122 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. Supplementary Data from Long-Term Survival in Patients Responding to Anti–PD-1/PD-L1 Therapy and Disease Outcome upon Treatment Discontinuation
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Aurélien Marabelle, Christophe Massard, Caroline Robert, Jean-Charles Soria, Antoine Hollebecque, Vincent Ribrag, Eric Angevin, Sophie Postel-Vinay, Jean-Marie Michot, Anas Gazzah, Rastilav Bahleda, Capucine Baldini, Andrea Varga, Sandrine Aspeslagh, Samy Ammari, Caroline Caramella, Stéphane Champiat, Emilie Lanoy, and Marie-Léa Gauci
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Sup Data Table S1: Characteristic features of long responder patients Sup Data Figure S1: a: PFS and OS from the first objective response assessed for responder patients; b: PFS and OS from the first objective response assessed for partial responders; c: OS and PFS from the first complete response assessed (crPFS and crOS) Sup Data Figure S2: Risk of relapse upon therapy discontinuation function of therapy duration Sup Data Figure S3: Survival from relapse and PFS from OR of secondary refractory disease Sup Data Figure S4: PFS from OR of secondary refractory disease function of tumor type Sup Data Table S2: Characteristics of secondary refractory disease Sup Data Table S3: Characteristics of long survival after immunotherapy initiation with progression first response/stable disease then progression: n=30 (%) Sup Data Table S4: Objective response rate (ORR) as a function of tumor type (%) Sup Data Figure S5a: PFS function of RMH score Sup Data Figure S5b: OS function of the RMH score Sup Data Figure 6: a: Overall survival function of NLR, b: Overall survival for patients presenting progressive disease as best response function of the NLR, c: Overall survival for patients presenting stable disease as best response function of the NLR d: Overall survival for patients presenting objective response as best response function of the NLR Sup Data Figure S7: a: Response function of neutrophil and lymphocyte counts, b: comparison of lymphocyte count function of response, c: comparison of neutrophil count function of response
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- 2023
16. Data from Long-Term Survival in Patients Responding to Anti–PD-1/PD-L1 Therapy and Disease Outcome upon Treatment Discontinuation
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Aurélien Marabelle, Christophe Massard, Caroline Robert, Jean-Charles Soria, Antoine Hollebecque, Vincent Ribrag, Eric Angevin, Sophie Postel-Vinay, Jean-Marie Michot, Anas Gazzah, Rastilav Bahleda, Capucine Baldini, Andrea Varga, Sandrine Aspeslagh, Samy Ammari, Caroline Caramella, Stéphane Champiat, Emilie Lanoy, and Marie-Léa Gauci
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Purpose:Anti–PD-(L)1 can provide overall survival (OS) benefits over conventional treatments for patients with many different cancer types. However, the long-term outcome of cancer patients responding to these therapies remains unknown. This study is an exploratory study that aimed to describe the long-term survival of patients responding to anti–PD-(L)1 monotherapy across multiple cancer types.Patients and Methods: Data from patients treated with an anti–PD-(L)1 monotherapy in a phase I trial at Gustave Roussy were retrospectively analyzed over a period of 5 years. All cancer types (n = 19) were included. Clinical and biological factors associated with response, long-term survival, and secondary refractory disease were studied.Results:Among 262 eligible patients, the overall objective response rate was 29%. The median progression-free survival of responder patients (RP) at 3 months was 30 months, and the median OS of RP was not reached after a median follow-up of 34 months. In RPs, 3- and 5-year OS percentages were 84% and 64%, respectively. No death occurred in the 21 complete responders (CR) during the overall follow-up. However, many partial responders (PR) showed subsequent tumor relapses to treatment. Long responders (response ≥2 years) represented 11.8% of the overall population. These findings should be validated in further prospective studies.Conclusions:There are currently no differences in therapeutic strategies between CRs and PRs to anti–PD-(L)1. We found a striking difference in OS between these two types of responses. Our results are in favor of evaluating patient stratification strategies and intensification of treatments when tumor lesions of a partial responder to immunotherapy stop improving.See related commentary by Cohen and Flaherty, p. 910
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- 2023
17. 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
18. Advanced cutaneous squamous cell carcinoma of the head in two renal transplanted patients treated with cemiplimab
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A Le Moine, D. Van Gestel, N Cuylits, S Luce, J Tannous, S Carlot, Sandrine Aspeslagh, C. Orte Cano, T Van Meerhaeghe, V. Del Marmol, and Danielle Liénard
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Oncology ,medicine.medical_specialty ,education.field_of_study ,Cutaneous squamous cell carcinoma ,business.industry ,Population ,Dermatology ,Aggressive course ,Organ transplantation ,Immunosurveillance ,Infectious Diseases ,Immune system ,Internal medicine ,medicine ,Solid organ transplantation ,business ,education - Abstract
It is well known that organ transplant recipients are prone to develop non-melanoma skin cancers, particularly cutaneous squamous cell carcinoma (cSCC). This is explained by the long-term use of immunosuppressants and thus the decrease of the immunosurveillance that protects from developing malignant tumours. Solid organ transplant recipients (SOTRs) are 65-250 times more likely to develop cSCC compared to the general population (Am J Transplant 2017; 17: 2509). Moreover, in these patients cSCCs follow a more aggressive course. Close follow-up and regular skin check-ups by a dermatologist are, therefore, crucial in the management of these patients. When detected early, cSCC can be easily and effectively treated by a simple excision. However, when advanced, outcomes are poor. Immune checkpoints inhibitors (ICIs) have been recently added to our arsenal and represent a breakthrough, having proved to be effective in achieving long-term responses. We, hereby, present two cases of difficult-to-treat cSCCs in renal transplanted patients.
