18 results on '"Sandrine Aspeslagh"'
Search Results
2. Isolated adrenocorticotropic hormone deficiency and sialadenitis associated with nivolumab: a case report
- Author
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Sylvain Raoul Simeni Njonnou, Sandrine Aspeslagh, Marie-Josiane Ntsama Essomba, Marie-Lucie Racu, Fernando Kemta Lekpa, and Frédéric Vandergheynst
- Subjects
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
- Full Text
- View/download PDF
3. Durvalumab-induced thyroiditis in a patient with non-small cell lung carcinoma: a case report and review of pathogenic mechanisms
- Author
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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
- Subjects
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
- Full Text
- View/download PDF
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)
- Author
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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
- Subjects
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
- Full Text
- View/download PDF
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
- Subjects
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
- Full Text
- View/download PDF
6. 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
- Abstract
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
- Published
- 2023
7. Data from Long-Term Survival in Patients Responding to Anti–PD-1/PD-L1 Therapy and Disease Outcome upon Treatment Discontinuation
- Author
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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
- Abstract
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
- Published
- 2023
8. 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
- Author
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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
- Subjects
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).
- Published
- 2023
9. 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
- Subjects
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
10. Isolated adrenocorticotropic hormone deficiency and sialadenitis associated with nivolumab
- Author
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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
- Subjects
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.
- Published
- 2022
11. 2022-RA-638-ESGO Pembrolizumab with multimodal immunomodulation in chemotherapy-pretreated cervical, endometrial, and uterine cancer: the PRIMMO phase II trial
- Author
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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
- Published
- 2022
12. Severe treatment-induced inflammatory polyarthritis in advanced melanoma patients
- Author
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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
- Subjects
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.
- Published
- 2022
13. Immunosuppressive therapy management in cancer patients with autoimmune diseases treated with immune checkpoint inhibitors: A case series and systematic literature review
- Author
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Stephanie C.M. Wuyts, Charlotte A.H. Cappelle, Marthe Verhaert, Bert Bravenboer, and Sandrine Aspeslagh
- Subjects
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.
- Published
- 2023
14. First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1)
- Author
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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
- Subjects
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.
- Published
- 2023
15. Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade
- Author
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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
16. 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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17. 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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18. 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.
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- 2022
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