université Paris-Sud 11 - Faculté de médecine ( UP11 UFR Médecine ), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] ( DITEP ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Microorganismes, Molécules Bioactives et Physiopathologie Intestinale ( LBM-E4 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] ( DHU i2B ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Institut Mutualiste de Montsouris ( IMM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse ( U981 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ), Différenciation et physiologie des lymphocytes T ( U1020 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Necker Enfants-Malades ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre de recherche sur l'Inflammation ( CRI ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biologie et de Pharmacologie Appliquée ( LBPA ), École normale supérieure - Cachan ( ENS Cachan ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service de rhumatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut Bergonié [Bordeaux], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Medical Centre of the Johannes Gutenberg University Mainz, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan), Medical Oncology, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École Pratique des Hautes Études (EPHE), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU)
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Immunology ,PDGFRA ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Immunology and Allergy ,[ SDV.IMM ] Life Sciences [q-bio]/Immunology ,neoplasms ,Original Research ,Tumor microenvironment ,GiST ,business.industry ,Cancer ,medicine.disease ,digestive system diseases ,3. Good health ,Immunosurveillance ,030104 developmental biology ,Imatinib mesylate ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,business ,Tyrosine kinase - Abstract
International audience; Despite effective targeted therapy acting on KIT and PDGFRA tyrosine kinases, gastrointestinal stromal tumors (GIST) escape treatment by acquiring mutations conveying resistance to imatinib mesylate (IM). Following the identification of NKp30-based immunosurveillance of GIST and the off-target effects of IM on NK cell functions, we investigated the predictive value of NKp30 isoforms and NKp30 soluble ligands in blood for the clinical response to IM. The relative expression and the proportions of NKp30 isoforms markedly impacted both event-free and overall survival, in two independent cohorts of metastatic GIST. Phenotypes based on disbalanced NKp30B/NKp30C ratio (Delta BClow) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This Delta BClow blood phenotype was associated with a pro-inflammatory and immunosuppressive tumor microenvironment. In addition, detectable levels of the NKp30 ligand sB7-H6 predicted a worse prognosis in metastatic GIST. Soluble BAG6, an alternate ligand for NKp30 was associated with low NKp30 transcription and had additional predictive value in GIST patients with high NKp30 expression. Such GIST microenvironments could be rescued by therapy based on rIFN-alpha and anti-TRAIL mAb which reinstated innate immunity.
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- 2017
36. Phase I dose-escalation study of plitidepsin in combination with sorafenib or gemcitabine in patients with refractory solid tumors or lymphomas
- Author
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Antoine Hollebecque, Sonia Extremera, Gilles Salles, Vicente Alfaro, Sandrine Aspeslagh, Mark N. Stein, Emmanuel Gyan, Salvador Fudio, Rastilav Bahleda, Arturo Soto-Matos, Jean-Charles Soria, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Medical Oncology
- Subjects