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- 2021
19. 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
20. 2022-RA-638-ESGO Pembrolizumab with multimodal immunomodulation in chemotherapy-pretreated cervical, endometrial, and uterine cancer: the PRIMMO phase II trial
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Emiel A De Jaeghere, Sandra Tuyaerts, An MT van Nuffel, Ann Belmans, Kris Bogaerts, Regina Baiden-Amissah, 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, and Hannelore G Denys
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- 2022
21. 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
22. Immunosuppressive therapy management in cancer patients with autoimmune diseases treated with immune checkpoint inhibitors: A case series and systematic literature review
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Stephanie C.M. Wuyts, Charlotte A.H. Cappelle, Marthe Verhaert, Bert Bravenboer, and Sandrine Aspeslagh
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Oncology ,Pharmacology (medical) - Abstract
Introduction Prescribing immune checkpoint inhibitors (ICIs) to cancer patients with an autoimmune disease (AID) is presumed safe when cautious adverse event management is applied. However, guidelines on immunosuppressant (IS) adaptations are limited and real-world evidence is scarce. Methods Current practice of IS adaptations is described in a case series of AID patients treated with ICIs in a tertiary university hospital in Belgium (1/1/2016–31/12/2021). Patient, drug and disease-related data were documented using retrospective chart review. A systematic search of the PubMed database was performed to identify similar cases (1/1/2010–30/11/2022). Results Sixteen patients were described in the case series (62% with active AID). Systemic IS were changed before ICI initiation in 5/9 patients. Four patients continued therapy, of which one achieved partial remission. Patients who had IS (partially) stopped before ICI start (n = 4) had AID flares in two cases; immune-related adverse events in three cases. In the systematic review, 37 cases were identified in 9 articles. Corticosteroids (n = 12) and non-selective IS (n = 27) were continued in, respectively, 66% and 68% of patients. Methotrexate was frequently discontinued (13/21). Biologicals, excluding tocilizumab and vedolizumab, were withheld during ICI treatment. Out of all patients with flares (n = 15), 47% had stopped IS therapy before ICI start and 53% had continued their AID drugs. Conclusions A detailed overview of IS management in patients with AID receiving ICI therapy is presented. Expanding the knowledge base germane to IS management with ICI therapy in the diverse population is essential to evaluate their mutual impact, thus advancing responsible patient care.
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- 2023
23. 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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Sophie Postel-Vinay, Vincent K Lam, Willeke Ros, Todd M Bauer, Aaron R Hansen, Daniel C Cho, F Stephen Hodi, Jan H M Schellens, Jennifer K Litton, Sandrine Aspeslagh, Karen A Autio, Frans L Opdam, Meredith McKean, Neeta Somaiah, Stephane Champiat, Mehmet Altan, Anna Spreafico, Osama Rahma, Elaine M Paul, Christoph M Ahlers, Helen Zhou, Herbert Struemper, Shelby A Gorman, Maura Watmuff, Kaitlin M Yablonski, Niranjan Yanamandra, Michael J Chisamore, Emmett V Schmidt, Axel Hoos, Aurelien Marabelle, Jeffrey S Weber, and John V Heymach
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Pharmacology ,Cancer Research ,Oncology ,Immunology ,Molecular Medicine ,Immunology and Allergy - Abstract
BackgroundThe 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.MethodsGSK3174998 (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.Results138 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.ConclusionsGSK3174998±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 numberNCT02528357.
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- 2023
24. Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?
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Bastiaan Sol, Sandrine Aspeslagh, Gil Awada, Jeroen de Filette, Bart Neyns, Steven Raeymaeckers, Brigitte Velkeniers, Corina Andreescu, Internal Medicine, Rheumatology, Faculty of Medicine and Pharmacy, Clinical sciences, Basic (bio-) Medical Sciences, Radiology, Medical Oncology, Laboratory for Medical and Molecular Oncology, and Laboratory of Molecullar and Cellular Therapy
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Adenoma ,Adult ,Male ,medicine.medical_specialty ,Side effect ,Hypophysitis ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Somatic hypermutation ,030209 endocrinology & metabolism ,Ipilimumab ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Internal Medicine ,medicine ,Humans ,Immune Checkpoint Inhibitor Therapy ,Chemotherapy ,Temozolomide ,business.industry ,Brief Report ,Carcinoma ,Cell Cycle Checkpoints ,General Medicine ,ACTH-Secreting Pituitary Carcinoma ,medicine.disease ,Treatment ,ACTH-Secreting Pituitary Adenoma ,Nivolumab ,Radiology Nuclear Medicine and imaging ,030220 oncology & carcinogenesis ,oncology ,Pituitary carcinoma ,Cancer research ,business ,medicine.drug - Abstract
Background Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report. Case We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy. Discussion Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma. Conclusion ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
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- 2021
25. Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade
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Carlos Gomez-Roca, Philippe Cassier, Dmitriy Zamarin, Jean-Pascal Machiels, Jose Luis Perez Gracia, F Stephen Hodi, Alvaro Taus, Maria Martinez Garcia, Valentina Boni, Joseph P Eder, Navid Hafez, Ryan Sullivan, David Mcdermott, Stephane Champiat, Sandrine Aspeslagh, Catherine Terret, Anna-Maria Jegg, Wolfgang Jacob, Michael A Cannarile, Carola Ries, Konstanty Korski, Francesca Michielin, Randolph Christen, Galina Babitzki, Carl Watson, Georgina Meneses-Lorente, Martin Weisser, Dominik Rüttinger, Jean-Pierre Delord, Aurelien Marabelle, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Unité d'oncologie médicale, UCL - (SLuc) Centre du cancer, Laboratory for Medical and Molecular Oncology, Clinical sciences, and Medical Oncology
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Cancer Research ,Lung Neoplasms ,Carcinoma, Non-Small-Cell Lung/drug therapy ,T-Lymphocytes ,Immunology ,Antibodies, Monoclonal/adverse effects ,Antibodies, Monoclonal, Humanized ,Ligands ,Carcinoma, Non-Small-Cell Lung ,Immunology and Allergy ,Humans ,Melanoma/drug therapy ,Lung Neoplasms/drug therapy ,Immune Checkpoint Inhibitors ,Melanoma ,Fatigue ,Pharmacology ,Clinical Trials as Topic ,Urinary Bladder Neoplasms/drug therapy ,Macrophages ,Antibodies, Monoclonal ,Receptor Protein-Tyrosine Kinases ,Oncology ,Urinary Bladder Neoplasms ,Fatigue/chemically induced ,Molecular Medicine ,Drug Therapy, Combination ,Immunotherapy - Abstract
BackgroundThis phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs).MethodsEmactuzumab (500–1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients.ResultsOverall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients.ConclusionEmactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.
