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1. A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells in solid tumors

Author

Vounckx, Manon, Tijtgat, Jens, Stevens, Latoya, Dirven, Iris, Ilsen, Bart, Vandenbroucke, Frederik, Raeymaeckers, Steven, Vekens, Karolien, Forsyth, Ramses, Geeraerts, Xenia, Van Riet, Ivan, Schwarze, Julia Katharina, Tuyaerts, Sandra, Decoster, Lore, De Ridder, Mark, Dufait, Ines, and Neyns, Bart

Published
2024
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2. 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

De Jaeghere, Emiel A., Tuyaerts, Sandra, Van Nuffel, An M. T., Belmans, Ann, Bogaerts, Kris, Baiden-Amissah, Regina, Lippens, Lien, Vuylsteke, Peter, Henry, Stéphanie, Trinh, Xuan Bich, van Dam, Peter A., Aspeslagh, Sandrine, De Caluwé, Alex, Naert, Eline, Lambrechts, Diether, Hendrix, An, De Wever, Olivier, Van de Vijver, Koen K., Amant, Frédéric, Vandecasteele, Katrien, and Denys, Hannelore G.

Published
2023
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4. An open-label, single-arm, prospective, multi-center, tandem two-stage designed phase II study to evaluate the efficacy of fulvestrant in women with recurrent/metastatic estrogen receptor-positive gynecological malignancies (FUCHSia study)

Author

Trozzi, Rita, primary, Tuyaerts, Sandra, additional, Annibali, Daniela, additional, Herreros Pomares, Alejandro, additional, Boog, Lotte, additional, Van Dam, Peter, additional, Leunen, Karin, additional, Deroose, Christophe, additional, Trum, Hans, additional, and Amant, Frédéric, additional

Published
2024
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5. PI3K/mTOR inhibition induces tumour microenvironment remodelling and sensitises pS6high uterine leiomyosarcoma to PD‐1 blockade

Author

De Wispelaere, Wout, primary, Annibali, Daniela, additional, Tuyaerts, Sandra, additional, Messiaen, Julie, additional, Antoranz, Asier, additional, Shankar, Gautam, additional, Dubroja, Nikolina, additional, Herreros‐Pomares, Alejandro, additional, Baiden‐Amissah, Regina E. M., additional, Orban, Marie‐Pauline, additional, Delfini, Marcello, additional, Berardi, Emanuele, additional, Van Brussel, Thomas, additional, Schepers, Rogier, additional, Philips, Gino, additional, Boeckx, Bram, additional, Baietti, Maria Francesca, additional, Congedo, Luigi, additional, HoWangYin, Kiave Yune, additional, Bayon, Emilie, additional, Van Rompuy, Anne‐Sophie, additional, Leucci, Eleonora, additional, Tabruyn, Sebastien P., additional, Bosisio, Francesca, additional, Mazzone, Massimiliano, additional, Lambrechts, Diether, additional, and Amant, Frédéric, additional

Published
2024
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6. A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells in solid tumors

Author

Vounckx, Manon, Tijtgat, Jens, Stevens, Latoya, Dirven, Iris, Ilsen, Bart, Vandenbroucke, Frederik, Raeymaeckers, Steven, Vekens, Karolien, Forsyth, Ramses, Geeraerts, Xenia, Van Riet, Ivan, Schwarze, Julia Katharina, Tuyaerts, Sandra, Decoster, Lore, De Ridder, Mark, Dufait, Ines, and Neyns, Bart

Subjects
STEREOTACTIC radiotherapy, MYELOID cells, DENDRITIC cells, NON-small-cell lung carcinoma, CLINICAL trials
Abstract