0301 basic medicine ,Oncology ,Male ,Cancer Research ,Lymphoma ,Administration, Oral ,Deoxycytidine ,Gastroenterology ,Depsipeptides/administration & dosage ,0302 clinical medicine ,Depsipeptides ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Pharmacology (medical) ,Prospective Studies ,Fatigue ,Nausea ,Antineoplastic Combined Chemotherapy Protocols/administration & dosage ,Middle Aged ,3. Good health ,030220 oncology & carcinogenesis ,Toxicity ,Vomiting ,young adult ,Female ,France ,medicine.symptom ,medicine.drug ,Niacinamide ,Sorafenib ,Adult ,medicine.medical_specialty ,Patients ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Peptides, Cyclic ,03 medical and health sciences ,Niacinamide/administration & dosage ,Refractory ,Internal medicine ,Humans ,Adverse effect ,Deoxycytidine/administration & dosage ,Aged ,Lymphoma/drug therapy ,Pharmacology ,therapy ,Dose-Response Relationship, Drug ,business.industry ,Phenylurea Compounds ,toxicity ,medicine.disease ,Gemcitabine ,Thrombocytopenia ,Neoplasms/drug therapy ,SORAFENIB ,030104 developmental biology ,Phenylurea Compounds/administration & dosage ,Erythema ,business ,aged, 80 and over - Abstract
International audience; This phase I trial evaluated the combination of the marine-derived cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine in advanced cancer and lymphoma patients. The study included two treatment arms: a sorafenib/plitidepsin (S/P) and a gemcitabine/plitidepsin (G/P) arm. In the S/P arm, patients were treated orally with sorafenib continuous dosing at two dose levels (DL1: 200 mg twice daily and DL2: 400 mg twice daily) combined with plitidepsin (1.8 mg/m, day 1, day 8, day 15, and, q4wk, intravenously). In the G/P arm, patients with solid tumors or lymphoma were treated at four different DLs with a combination of gemcitabine (DL1: 750 mg/m, DL2-DL4: 1000 mg/m) and plitidepsin (DL1-DL2: 1.8 mg/m; DL3: 2.4 mg/m; DL4: 3 mg/m). Both agents were administered intravenously on day 1, day 8, day 15, and, q4wk. Forty-four patients were evaluable for safety and toxicity. The safety of the combination of plitidepsin with sorafenib or gemcitabine was manageable. Most adverse events (AEs) were mild; no grade 4 treatment-related AEs were reported in any of the groups (except for one grade 4 thrombocytopenia in the gemcitabine arm). The most frequently reported study drug-related (or of unknown relationship) AEs were palmar-plantar erythrodysesthesia, erythema, nausea, vomiting, and fatigue in the S/P arm and nausea, fatigue, and vomiting in the G/P arm. In the S/P arm, one dose-limiting toxicity occurred in two out of six patients treated at the maximum dose tested (DL2): palmar-plantar erythrodysesthesia and grade 2 aspartate aminotransferase/alanine aminotransferase increase that resulted in omission of days 8 and 15 plitidepsin infusions. In the G/P arm, one dose-limiting toxicity occurred in two out of six patients at DL4: grade 2 alanine aminotransferase increase resulted in omission of days 8 and 15 plitidepsin infusions and grade 4 thrombocytopenia. The recommended dose for the combination of plitidepsin with sorafenib was not defined because of a sponsor decision (no expansion cohort to confirm) and for plitidepsin with gemcitabine, it was 2.4 mg/m plitidepsin with 1000 mg/m gemcitabine. In the S/P group, objective disease responses were not observed; however, disease stabilization (\textgreater/=3months) was observed in four patients. In the gemcitabine group, two lymphoma patients showed an objective response (partial response and complete response) and nine patients showed disease stabilization (\textgreater/=3months). Combining plitidepsin with gemcitabine and sorafenib is feasible for advanced cancer patients; some objective responses were observed in heavily pretreated lymphoma patients
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- 2016
37. Cancer immunotherapy:From the lab to clinical applications - Potential impact on cancer centres' organisation
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Per thor Straten, Andrea A. Anichini, Paolo P. Ascierto, Linda Cairns, Nicolle N. Rekers, Christian C. Blank, Jon Amund Kyte, Ahmad Awada, Sandrine Aspeslagh, and Medical Oncology
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.drug_class ,T cell ,medicine.medical_treatment ,Cancer vaccines ,Monoclonal antibody ,Environnement et pollution ,Immune system ,Cancer immunotherapy ,Internal medicine ,medicine ,Potential impact ,business.industry ,Cancer ,Conference Report ,Immunotherapy ,medicine.disease ,Cancérologie ,medicine.anatomical_structure ,Cancer cell ,Immunology ,Monoclonal antibodies ,immunotherapy ,monoclonal antibodies ,business ,cancer vaccines - Abstract