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- 2022
26. HLA-DR4/DR13 in a patient with durvalumab-induced thyroiditis
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Filette, de, primary, M.K, Jeroen, additional, Rop, Jonas De, additional, Stephanie, Andre, additional, Lynn, De Mey, additional, Sandrine, Aspeslagh, additional, Rafik, Karmali, additional, der, Auwera Bart J Van, additional, and Bert, Bravenboer, additional
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- 2021
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27. COVID-19 & Cushing's disease in a patient with ACTH-secreting pituitary carcinoma
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Jeroen, M.K. de Filette, primary, Bastiaan, Sol, additional, Gil, Awada, additional, Corina, E. Andreescu, additional, David, Unuane, additional, Duc, Nam Nguyen, additional, Sandrine, Aspeslagh, additional, Jan, Poelaert, additional, Brigitte, Velkeniers, additional, and Bert, Bravenboer, additional
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- 2021
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28. 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
29. C-reactive protein as a biomarker for immune-related adverse events in melanoma patients treated with immune checkpoint inhibitors in the adjuvant setting
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Gil Awada, Aline Beckwée, Valerie Vandersleyen, Julia Katharina Schwarze, Arno Santens, Justine Lauwyck, Sandrine Aspeslagh, Bart Neyns, Medical Oncology, Faculty of Medicine and Pharmacy, Laboratory of Molecular and Medical Oncology, Internal Medicine, and Clinical sciences
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Male ,Cancer Research ,medicine.medical_specialty ,Skin Neoplasms ,Hypophysitis ,Dermatology ,Gastroenterology ,Thyroiditis ,Internal medicine ,Sicca syndrome ,Biomarkers, Tumor ,Medicine ,Humans ,Pediatrics, Perinatology, and Child Health ,Adverse effect ,Immune Checkpoint Inhibitors ,Melanoma ,Pneumonitis ,Hepatitis ,biology ,business.industry ,C-reactive protein ,medicine.disease ,C-Reactive Protein ,oncology ,biology.protein ,Biomarker (medicine) ,biomarker ,Female ,business - Abstract
The objective of this study was to evaluate the utility of serum C-reactive protein (CRP) as biomarker for the early diagnosis of immune-related adverse events (irAEs) in melanoma patients treated with immune checkpoint inhibitors (ICIs) in the adjuvant setting, and its potential correlation with relapse-free survival (RFS). Prospectively collected data from 72 melanoma patients treated with adjuvant ICIs were pooled. CRP values at diagnosis of 10 irAEs were descriptively analysed. Correlations between RFS and the occurrence of irAEs, the grade of the irAE, the extent of CRP-elevation and the use of corticosteroids for irAE treatment were investigated. A total of 191 irAEs (grade 1/2, n = 182; grade 3/4, n = 9) occurred in 64 patients [skin toxicity (n = 70), fatigue (n = 50), thyroiditis (n = 12), musculoskeletal toxicity (n = 11), sicca syndrome (n = 10), other (n = 23), pneumonitis (n = 6), colitis (n = 4), hepatitis (n = 3) and hypophysitis (n = 2)]. In pneumonitis and hypophysitis, the median CRP levels at diagnosis exceeded the upper limit of normal (ULN, 5 mg/L). After a median follow-up of 26.5 months, 28 patients (39%) had been diagnosed with a melanoma relapse. Patients who experienced no irAE were at the highest risk for relapse (P = 0.008). A trend was observed for patients diagnosed with an irAE that was associated with an elevated CRP (>2xULN) to be at higher risk for relapse as compared to those diagnosed with an irAE and CRP
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- 2021
30. Patient-reported outcomes for monitoring symptomatic toxicities in cancer patients treated with immune-checkpoint inhibitors: A Delphi study
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Bart Neyns, Alfredo Addeo, Helle Pappot, Sandrine Aspeslagh, André Manuel da Silva Lopes, Olivier Michielin, Gilliosa Spurrier-Bernard, Manuela Eicher, Anne Rogiers, John B. A. G. Haanen, Nuria Neisy Mederos Alfonso, Sara Colomer-Lahiguera, Veronica Aedo-Lopez, Lærke Kjær Tolstrup, Sandra A. Mitchell, Laboratory for Medical and Molecular Oncology, Clinical sciences, and Medical Oncology
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Cancer Research ,medicine.medical_specialty ,Consensus ,Delphi Technique ,Drug-Related Side Effects and Adverse Reactions ,Immune checkpoint inhibitors ,Delphi method ,Severity of Illness Index ,Neoplasms ,medicine ,Content validity ,Humans ,In patient ,Patient Reported Outcome Measures ,Prospective Studies ,Intensive care medicine ,Adverse effect ,Immune Checkpoint Inhibitors ,Core set ,Patient-reported outcomes ,business.industry ,Cancer ,medicine.disease ,Symptomatic immune-related adverse events ,Delphi consensus ,PATIENT-REPORTED OUTCOMES ,oncology ,PRO-CTCAE™ ,Surveillance and monitoring ,Drug Monitoring ,business - Abstract
Background Immune-related adverse events (IrAEs) associated with the use of immune checkpoint inhibitors (ICIs) may not be fully covered by existing measures like the PRO-CTCAE™. Selecting PRO-CTCAE™ items for monitoring symptomatic adverse events is hindered by the heterogeneity and complexity of IrAEs, and no standardised selection process exists. We aimed to reach expert consensus on the PRO-CTCAE™ symptom terms relevant for cancer patients receiving ICIs and to gather preliminary expert opinions about additional symptom terms reflecting ICI symptomatic toxicities. Additionally, we gathered expert consensus about a core set of priority symptom terms for prospective surveillance and monitoring. Design This Delphi study involved an international panel of experts (n = 6 physicians; n = 3 nurses, n = 1 psychiatrist and n = 1 patient advocates). Experts prioritised the relevance and importance of symptom terms to monitor in patients treated with ICIs. Results Experts reached a consensus on the relevance of all (n = 80) PRO-CTCAE™ Symptom Terms. Consensus on the importance of these symptom terms for prospective monitoring in patients receiving ICIs was reached for 81% (n = 65) of these terms. Additional symptoms terms (n = 56) were identified, with a consensus that 84% (47/56) of these additional symptom terms should also be considered when monitoring symptomatic IrAEs. Conclusion This study identified a prioritised list of symptom terms for prospective surveillance for symptomatic IrAEs in patients receiving ICI treatment. Our results indicate the need to strengthen the validity of PRO measures used to monitor patients receiving ICIs. While these results provided some support for the content validity of the PRO CTCAE™ and resulted in a preliminary set of salient symptomatic adverse events related to the use of ICIs, broader international agreement and patient involvement are needed to further validate our initial findings.
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- 2021
31. How to assimilate the tsunami of immune checkpoints inhibitors data into clinical practice?
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Sandrine Aspeslagh, Ahmad Awada, Luís Castelo-Branco, Nuria Kotecki, Medical Oncology, and Laboratory for Medical and Molecular Oncology
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0301 basic medicine ,Cancer Research ,Knowledge management ,business.industry ,Immune checkpoint inhibitors ,MEDLINE ,Clinical Practice ,Clinical trial ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Neoplasms ,030220 oncology & carcinogenesis ,Humans ,Medicine ,Immunotherapy ,business ,Randomized Controlled Trials as Topic - Abstract
Purpose of review Immune checkpoint inhibitors (ICIs) are rapidly changing practice across different tumor settings. With this article, we reflect on how to assimilate the tsunami of ICIs data into clinical practice. Recent findings A tremendous increase on approvals, number of publications, and clinical trials ongoing with ICIs on many different tumor types. Summary ICIs are innovative treatments that are showing a significant benefit on different tumors. More approvals and an explosive increase of knowledge around the usage of ICI are to be expected in the near future, bringing new challenges on how to integrate this fast-growing evidence with ICI into clinical practice. To be updated, oncologists could follow approved guidelines from relevant societies and complement it with an appropriate search from publication databases. There are also some available courses, conferences and online material that are useful to improve knowledge in this so rapidly changing environment. In the future, we believe the integration of artificial intelligence and learning machines will play an important role to facilitate best clinical practices in different fields of medicine but particularly for oncology.