Background: Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)+/CD141(BDCA-3)+ myeloid dendritic cells (myDC) in the tumor microenvironment are indispensable at initiating effector T-cell responses and response to ICB. Methods: In this phase II clinical trial, anti-PD-1 ICB pretreated oligometastatic patients (tumor agnostic) underwent a leukapheresis followed by isolation of CD1c(BDCA-1)+/CD141(BDCA-3)+ myDC. Following hypofractionated stereotactic body RT (3 × 8 Gy), patients were randomized (3:1). Respectively, in arm A (immediate treatment), intratumoral (IT) ipilimumab (10 mg) and avelumab (40 mg) combined with intravenous (IV) pembrolizumab (200 mg) were administered followed by IT injection of myDC; subsequently, IV pembrolizumab and IT ipilimumab/avelumab were continued (q3W). In arm B (contemporary control arm), patients received IV pembrolizumab, with possibility to cross-over at progression. Primary endpoint was 1-year progression-free survival rate (PFS). Secondary endpoints were safety, feasibility, objective response rate, PFS, and overall survival (OS). Results: Thirteen patients (10 in arm A, eight non-small cell lung cancer, and five melanoma) were enrolled. Two patients crossed over. One-year PFS rate was 10% in arm A and 0% in arm B. Two patients in arm A obtained a partial response, and one patient obtained a stable disease as best response. In arm B, one patient obtained a SD. Median PFS and OS were 21.8 weeks (arm A) versus 24.9 (arm B), and 62.7 versus 57.9 weeks, respectively. An iatrogenic pneumothorax was the only grade 3 treatment-related adverse event. Conclusion: SBRT and pembrolizumab with or without IT avelumab/ipilimumab and IT myDC in oligometastatic patients are safe and feasible with a clinically meaningful tumor response rate. However, the study failed to reach its primary endpoint. Trial registration number: Clinicaltrials.gov: NCT04571632 (09 AUG 2020). EUDRACT: 2019-003668-32. Date of registration: 17 DEC 2019, amendment 1: 6 MAR 2021, amendment 2: 4 FEB 2022. [ABSTRACT FROM AUTHOR]

Published
2024
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8. PI3K/mTOR inhibition induces tumour microenvironment remodelling and sensitises pS6high uterine leiomyosarcoma to PD‐1 blockade.

Author

De Wispelaere, Wout, Annibali, Daniela, Tuyaerts, Sandra, Messiaen, Julie, Antoranz, Asier, Shankar, Gautam, Dubroja, Nikolina, Herreros‐Pomares, Alejandro, Baiden‐Amissah, Regina E. M., Orban, Marie‐Pauline, Delfini, Marcello, Berardi, Emanuele, Van Brussel, Thomas, Schepers, Rogier, Philips, Gino, Boeckx, Bram, Baietti, Maria Francesca, Congedo, Luigi, HoWangYin, Kiave Yune, and Bayon, Emilie

Subjects
TUMOR microenvironment, T-cell exhaustion, PROGRAMMED cell death 1 receptors, LEIOMYOSARCOMA, IMMUNE checkpoint proteins
Abstract

Background: Uterine leiomyosarcomas (uLMS) are aggressive tumours with poor prognosis and limited treatment options. Although immune checkpoint blockade (ICB) has proven effective in some 'challenging‐to‐treat' cancers, clinical trials showed that uLMS do not respond to ICB. Emerging evidence suggests that aberrant PI3K/mTOR signalling can drive resistance to ICB. We therefore explored the relevance of the PI3K/mTOR pathway for ICB treatment in uLMS and explored pharmacological inhibition of this pathway to sensitise these tumours to ICB. Methods: We performed an integrated multiomics analysis based on TCGA data to explore the correlation between PI3K/mTOR dysregulation and immune infiltration in 101 LMS. We assessed response to PI3K/mTOR inhibitors in immunodeficient and humanized uLMS patient‐derived xenografts (PDXs) by evaluating tumour microenvironment modulation using multiplex immunofluorescence. We explored response to single‐agent and a combination of PI3K/mTOR inhibitors with PD‐1 blockade in humanized uLMS PDXs. We mapped intratumoural dynamics using single‐cell RNA/TCR sequencing of serially collected biopsies. Results: PI3K/mTOR over‐activation (pS6high) associated with lymphocyte depletion and wound healing immune landscapes in (u)LMS, suggesting it contributes to immune evasion. In contrast, PI3K/mTOR inhibition induced profound tumour microenvironment remodelling in an ICB‐resistant humanized uLMS PDX model, fostering adaptive anti‐tumour immune responses. Indeed, PI3K/mTOR inhibition induced macrophage repolarisation towards an anti‐tumourigenic phenotype and increased antigen presentation on dendritic and tumour cells, but also promoted infiltration of PD‐1+ T cells displaying an exhausted phenotype. When combined with anti‐PD‐1, PI3K/mTOR inhibition led to partial or complete tumour responses, whereas no response to single‐agent anti‐PD‐1 was observed. Combination therapy reinvigorated exhausted T cells and induced clonal hyper‐expansion of a cytotoxic CD8+ T‐cell population supported by a CD4+ Th1 niche. Conclusions: Our findings indicate that aberrant PI3K/mTOR pathway activation contributes to immune escape in uLMS and provides a rationale for combining PI3K/mTOR inhibition with ICB for the treatment of this patient population. [ABSTRACT FROM AUTHOR]