This report covers the Immunotherapy sessions of the 2016 Organisation of European Cancer Institutes (OECI) Oncology Days meeting, which was held on 15th-17th June 2016 in Brussels, Belgium. Immunotherapy is a potential cancer treatment that uses an individual's immune system to fight the tumour. In recent years significant advances have been made in this field in the treatment of several advanced cancers. Cancer immunotherapies include monoclonal antibodies that are designed to attack a very specific part of the cancer cell and immune checkpoint inhibitors which are molecules that stimulate or block the inhibition of the immune system. Other cancer immunotherapies include vaccines and T cell infusions. This report will summarise some of the research that is going on in this field and will give us an update on where we are at present., SCOPUS: ar.j, info:eu-repo/semantics/published
- Published
- 2016
38. Rapid and objective CT scan prognostic scoring identifies metastatic patients with long-term clinical benefit on anti-PD-1/-L1 therapy
- Author
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Linda Mahjoubi, Sophie Postel-Vinay, Christophe Massard, Aurélien Marabelle, Stéphane Champiat, Samy Ammari, Martin Schlumberger, Nyam Kamsu-Kom, Charles Ferté, Sandrine Aspeslagh, Laurent Dercle, Romain-David Seban, Jean-Charles Soria, Caroline Robert, Lokmane Taihi, and Medical Oncology
- Subjects
0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,B7-H1 Antigen/antagonists & inhibitors ,Computed tomography ,Antineoplastic Agents ,Kaplan-Meier Estimate ,B7-H1 Antigen ,Disease-Free Survival ,Neoplasms, Multiple Primary ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Humans ,Young adult ,Neoplasm Metastasis ,Response Evaluation Criteria in Solid Tumors ,Aged ,Proportional Hazards Models ,Neoplasms, Multiple Primary/diagnostic imaging ,medicine.diagnostic_test ,Performance status ,business.industry ,Proportional hazards model ,Hazard ratio ,Antineoplastic Agents/therapeutic use ,Cancer ,Middle Aged ,medicine.disease ,Prognosis ,Confidence interval ,030104 developmental biology ,030220 oncology & carcinogenesis ,young adult ,Female ,Radiology ,business ,aged, 80 and over ,Tomography, X-Ray Computed - Abstract
BACKGROUND: Drugs targeting programmed death receptor-1 (PD-1) and its ligand PD-L1 have shown activity in multiple malignancies. Considering their novel mechanism of action, whether traditional prognostic scores also apply to patients treated with these drugs is unknown. We investigated whether a baseline 3-point (pt) computed tomography (CT) scan (PS3-CT) score and a 7-pt prognostic (PS7) score allowed identifying long-term survivors on anti-PD-1/-L1 therapy. MATERIALS AND METHODS: We reviewed 251 consecutive patients enrolled in phase I trials evaluating anti-PD-1/-L1 agents between 26th December 2011 and 7th September 2015. PS3-CT was calculated using high tumour burden (TB1D-RECIST > 9 cm), low skeletal muscle index (SMI < 53 cm(2) m(-2)) and non-pulmonary visceral metastases (NPVM) (1 pt each). PS7 was calculated by adding lower performance status, decreased serum albumin, increased serum lactate dehydrogenase and more than two distant metastases (1 pt each). Effect on overall survival (OS) of each parameter was tested using Kaplan-Meier and multivariable Cox analyses. RESULTS: PS3-CT was a significant independent predictor of OS (hazard ratio [HR] = 1.39 [95% confidence interval {CI} = 1.07-1.81], p = 0.01) when compared to the Royal Marsden Hospital, Barbot and American Joint Committee on Cancer scores. High TB (n = 78), low SMI (n = 55) and NPVM (n = 146) were associated with poorer survival (p < 0.01). High TB and low SMI were independent predictors of OS (respective HR of death: 2.00 [95% CI = 1.38-2.88], p < 0.01 and 1.75 [95% CI = 1.15-2.66], p < 0.01). PS7 was a significant predictor of OS (HR = 1.40 [95% CI = 1.25-1.56], p < 0.01). CONCLUSION: Objective and rapid-risk scoring based on three CT scan parameters allows identifying patients with prolonged OS on anti-PD-1/-L1 therapy, independently from conventional clinical-biological prognostic scores.