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- 2019
32. Eosinophilic Fasciitis in a Patient Treated by Atezolizumab for Metastatic Triple-Negative Breast Cancer
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Vanessa Smith, Andrea Gombos, Amber Vanhaecke, Ruth Wittoek, Yacine Wissam, Daphné t'Kint de Roodenbeke, Laila Belcaid, Lennart Jans, Sandrine Aspeslagh, and Sofie De Schepper
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Atezolizumab ,medicine ,Immunology and Allergy ,Eosinophilia ,Triple-negative breast cancer ,medicine.diagnostic_test ,business.industry ,Cancer ,Immunotherapy ,medicine.disease ,Dermatology ,Eosinophilic fasciitis ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Skin biopsy ,medicine.symptom ,business - 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
33. Sarcoid-like reaction in a BRAF V600E-mutated metastatic melanoma patient during treatment with BRAF/MEK-targeted therapy
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Julia Katharina Schwarze, Bart Neyns, Sandrine Aspeslagh, Jens Tijtgat, Gil Awada, Laboratory of Molecular and Medical Oncology, Clinical sciences, Medical Oncology, Faculty of Medicine and Pharmacy, and Internal Medicine
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0301 basic medicine ,Oncology ,Proto-Oncogene Proteins B-raf ,Cancer Research ,medicine.medical_specialty ,Ipilimumab ,Dermatology ,Skin Diseases ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Humans ,Melanoma ,Pneumonitis ,Trametinib ,business.industry ,Dabrafenib ,Middle Aged ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,Nivolumab ,business ,Progressive disease ,medicine.drug ,Brain metastasis - Abstract
Treatment with combined BRAF and MEK inhibition is widely accepted as a first-line treatment option for patients with advanced BRAF V600E mutant melanoma. It is generally well-tolerated and has limited side-effects. However, we report a case of a sarcoid-like syndrome induced by treatment with dabrafenib/trametinib (D/T) in a patient with stage IV-M1d melanoma. Sarcoid-like syndrome is a known side-effect of immune checkpoint-inhibition therapy but has only rarely been described in BRAF/MEK inhibition. However, recognizing this side-effect is important because of potential misinterpretation as progressive disease and influence on treatment. We describe a 48-year-old female patient who initially presented with solitary brain metastasis and diffuse lung lesions. She was treated with D/T to which she had an initial response in all lesions. One year later, new hilar and mediastinal lymphadenopathies were detected. Imaging was suggestive of the sarcoid-like syndrome. An endoscopic biopsy of the enlarged lymph node showed no melanoma cells. Treatment was continued. Three months later, the patient experienced a drop in hemoglobin, which prompted further investigations into possible occult intestinal metastasis. Video capsule examination revealed a metastatic lesion in the small intestine. A treatment switch to the combination of checkpoint inhibitors nivolumab and ipilimumab successfully treated both lung and small intestine lesions. After the third dose of this combination therapy, she developed an immune-related pneumonitis. Treatment with corticosteroids resolved the pneumonitis and decreased metabolism in the sarcoid-like syndrome. The treatment was not restarted afterward. She remains free of the disease up to today, 2.5 years after diagnosis.
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- 2021
34. 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
35. 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
36. Immunotherapy
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Lore Decoster and Sandrine Aspeslagh
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- 2021
37. Abstract P3-02-05: Assessment of repeatability and uptake quantification of 68GaNOTA-anti-HER2 sdAb PET/CT in patients with locally advanced or metastatic breast cancer
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Odrade Gondry, Catarina Xavier, Wim Waelput, Omar Al Dabssi, Marian Vanhoeij, Sandrine Aspeslagh, Sofie Joris, Christel Fontaine, Guy Verfaillie, Jacques De Grève, Katrien Glorieus, Ine Luyten, Frederik Vandenbroucke, Sophie Bourgeois, Laurens Raes, Sheeno Thyparambil, Nick Devoogdt, Ilse Vaneycken, Julie Cousaert, Vicky Caveliers, Hendrik Everaert, Tony Lahoutte, and Marleen Keyaerts
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Cancer Research ,Oncology ,skin and connective tissue diseases - Abstract
Background: Human epidermal growth factor receptor 2 (HER2) status is an important predictive biomarker in breast cancer (BC). Tumor heterogeneity has been described, with changes in HER2 expression levels between lesions and over the disease course. HER2 expression is assessed on tissue biopsies, at primary diagnosis and in metastatic lesions. A whole-body imaging technique such as PET/CT could help understand expression levels in different lesions. A 68Ga-labeled single domain antibody (sdAb) targeting the HER2 receptor has been developed and proven safe (Keyaerts et al., 2016). Imaging is performed at 90 min post-injection (pi). We report results of a phase II trial to assess the repeatability of the technique in 20 patients and the correlation of tracer uptake with HER2 tissue expression of the lesions present at the time of imaging. Methods: Twenty patients (pts) with a locally advanced or metastatic BC with at least one lesion of minimum 12 mm were included. Pts were injected intravenously with a typical protein mass of 100 µg and a radioactive dose ranging from 98-168 MBq 68GaNOTA-anti-HER2 sdAb. PET/CT images were obtained at 90 min pi. A second tracer injection followed by PET/CT was done with a maximal interval of 8 days. To assess repeatability, up to 5 lesions per pt were selected, with no more than 2 in a single organ. Peak Standard Uptake Values (SUVpeak) of the lesions were measured on both scans and compared with a t-test and Bland-Altman Plots. Images were compared to other available medical or imaging data and interpreted considering the subject’s disease course. Serum and plasma samples were collected before injection and between 60 and 365 days pi and stored for future detection of anti-drug antibodies (ADA) and liquid biopsies analysis for the presence of HER2 amplification. Tissue samples were assessed by central labs using mass spectrometry, immunohistochemistry and in fluorescence situ hybridization. Results: Twenty women with BC (6 HER2+, 14 HER2-) with a mean age of 58.6 y (37-81) were included. Three pts were scanned only once (2 due to withdrawal of consent, 1 due to covid pandemic). Repeatability of the technique was visually scored as excellent. For quantification, 50 lesions were compared on both scans in 17 pts without significant differences between the two measurements (p=0.40). The