Published
2024
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9. 694 A randomized phase II clinical trial of SBRT and pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c(BDCA-1)+/CD141(BDCA-3)+myeloid dendritic cells in solid tumors

Author

Vounckx, Manon, primary, Tijtgat, Jens, additional, Dirven, Iris, additional, Vandenbroucke, Frederik, additional, Raemaeckers, Steven, additional, Ilsen, Bart, additional, Mustapha, Selma Ben, additional, Loon, Jens Van, additional, Stevens, Latoya, additional, Geeraerts, Xenia, additional, Riet, Ivan Van, additional, Dufait, Ines, additional, Tuyaerts, Sandra, additional, Decoster, Lore, additional, Ridder, Mark De, additional, and Neyns, Bart, additional

Published
2023
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13. 790 Phase I clinical trial on intratumoral administration of autologous CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells plus ipilimumab and AS01B in combination with intravenously administered nivolumab

Author

Tijtgat, Jens, Schwarze, Julia Katharina, Vander Mijnsbrugge, An-Sofie, Raeymaeckers, Steven, Van Riet, Ivan, Geeraerts, Xenia, Stevens, Latoya, Tuyaerts, Sandra, Neyns, Bart, Faculty of Economic and Social Sciences and Solvay Business School, Laboratory of Molecular and Medical Oncology, Clinical sciences, Medical Oncology, Faculty of Medicine and Pharmacy, Basic (bio-) Medical Sciences, Radiology, and Hematology

Published
2022

14. 790 Phase I clinical trial on intratumoral administration of autologous CD1c (BDCA-1)+/CD141 (BDCA-3)+myeloid dendritic cells plus ipilimumab and AS01Bin combination with intravenously administered nivolumab

Author

Tijtgat, Jens, primary, Schwarze, Julia Katharina, additional, Mijnsbrugge, An-Sofie Vander, additional, Raeymaeckers, Steven, additional, Riet, Ivan Van, additional, Geeraerts, Xenia, additional, Stevens, Latoya, additional, Tuyaerts, Sandra, additional, and Neyns, Bart, additional

Published
2022
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15. CTIM-12. A PHASE I CLINICAL TRIAL ON THE INTRACRANIAL ADMINISTRATION OF INCREASING DOSES OF IPILIMUMAB PLUS FIXED DOSE NIVOLUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA (RGB)

Author

Geens, Wietse, primary, Schwarze, Julia Katharina, additional, Tijtgat, Jens, additional, Lescrauwaet, Louise, additional, Tuyaerts, Sandra, additional, Geeraerts, Xenia, additional, Stevens, Latoya, additional, Vanbinst, Anne-Marie, additional, Everaert, Hendrik, additional, Bruneau, Michaël, additional, Duerinck, Johnny, additional, and Neyns, Bart, additional

Published
2022
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16. 2022-RA-638-ESGO Pembrolizumab with multimodal immunomodulation in chemotherapy-pretreated cervical, endometrial, and uterine cancer: the PRIMMO phase II trial

Author

De Jaeghere, Emiel A, primary, Tuyaerts, Sandra, additional, van Nuffel, An MT, additional, Belmans, Ann, additional, Bogaerts, Kris, additional, Baiden-Amissah, Regina, additional, Vuylsteke, Peter, additional, Henry, Stéphanie, additional, Trinh, Xuan Bich, additional, van Dam, Peter A, additional, Aspeslagh, Sandrine, additional, de Caluwé, Alex, additional, Naert, Eline, additional, Lambrechts, Diether, additional, Hendrix, An, additional, de Wever, Olivier, additional, van de Vijver, Koen K, additional, Amant, Frédéric, additional, Vandecasteele, Katrien, additional, and Denys, Hannelore G, additional

Published
2022
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17. Intratumoral administration of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myeloid dendritic cells in combination with talimogene laherparepvec in immune checkpoint blockade refractory advanced melanoma patients: a phase I clinical trial

Author

Schwarze, Julia Katharina, primary, Tijtgat, Jens, additional, Awada, Gil, additional, Cras, Louise, additional, Vasaturo, Angela, additional, Bagnall, Christopher, additional, Forsyth, Ramses, additional, Dufait, Inès, additional, Tuyaerts, Sandra, additional, Van Riet, Ivan, additional, and Neyns, Bart, additional