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- 2016
39. Bacterial CD1d-restricted glycolipids induce IL-10 production by human regulatory T cells upon cross-talk with invariant NKT cells
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Koen Venken, Sandrine Aspeslagh, Dirk Elewaut, Bart N. Lambrecht, Serge Van Calenbergh, Tine Decruy, and Medical Oncology
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medicine.medical_treatment ,T cell ,Natural Killer T-Cells/immunology ,Immunology ,chemical and pharmacologic phenomena ,T-Lymphocytes, Regulatory/immunology ,Lymphocyte Activation/immunology ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,Immune system ,medicine ,Immunology and Allergy ,Humans ,IL-2 receptor ,Antigens, CD1d/immunology ,biology ,Receptor Cross-Talk/immunology ,FOXP3 ,hemic and immune systems ,Receptor Cross-Talk ,Interleukin-10/biosynthesis ,Natural killer T cell ,Flow Cytometry ,Coculture Techniques ,Interleukin-10 ,Interleukin 10 ,Cytokine ,medicine.anatomical_structure ,CD1D ,Glycolipids/immunology ,biology.protein ,Natural Killer T-Cells ,Antigens, CD1d ,Glycolipids - Abstract
Invariant NKT (iNKT) cells and CD4+CD25+FOXP3+ regulatory T cells (Tregs) are important immune regulatory T cells with Ag reactivity to glycolipids and peptides, respectively. However, the functional interplay between these cells in humans is poorly understood. We show that Tregs suppress iNKT cell proliferation induced by CD1d-restricted glycolipids, including bacterial-derived diacylglycerols, as well as by innate-like activation. Inhibition was related to the potency of iNKT agonists, making diacylglycerol iNKT responses very prone to suppression. Cytokine production by iNKT cells was differentially modulated by Tregs because IL-4 production was reduced more profoundly compared with IFN-γ. A compelling observation was the significant production of IL-10 by Tregs after cell contact with iNKT cells, in particular in the presence of bacterial diacylglycerols. These iNKT-primed Tregs showed increased FOXP3 expression and superior suppressive function. Suppression of iNKT cell responses, but not conventional T cell responses, was IL-10 dependent, suggesting that there is a clear difference in mechanism between the Treg-mediated inhibition of these cell types. Our data highlight a physiologically relevant interaction between human iNKT and Tregs upon pathogen-derived glycolipid recognition that has a significant impact on the design of iNKT cell–based therapeutics.
- Published
- 2013
40. Preclinical Evaluation of Invariant Natural Killer T-Cells in the 5T33 Multiple Myeloma Model
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Haneen Nur, Elke De Bruyne, Eline Menu, Els Van Valckenborgh, Sandrine Aspeslagh, Karin Vanderkerken, Dirk Elewaut, Hematology, and Immunology and Microbiology
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biology ,business.industry ,CD3 ,Immunology ,Spleen ,chemical and pharmacologic phenomena ,Cell Biology ,Hematology ,Natural killer T cell ,Major histocompatibility complex ,Biochemistry ,medicine.anatomical_structure ,myeloma ,Antigen ,In vivo ,CD1D ,biology.protein ,medicine ,Receptor ,business - Abstract
Abstract 938 Natural killer T (NKT) cells are T-lymphocytes that co-express conventional T-cell (CD3) and NK cell (NK1.1) surface receptors, while invariant NKT cells (iNKTs) also express a unique semi-invariant TCR α-chain encoded by Vα14.Jα18 in mice and Vα24.Jα18 in human. These iNKTs can recognize glycolipid antigens such as α-Galactosylceramide (α-GalCer) presented by the class I-like major histocompatibility complex (MHC) molecule CD1d. Activation of iNKTs can lead to an anti-tumor Th1 (IFN-γ) response or an immunosuppressive Th2 (IL-4) response. Clinical studies in MM patients (1, 2) showed a low frequency and dysfunction of iNKTs which resulted in a low IFN-γ secretion. This defect could be overcome in vitro by stimulating the iNKTs with α-GalCer loaded DCs. Furthermore, when MM patients were injected with loaded DCs their iNKT pool expanded 100 fold. This make MM cells an interesting target for iNKT therapy. However, the data on NKT activity in MM patients is limited and the use of α-GalCer as a drug has not been preclinically evaluated yet. Therefore, in this study, we investigated the characteristics of iNKTs in the syngeneic 5T33MM murine model, which is an immunocompetent model of myeloma which mimics the human disease closely. We first investigated the frequency of iNKTs in the blood, BM, spleen and liver of both healthy and terminally diseased 5T33MM mice. The highest percentage of iNKTs was found in the liver (naive 7%) with a significant decrease in 5T33MM mice (2.6%). The percentage was also slightly decreased in spleen (from 1.5% in naive to 0.7% in 5T33MM mice) while no significant differences were observed in the other tissues. Next, we followed the frequency of iNKTs in the liver and spleen of