repeatability coefficient (RC) was 38.2%. The mean absolute percentage difference (MAPD) was 13.6%, comparable to repeat values reported for 18F-FDG. In 3 out of 6 HER2-positive (HER2+) patients, lesions showed high uptake, even better visible than using 18F-FDG in 2 of them. In 2 HER2+ subjects with a negative scan, lesions were confirmed to be true negatives: one patient did not relapse from BC but had tuberculosis; the other was confirmed to have a radiopneumonitis after radiotherapy and no relapse. In 1 HER2+ patient, the uptake was unexpectedly low. However, the HER2 status was also not reconfirmed in the metastatic setting for this subject. In 1 HER2-negative patient, the tumor HER2 status was changed from negative to positive based on a subsequent image-guided biopsy performed in this study. High tracer uptake was also seen in many of the patients presenting with HER2-low BC (IHC 1+ or 2+), indicating the potential of the tracer to detect low-level HER2 expression. Additional correlation to centrally performed tissue and blood analysis is ongoing. Conclusion: 68GaNOTA-Anti-HER2 PET/CT shows high uptake in HER2-expressing BC lesions but also in HER2-low lesions. The technique shows good repeatability and, in some cases, even better sensitivity than 18F-FDG PET/CT. Specificity was confirmed in relapse-free lesions such as tuberculosis and radiopneumonitis. Its sensitivity makes it a promising technique to assess HER2+ and HER2-low lesions in BC patients. Citation Format: Odrade Gondry, Catarina Xavier, Wim Waelput, Omar Al Dabssi, Marian Vanhoeij, Sandrine Aspeslagh, Sofie Joris, Christel Fontaine, Guy Verfaillie, Jacques De Grève, Katrien Glorieus, Ine Luyten, Frederik Vandenbroucke, Sophie Bourgeois, Laurens Raes, Sheeno Thyparambil, Nick Devoogdt, Ilse Vaneycken, Julie Cousaert, Vicky Caveliers, Hendrik Everaert, Tony Lahoutte, Marleen Keyaerts. Assessment of repeatability and uptake quantification of 68GaNOTA-anti-HER2 sdAb PET/CT in patients with locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-02-05.
- Published
- 2022
38. An atypical sarcoid-like reaction during anti-protein death 1 treatment in a patient with metastatic melanoma
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Gil Awada, Bart Neyns, Louise Cras, Stijn De Keukeleire, Julia Katharina Schwarze, Sandrine Aspeslagh, Anne Van Binst, Hendrik Everaert, Internal Medicine, Clinical sciences, Faculty of Medicine and Pharmacy, Supporting clinical sciences, Medical Imaging, Nuclear Medicine, Radiology, Pathology/molecular and cellular medicine, Pathology, Medical Oncology, Laboratory of Molecular and Medical Oncology, and Laboratory of Molecullar and Cellular Therapy
- Subjects
0301 basic medicine ,Male ,Cancer Research ,medicine.medical_specialty ,Skin Neoplasms ,Dermatology ,Lumbar vertebrae ,Pembrolizumab ,Asymptomatic ,Metastasis ,Lesion ,03 medical and health sciences ,0302 clinical medicine ,Biopsy ,medicine ,Humans ,Stage (cooking) ,Neoplasm Metastasis ,Melanoma ,medicine.diagnostic_test ,business.industry ,Middle Aged ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Radiology ,medicine.symptom ,business - Abstract
We report a case of anti-protein death 1-induced sarcoid-like reaction in a 63-year-old Caucasian male who was diagnosed with stage IV-M1a melanoma. He was initially treated with pembrolizumab monotherapy (Q3W) and had a complete response after 14 cycles. However, relapse was suspected 3 months later with appearance of hilar, mediastinal and hepatic hilar lymph nodes as well as a skin lesion. Biopsy of both the hilar lymph nodes and the skin lesion demonstrated sarcomatoid granulomatosis. Pembrolizumab was discontinued temporarily. While on F-FDG-PET/CT, all sarcoid-like lesions regressed in size and activity, a new hypermetabolic solitary skeletal lesion was detected in a lumbar vertebra, suspicious for metastasis. However, since the patient was asymptomatic, a watchful-waiting attitude was taken. During this period, a spontaneous and complete resolution of the metabolic activity was observed of the skeletal lesion. Until today, the patient remains in complete remission. Current case presents an atypical presentation and evolution of anti-PD-1-induced sarcoid-like reaction, illustrating the difficulty of differentiating it from disease progression. Before considering (re-)initiation of anti-melanoma therapy, a tissue biopsy of one of the suspected lesions may be performed to confirm diagnosis. Physicians treating patients with ICI should be aware of this difficulty and critically assess the nature of lesions suspect of progression in patients responding to ICI and presenting with a sarcoid-like reaction.
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- 2020
39. 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 (
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- 2020
40. 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
41. Immunotherapy
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Lore Decoster and Sandrine Aspeslagh
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- 2020
42. Development of Immunotherapeutic Strategies for Early Phase Clinical Trials
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Adrien Procureur, Sandrine Aspeslagh, Roman Chabanon, Patricia Martin-Romano, and Sophie Postel-Vinay
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Clinical trial ,medicine.medical_specialty ,Drug development ,business.industry ,Novel agents ,Phase 1 trials ,Cancer therapy ,Drug approval ,Medicine ,business ,Cytotoxic Therapy ,Intensive care medicine ,Early phase - Abstract
Immunotherapy has revolutionized cancer therapy and outcomes over the past 5 years. Following the initial successes of anti-PD-(L)1 and anti-CTLA-4 agents, a huge wave of novel agents and novel combinations has entered early phase trials, leading to an unprecedented exponential increase in phase 1 trials. These agents, which display different characteristics from conventional cytotoxic therapy and targeted therapies, have deeply challenged many paradigms of traditional phase 1 studies, including dose-determination, safety, pharmacokinetics and pharmacodynamics, efficacy evaluation, patient selection, routes of administration, trial design and endpoints. The historical “safety” phase 1 trials have been transformed to “phase 1 registration” trials, using seamless designs, enrolling several hundreds of patients and sometimes leading to drug approval. However, severe unexpected toxicities have also been observed, especially in combination trials, calling for cautious, rationale and measured drug development. In this chapter, we present the different types of immunotherapy agents currently being evaluated in phase 1 trials, detail the major transformations in phase 1 trial designs, and discuss challenges that will need to be tackled to rationally optimize immunotherapy development.