Published
2022
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18. 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

De Jaeghere, Emiel A., primary, Tuyaerts, Sandra, additional, Van Nuffel, An M. T., additional, Belmans, Ann, additional, Bogaerts, Kris, additional, Baiden-Amissah, Regina, additional, Lippens, Lien, additional, Vuylsteke, Peter, additional, Henry, Stéphanie, additional, Trinh, Xuan Bich, additional, van Dam, Peter A., additional, Aspeslagh, Sandrine, additional, De Caluwé, Alex, additional, Naert, Eline, additional, Lambrechts, Diether, additional, Hendrix, An, additional, De Wever, Olivier, additional, Van de Vijver, Koen K., additional, Amant, Frédéric, additional, Vandecasteele, Katrien, additional, and Denys, Hannelore G., additional

Published
2022
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19. Trial watch: Dendritic cell (DC)-based immunotherapy for cancer

Author

Laureano, Raquel S, primary, Sprooten, Jenny, additional, Vanmeerbeerk, Isaure, additional, Borras, Daniel M, additional, Govaerts, Jannes, additional, Naulaerts, Stefan, additional, Berneman, Zwi N, additional, Beuselinck, Benoit, additional, Bol, Kalijn F, additional, Borst, Jannie, additional, Coosemans, an, additional, Datsi, Angeliki, additional, Fučíková, Jitka, additional, Kinget, Lisa, additional, Neyns, Bart, additional, Schreibelt, Gerty, additional, Smits, Evelien, additional, Sorg, Rüdiger V, additional, Spisek, Radek, additional, Thielemans, Kris, additional, Tuyaerts, Sandra, additional, De Vleeschouwer, Steven, additional, de Vries, I Jolanda M, additional, Xiao, Yanling, additional, and Garg, Abhishek D, additional

Published
2022
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20. 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

De Jaeghere, Emiel, Tuyaerts, Sandra, Van Nuffel, An M T, Belmans, Ann, Bogaerts, Kris, Baiden-Amissah, Regina, Lippens, Lien, Vuylsteke, Peter, Henry, Stéphanie, Trinh, Xuan Bich, Van Dam, Peter P.A., Aspeslagh, Sandrine, De Caluwé, Alex, Naert, Eline, Lambrechts, Diether, Hendrix, An, De Wever, Olivier, Van de Vijver, Koen, Amant, Frédéric, Vandecasteele, Katrien, Denys, Hannelore, De Jaeghere, Emiel, Tuyaerts, Sandra, Van Nuffel, An M T, Belmans, Ann, Bogaerts, Kris, Baiden-Amissah, Regina, Lippens, Lien, Vuylsteke, Peter, Henry, Stéphanie, Trinh, Xuan Bich, Van Dam, Peter P.A., Aspeslagh, Sandrine, De Caluwé, Alex, Naert, Eline, Lambrechts, Diether, Hendrix, An, De Wever, Olivier, Van de Vijver, Koen, Amant, Frédéric, Vandecasteele, Katrien, and Denys, Hannelore

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)., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2022

21. A phase I clinical trial on intracranial administration of autologous myeloid dendritic cells (myDC) in combination with ipilimumab and nivolumab in patients with recurrent glioblastoma (rGB).

Author

Schwarze, Julia Katharina, primary, Geens, Wietse, additional, Tijtgat, Jens, additional, Awada, Gil, additional, Seynaeve, Laura, additional, Vanbinst, Anne-Marie, additional, Everaert, Hendrik, additional, Michotte, Alex, additional, Bruneau, Michaël, additional, Van Riet, Ivan, additional, Tuyaerts, Sandra, additional, Duerinck, Johnny, additional, and Neyns, Bart, additional

Published
2022
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23. INTRA-CRANIAL ADMINISTRATION OF CTLA-4 AND PD-1 IMMUNE CHECKPOINT-INHIBITING MONOCLONAL ANTIBODIES IN RECURRENT GLIOBLASTOMA PATIENTS: A MULTI-COHORT ADAPTIVE PHASE I CLINICAL TRIAL