MM mice during the development of the disease. We analyzed the number of iNKTs in the first, second, third and terminal week. We found that the percentage of iNKTs declined at the end stage of MM disease. To analyze the activity of iNKTs in vitro, liver iNKTs were cocultured with naive matured BM derived DCs in the presence or absence of 100 ng/ml α-GalCer. Naive iNKTs could secrete up to 2.3 ng/ml IFN-γ when stimulated with α-GalCer, and this level increased with the progression of MM to reach 3.3 ng/ml at week 2. However, the activity of the iNKTs dropped to undetectable levels upon further progression of the disease (week 4). In contrast, very slight IL-4 production was observed indicating that liver iNKTs are skewed to a Th1 profile and can therefore be used as an immunotherapeutic tool in MM. The activity of the NKTs was also followed in vivo. The serum level of IFN-γ peaked at 18h after α-GalCer injection in naive and non-terminal diseased mice and returned to baseline by 48h, however, the response of IFN-γ in diseased mice was twice (6 ng/ml) that measured in naive mice, confirming the possibility of inducing Th1 responses with α-GalCer in vivo in healthy and diseased mice. No response could be detected from terminally diseased mice. It has been described previously that CD1d is significantly downregulated in patients with advanced stages of MM (3). To investigate if this is similar in the 5T33MM model, we followed the expression of CD1d on spleen and BM cells during the course of the disease. Results showed a significant downregulation of CD1d expression on spleen cells from 93% CD1d (naive) to 68% at end stage. On BM cells, CD1d was less expressed compared to spleen cells, 52% in naive mice and expression declined significantly to 35%. CD1d expression on the MM cells themselves was high (79%) and did not alter during the course of the disease. We finally evaluated the effect of α-GalCer on the survival of MM mice. Survival was significantly increased when mice were injected with α-GalCer loaded DCs on the same day of 5T33MM inoculation (29 days survival) compared to mice injected with unloaded DCs (22 days survival). Taken together, our data demonstrate for the first time the possibility of using a murine model as a preclinical MM model to study the effects of α-GalCer on iNKTs and shows promising results of treating MM patients with a low tumorload. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2012
41. Divergent synthetic approach to 6'-modified α-GalCer analogues
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Esther Dawen Yu, Serge Van Calenbergh, Dirk Elewaut, Gerd Vanhoenacker, Bruno Linclau, Koen Sandra, Dirk M. Zajonc, Nora Pauwels, Sandrine Aspeslagh, and Medical Oncology
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mice ,Stereochemistry ,Molecular Conformation ,Stereoisomerism ,Galactosylceramides ,Biochemistry ,Article ,chemistry.chemical_compound ,Glycolipid ,Cytokines metabolism ,Galacturonic acid ,Animals ,Physical and Theoretical Chemistry ,Sphingosine ,Chemistry ,Hexuronic Acids ,Organic Chemistry ,Cytokines/metabolism ,Hexuronic Acids/administration & dosage ,Galactosylceramides/administration & dosage ,Rhamnogalacturonan I ,Cytokines ,Galactosyl ceramide ,surface plasmon resonance - Abstract
A synthetic approach is presented for the synthesis of galacturonic acid and D-fucosyl modified KRN7000. The approach allows for late-stage functionalisation of both the sugar 6′′-OH and the sphingosine amino groups, which enables convenient synthesis of promising 6′′-modified KRN7000 analogues.
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- 2011
42. Synthesis and Evaluation of Amino-Modified α-GalCer Analogues
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Yali Li, Serge Van Calenbergh, René Chofor, Bruno Linclau, Sandrine Aspeslagh, Matthias Trappeniers, Dirk M. Zajonc, and Dirk Elewaut
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Ceramide ,Stereochemistry ,Galactosylceramides ,Molecular Conformation ,Stereoisomerism ,VARIANTS ,GLYCOLIPIDS ,Biochemistry ,Article ,Phthalimide ,SPONGE AGELAS-MAURITIANUS ,chemistry.chemical_compound ,Glycolipid ,In vivo ,Medicine and Health Sciences ,HUMAN CD1D ,Physical and Theoretical Chemistry ,Receptor ,T-CELL-RECEPTOR ,CERAMIDE ,Organic Chemistry ,RECOGNITION ,chemistry ,GALACTOSYLCERAMIDES ,Mitsunobu reaction - Abstract
alpha-GalCer analogues featuring a phytoceramide 3- and 4-amino group have been synthesized. A Mitsunobu reaction involving phthalimide was employed for the introduction of the amino groups at the 3- and 4-positions of suitable phytosphingosine-derived precursors. The influence of these modifications on the interaction with the T-cell receptor of NKT cells was investigated, as well as the capacity of the amino-modified analogues to induce a cytokine response after in vivo administration.
- Published
- 2010
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