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- 2020
43. Combinaison de médicaments épigénétiques avec d'autres thérapies pour les tumeurs solides - leçons du passé et promesses d'avenir
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Sophie Postel-Vinay, Sandrine Aspeslagh, Geneviève Almouzni, Daniel Jeffery, Daphné Morel, Dynamique du noyau [Institut Curie], Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Institut Gustave Roussy (IGR), and Medical Oncology
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Epigenomics ,0301 basic medicine ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,Antineoplastic Agents ,Cancer immunotherapy ,Drug development ,Bioinformatics ,Epigenesis, Genetic ,Targeted therapy ,03 medical and health sciences ,Targeted therapies ,0302 clinical medicine ,Cancer epigenetics ,Neoplasms ,medicine ,Humans ,Molecular Targeted Therapy ,MESH: Cancer epigenetics ,Combination drug therapy ,Clinical Trials as Topic ,business.industry ,Cancer ,DNA, Neoplasm ,Genetic Therapy ,Precision medicine ,medicine.disease ,Combined Modality Therapy ,3. Good health ,Radiation therapy ,Clinical trial ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Hormone therapy ,business - Abstract
International audience; Epigenetic dysregulation has long been recognized as a key factor contributing to tumorigenesis and tumour maintenance that can influence all of the recognized hallmarks of cancer. Despite regulatory approvals for the treatment of certain haematological malignancies, the efficacy of the first generation of epigenetic drugs (epi-drugs) in patients with solid tumours has been disappointing; however, successes have now been achieved in selected solid tumour subtypes, thanks to the development of novel compounds and a better understanding of cancer biology that have enabled precision medicine approaches. Several lines of evidence support that, beyond their potential as monotherapies, epigenetic drugs could have important roles in synergy with other anticancer therapies or in reversing acquired therapy resistance. Herein, we review the mechanisms by which epi-drugs can modulate the sensitivity of cancer cells to other forms of anticancer therapy, including chemotherapy, radiation therapy, hormone therapy, molecularly targeted therapy and immunotherapy. We provide a critical appraisal of the preclinical rationale, completed clinical studies and ongoing clinical trials relating to combination therapies incorporating epi-drugs. Finally, we propose and discuss rational clinical trial designs and drug development strategies, considering key factors including patient selection, tumour biomarker evaluation, drug scheduling and response assessment and study end points, with the aim of optimizing the development of such combinations.; La dysrégulation épigénétique est depuis longtemps reconnue comme un facteur clé contribuant à la tumorigénèse et à la maintenance des tumeurs qui peut influencer toutes les caractéristiques reconnues du cancer. Malgré les approbations réglementaires pour le traitement de certaines malignités hématologiques, l'efficacité de la première génération de médicaments épigénétiques (épi-drugs) chez les patients atteints de tumeurs solides a été décevante ; cependant, des succès ont maintenant été obtenus dans certains sous-types de tumeurs solides, grâce au développement de nouveaux composés et à une meilleure compréhension de la biologie du cancer qui ont permis des approches médicales de précision. Plusieurs sources de preuves soutiennent que, au-delà de leur potentiel en tant que monothérapies, les médicaments épigénétiques pourraient jouer un rôle important en synergie avec d'autres thérapies anticancéreuses ou pour inverser la résistance acquise à la thérapie. Nous passons ici en revue les mécanismes par lesquels les médicaments épigénétiques peuvent moduler la sensibilité des cellules cancéreuses à d'autres formes de thérapie anticancéreuse, notamment la chimiothérapie, la radiothérapie, l'hormonothérapie, la thérapie moléculaire ciblée et l'immunothérapie. Nous fournissons une évaluation critique du raisonnement préclinique, des études cliniques achevées et des essais cliniques en cours concernant les thérapies combinées incorporant des médicaments d'épinéphrine. Enfin, nous proposons et discutons des plans d'essais cliniques rationnels et des stratégies de développement de médicaments, en tenant compte de facteurs clés tels que la sélection des patients, l'évaluation des biomarqueurs tumoraux, la programmation des médicaments et l'évaluation de la réponse et les résultats des études, dans le but d'optimiser le développement de ces combinaisons.
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- 2020
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44. Cancer immunotherapy-associated hypophysitis
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Michele Porcu, Karen Willard-Gallo, Marco Musi, Mario Scartozzi, Cinzia Solinas, Pushpamali De Silva, Luca Saba, Sandrine Aspeslagh, Stefano Mariotti, Medical Oncology, and Laboratory for Medical and Molecular Oncology
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Pediatrics ,medicine.medical_specialty ,Side effect ,Hypophysitis ,Programmed Cell Death 1 Receptor ,Hypophysitis/diagnosis ,Disease ,Antibodies, Monoclonal, Humanized ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Humans ,Medicine ,Endocrine system ,CTLA-4 Antigen ,030212 general & internal medicine ,Hormone replacement therapy ,Neoplasm Staging ,business.industry ,Programmed Cell Death 1 Receptor/antagonists & inhibitors ,Pituitary apoplexy ,Hematology ,medicine.disease ,CTLA-4 Antigen/antagonists & inhibitors ,Ipilimumab ,Immune checkpoint ,Immunotherapy/adverse effects ,Oncology ,Antibodies, Monoclonal, Humanized/adverse effects ,030220 oncology & carcinogenesis ,Ipilimumab/adverse effects ,Immunotherapy ,Differential diagnosis ,business ,Neoplasms/metabolism - Abstract
Side effects of immune checkpoint blockade are often said to be infrequent and usually mild. The uniqueness of endocrine immune-related adverse events is their non-reversibility, with incidence and prevalence destined to increase in the coming years, particularly if immunotherapy is used at earlier stages of neoplastic disease. Immune-related hypophysitis is one of these observed endocrine adverse events. It is often difficult to diagnose, sometimes occurring without specific symptoms. It can lead to irreversibly altered functioning of diverse endocrine glands. Radiographically, the differential diagnosis of hypophysitis includes pituitary apoplexy and primary and secondary neoplastic lesions. Immune-related hypophysitis is most common with single-agent anti-CTLA-4, followed by the combination of anti-CTLA-4 and anti-PD-1, while occurs infrequently when anti-PD-1 or anti-PD-L1 agents are administered alone. Hypophysitis with immune checkpoint blockade requires early recognition, diagnosis, and treatment. Patients can present with headache, visual disturbances or other endocrine-related syndromes or they can be asymptomatic. The manifestation of symptoms should prompt blood analysis and magnetic resonance imaging of the brain. Imaging is important to exclude secondary meningeal or parenchymal lesions. Management should include discontinuation of the immune checkpoint blockade, initiation of corticosteroid therapy and eventually hormone replacement therapy. Hypophysitis impacts treatment of the disease and usually requires long-term management of this irreversible side effect. A multidisciplinary team approach is merited to insure the correct diagnosis and management of immune-related hypophysitis.
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- 2018
45. Epigenetic modifiers as new immunomodulatory therapies in solid tumours
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Sophie Postel-Vinay, D. Morel, Jean-Charles Soria, Sandrine Aspeslagh, Medical Oncology, and Laboratory for Medical and Molecular Oncology
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0301 basic medicine ,medicine.medical_treatment ,immunomodulation ,Epigenesis, Genetic ,03 medical and health sciences ,Immune system ,Adjuvants, Immunologic ,Neoplasms ,Humans ,Medicine ,Epigenetics ,Cancer ,Cell Death ,epigenetics ,business.industry ,EZH2 ,Immuno-oncology ,Hematology ,Immunotherapy ,Immune checkpoint ,030104 developmental biology ,Oncology ,Cancer research ,Immunogenic cell death ,Cytokine secretion ,immunotherapy ,Histone deacetylase ,business - Abstract
Background Immune therapies have revolutionized cancer treatment over the last few years by allowing improvements in overall survival. However, the majority of patients is still primary or secondary resistant to such therapies, and enhancing sensitivity to immune therapies is therefore crucial to improve patient outcome. Several recent lines of evidence suggest that epigenetic modifiers have intrinsic immunomodulatory properties, which could be of therapeutic interest. Material and methods We reviewed preclinical evidence and clinical studies which describe or exploit immunomodulatory properties of epigenetic agents. Experimental approaches, clinical applicability and corresponding ongoing clinical trials are described. Results Several epigenetic modifiers, such as histone deacetylase inhibitors, DNA methyl transferase inhibitors, bromodomain inhibitors, lysine-specific histone demethylase 1 inhibitors and enhancer of zeste homolog 2 inhibitors, display intrinsic immunomodulatory properties. The latter can be achieved through the action of these drugs either on cancer cells (e.g. presentation and generation of neoantigens, induction of immunogenic cell death, modulation of cytokine secretion), on immune cells (e.g. linage, differentiation, activation status and antitumor capability), or on components of the microenvironment (e.g. regulatory T cells and macrophages). Several promising combinations, notably with immune checkpoint blockers or adoptive T-cell therapy, can be envisioned. Dedicated clinically relevant approaches for patient selection and trial design will be required to optimally develop such combinations. Conclusion In an era where immune therapies are becoming a treatment backbone in many tumour types, epigenetic modifiers could play a crucial role in modulating tumours’ immunogenicity and sensitivity to immune agents. Optimal trial design, including window of opportunity trials, will be key in the success of this approach, and clinical evaluation is ongoing.
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- 2018
46. Are phase I trials safe for older patients?
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Capucine Baldini, Antoine Hollebecque, Jean-Charles Soria, Carole Helissey, Olivier Mir, Sandrine Aspeslagh, Olivia Le Saux, Anas Gazzah, Christophe Massard, Eduardo Castanon, Andrea Varga, Rastilav Bahleda, Medical Oncology, and Laboratory of Molecular and Medical Oncology
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Male ,Aging ,medicine.medical_specialty ,Pediatrics ,Population ,Medical Oncology ,Phase I trial ,03 medical and health sciences ,0302 clinical medicine ,Older patients ,Neoplasms ,medicine ,Humans ,030212 general & internal medicine ,education ,Geriatric Assessment ,Toxicity profile ,Aged ,Cancer ,Aged, 80 and over ,education.field_of_study ,Clinical Trials, Phase I as Topic ,business.industry ,Clinical study design ,Age Factors ,toxicity ,Phase i trials ,drug development ,Clinical trial ,Cancer rate ,Oncology ,Drug development ,030220 oncology & carcinogenesis ,Polypharmacy ,Physical therapy ,Female ,Safety ,Geriatrics and Gerontology ,business - Abstract
Phase I clinical trials in oncology primarily aim to assess the toxicity profile of new drugs and determine recommended phase II doses (RP2D). Since the cancer rate increases with age and our population is continually aging, RP2D must necessarily be assessed in older patients. Few clinical studies include older patients, however, and particularly few Phase I trials. We reviewed published data on the safety and efficacy of Phase I trials in older patients. The majority of studies included primarily young, fit patients, with age thresholds varying widely from 65 to 80years. However, age does not seem to be associated with more toxicity or less efficacy. While Phase I trials seem feasible in fit older patients, geriatric-medicine score systems should be included in the clinical trial design in order to better characterize this population.
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- 2018
47. Is There Room for Immune Checkpoint Inhibitors in Patients Who Have NSCLC With Autoimmune Diseases?
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Benjamin Besse, Sandrine Aspeslagh, Jordi Remon, Lizza E.L. Hendriks, Medical Oncology, Laboratory of Molecular and Medical Oncology, Pulmonologie, Promovendi ODB, MUMC+: MA Med Staf Spec Longziekten (9), and RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy
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Pulmonary and Respiratory Medicine ,Clinical Trials as Topic ,Lung Neoplasms ,business.industry ,Immune checkpoint inhibitors ,Cell Cycle Checkpoints ,EFFICACY ,Prognosis ,medicine.disease ,Autoimmune Diseases ,LUNG-CANCER ,Antineoplastic Agents, Immunological ,Oncology ,SAFETY ,Carcinoma, Non-Small-Cell Lung ,Biomarkers, Tumor ,Cancer research ,medicine ,Humans ,In patient ,Molecular Targeted Therapy ,Lung cancer ,business - Published
- 2019
48. 1686P Selecting patient-reported outcomes to monitor symptomatic toxicities of immune-checkpoint inhibitors: A Delphi study
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J.B.A.G. Haanen, G. Spurrier-Bernard, Alfredo Addeo, Anne Rogiers, S. Colomer-Lahiguera, Lærke Kjær Tolstrup, Olivier Michielin, V Aedo Lopez, Bart Neyns, Helle Pappot, Sandra A. Mitchell, Sandrine Aspeslagh, N-N. Mederos-Alfonso, A.M.D.S. Lopes, and Manuela Eicher
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immune checkpoint inhibitors ,Delphi method ,Medicine ,Hematology ,business - Published
- 2021
49. Baseline lymphopenia should not be used as exclusion criteria in early clinical trials investigating immune checkpoint blockers (PD-1/PD-L1 inhibitors)
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Sophie Postel-Vinay, Charles Ferté, Antoine Hollebecque, Samy Ammari, Capucine Baldini, Jean-Charles Soria, Eduardo Castanon, Sandrine Aspeslagh, Aurélien Marabelle, Stéphane Champiat, Roger Sun, Elaine Johanna Limkin, Laurent Dercle, Christophe Massard, Eric Deutsch, and Medical Oncology
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,Multivariate analysis ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Clinical Trials, Phase I as Topic/methods ,Kaplan-Meier Estimate ,B7-H1 Antigen ,0302 clinical medicine ,Risk Factors ,Neoplasms ,Odds Ratio ,Molecular Targeted Therapy ,Lymphopenia/diagnosis ,Clinical Trials, Phase I as Topic ,biology ,Programmed Cell Death 1 Receptor/antagonists & inhibitors ,Middle Aged ,Treatment Outcome ,030220 oncology & carcinogenesis ,Immunotherapy/methods ,Female ,Immunotherapy ,medicine.medical_specialty ,B7-H1 Antigen/antagonists & inhibitors ,Antineoplastic Agents ,03 medical and health sciences ,Lymphopenia ,PD-L1 ,Internal medicine ,medicine ,Humans ,Lymphocyte Count ,Proportional Hazards Models ,business.industry ,Proportional hazards model ,Patient Selection ,Cancer ,Antineoplastic Agents/adverse effects ,Odds ratio ,medicine.disease ,Immune checkpoint ,Neoplasms/drug therapy ,Surgery ,Clinical trial ,Logistic Models ,030104 developmental biology ,Multivariate Analysis ,biology.protein ,business ,Molecular Targeted Therapy/methods - Abstract
INTRODUCTION: A number of phase I immunotherapy trials for cancer patients incorporate the absolute lymphocyte count (ALC) as an inclusion criteria. This study aims to assess whether ALC is associated with a lack of response to anti-PD-1/PD-L1 in early clinical trials. METHODS: All consecutive patients treated with anti-PD-1/PD-L1 monotherapy in phase I trials in our institution between December 2011 and January 2014 were reviewed. Baseline ALC, neutrophil-to-lymphocyte ratio (NLR), Royal-Marsden Hospital (RMH) prognostic score, objective response rate (ORR) and disease control rate (DCR = SD + PR + CR, stable disease (SD), partial response (PR), complete response (CR)) defined by Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 were retrieved. RESULTS: Out of a total of 167 patients, 48 (28.7%) and 8 patients (4.8%) had baseline ALCs of 1 G/l. When using 0.5 G/l as ALC threshold, we did not find any difference either in ORR or in DCR. In a multivariate Cox regression analysis, baseline ALC was not associated with overall survival, whereas the RMH and the number of previous lines of treatment remained independent prognostic factors. CONCLUSIONS: Baseline ALC was not associated with response to anti-PD-1/PD-L1 in cancer patients enrolled in phase I trials. Patients should not be excluded from early phase clinical trials testing immune checkpoints blockers because of ALC.
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- 2017
50. Tumor PD-L1 status and CD8+ tumor-infiltrating T cells: markers of improved prognosis in oropharyngeal cancer
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Liesbeth Ferdinande, Sandrine Aspeslagh, Sylvie Rottey, Philippe Deron, Fréderic Duprez, Jo Van Dorpe, Tijl Vermassen, Astrid De Meulenaere, Debby Laukens, and Medical Oncology
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EXPRESSION ,PD-L1 ,0301 basic medicine ,Oncology ,HPV ,medicine.medical_specialty ,Pathology ,CARCINOMA ,T cell ,TONSILLAR CANCER ,IMMUNE RESISTANCE ,ACTIVATION ,03 medical and health sciences ,0302 clinical medicine ,NECK-CANCER ,Internal medicine ,Medicine and Health Sciences ,Carcinoma ,medicine ,HEAD ,tumor infiltrating ,biology ,Proportional hazards model ,business.industry ,Tumor-infiltrating lymphocytes ,HUMAN-PAPILLOMAVIRUS ,Hazard ratio ,Biology and Life Sciences ,Cancer ,ASSOCIATION ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,tumor infiltrating lymphocytes ,030220 oncology & carcinogenesis ,biology.protein ,biomarker ,oropharynx ,business ,CD8 ,Research Paper - Abstract
// Astrid De Meulenaere 1, * , Tijl Vermassen 1 , Sandrine Aspeslagh 2 , Philippe Deron 3 , Frederic Duprez 4 , Debby Laukens 5 , Jo Van Dorpe 6 , Liesbeth Ferdinande 6, * and Sylvie Rottey 1, * 1 Department of Medical Oncology, Ghent University Hospital, 9000 Ghent, Belgium 2 DITEP, Gustave Roussy Cancer Centre, 94800 Villejuif, France 3 Department of Head, Neck and Maxillo-Facial Surgery, Ghent University Hospital, 9000 Ghent, Belgium 4 Department of Radiation Oncology, Ghent University Hospital, 9000 Ghent, Belgium 5 Department of Internal Medicine, Ghent University Hospital, 9000 Ghent, Belgium 6 Department of Pathology, Ghent University Hospital, 9000 Ghent, Belgium * These authors are senior authors Correspondence to: Astrid De Meulenaere, email: astrid.demeulenaere@ugent.be Keywords: oropharynx, HPV, PD-L1, tumor infiltrating lymphocytes, biomarker Received: March 06, 2017 Accepted: June 20, 2017 Published: July 06, 2017 ABSTRACT Introduction: The aim of this study was to evaluate the expression of PD-L1 in oropharyngeal squamous cell carcinoma. Its relation with clinicopathological variables, tumor infiltrating lymphocytes and survival was also determined. Results: Positive PD-L1 status for the SP142 clone related with improved overall survival in oropharyngeal squamous cell carcinoma. Tumors heavily infiltrated by tumor infiltrating lymphocytes were also linked with better outcome, and this as well for the total number of tumor infiltrating lymphocytes as for the CD3 + and CD8 + T cell count. A Cox proportional hazard model proved that solely infiltrating CD8 + T cells exhibit a positive effect on overall survival (hazard ratio = 0.31 [0.14–0.70]; P = 0.0050) Materials and Methods: Formalin-fixed, paraffin-embedded tissue from oropharyngeal tumors of 99 patients was immunohistochemically stained for PD-L1 (SP142 and 22C3 clones), CD3, CD8 and FoxP3. Expression of PD-L1, CD3, CD8, FoxP3 and HPV status were correlated with clinicopathological variables. Overall survival was determined by a log-rank (Mantel–Cox) test whereas the Cox proportional hazard model was used for multivariate analysis. Conclusions: Our results demonstrate that CD8 + T lymphocytes constitute an independent prognostic marker in patients diagnosed with oropharyngeal squamous cell carcinoma. PD-L1 positivity for SP142, but not for 22C3, also tends to have a positive effect on survival in oropharyngeal squamous cell carcinoma.
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- 2017
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