Author

Duerinck, Johnny, Geens, Wietse, Schwarze, Julia Katharina, Bertels, Cleo, Tijtgat, Jens, Awada, Gil, Vaeyens, Freya, Cras, Louise, Nijland, Lynn, Vanbinst, Anne-Marie, Everaert, Hendrik, Michotte, Alex, Janssen, Toon, Caljon, Ben, Cauwenbergh, Tom, Bruneau, Michael, Forsyth, Ramses, Tuyaerts, Sandra, Neyns, Bart, Surgical clinical sciences, Neuroprotection & Neuromodulation, Neurosurgery, Laboratory for Medical and Molecular Oncology, Faculty of Medicine and Pharmacy, Internal Medicine, Clinical sciences, Medical Oncology, Medical Genetics, Basic (bio-) Medical Sciences, Pathology, Supporting clinical sciences, Radiology, Medical Imaging, Nuclear Medicine, Neurology, Artificial Intelligence supported Modelling in clinical Sciences, and Experimental Pathology

Published
2021

25. CTIM-17. INTRA-CRANIAL ADMINISTRATION OF CTLA-4 AND PD-1 IMMUNE CHECKPOINT-INHIBITING MONOCLONAL ANTIBODIES IN RECURRENT GLIOBLASTOMA PATIENTS: A MULTI-COHORT ADAPTIVE PHASE I CLINICAL TRIAL

Author

Duerinck, Johnny, primary, Geens, Wietse, additional, Schwarze, Julia Katharina, additional, Bertels, Cleo, additional, Tijtgat, Jens, additional, Awada, Gil, additional, Vaeyens, Freya, additional, cras, Louise, additional, Nijland, Lynn, additional, Vanbinst, Anne-Marie, additional, Everaert, Hendrik, additional, Michotte, Alex, additional, Janssens, Toon, additional, Caljon, Ben, additional, Cauwenbergh, Tom, additional, Bruneau, Michaël, additional, Forsyth, Ramses, additional, Tuyaerts, Sandra, additional, and Neyns, Bart, additional

Published
2021
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32. Intratumoral Combinatorial Administration of CD1c (BDCA-1)+ Myeloid Dendritic Cells Plus Ipilimumab and Avelumab in Combination with Intravenous Low-Dose Nivolumab in Patients with Advanced Solid Tumors: A Phase IB Clinical Trial

Author

Schwarze, Julia Katharina, primary, Awada, Gil, additional, Cras, Louise, additional, Tijtgat, Jens, additional, Forsyth, Ramses, additional, Dufait, Inès, additional, Tuyaerts, Sandra, additional, Van Riet, Ivan, additional, and Neyns, Bart, additional

Published
2020
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33. Biological Function of PD-L2 and Correlation With Overall Survival in Type II Endometrial Cancer

Author

Marinelli, Oliviero, primary, Annibali, Daniela, additional, Morelli, Maria Beatrice, additional, Zeppa, Laura, additional, Tuyaerts, Sandra, additional, Aguzzi, Cristina, additional, Amantini, Consuelo, additional, Maggi, Federica, additional, Ferretti, Benedetta, additional, Santoni, Giorgio, additional, Amant, Frédéric, additional, and Nabissi, Massimo, additional

Published
2020
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34. The Effects of Cannabidiol and Prognostic Role of TRPV2 in Human Endometrial Cancer

Author

Marinelli, Oliviero, primary, Morelli, Maria Beatrice, additional, Annibali, Daniela, additional, Aguzzi, Cristina, additional, Zeppa, Laura, additional, Tuyaerts, Sandra, additional, Amantini, Consuelo, additional, Amant, Frédéric, additional, Ferretti, Benedetta, additional, Maggi, Federica, additional, Santoni, Giorgio, additional, and Nabissi, Massimo, additional

Published
2020
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36. PRIMMO study protocol: a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer.

Author

UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service d'oncologie médicale, Tuyaerts, Sandra, Van Nuffel, An M T, Naert, Eline, Van Dam, Peter A, Vuylsteke, Peter, De Caluwé, Alex, Aspeslagh, Sandrine, Dirix, Piet, Lippens, Lien, De Jaeghere, Emiel, Amant, Frédéric, Vandecasteele, Katrien, Denys, Hannelore, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service d'oncologie médicale, Tuyaerts, Sandra, Van Nuffel, An M T, Naert, Eline, Van Dam, Peter A, Vuylsteke, Peter, De Caluwé, Alex, Aspeslagh, Sandrine, Dirix, Piet, Lippens, Lien, De Jaeghere, Emiel, Amant, Frédéric, Vandecasteele, Katrien, and Denys, Hannelore

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 li

Published
2019

41. Fulvestrant in Gynaecological Cancers That Are Potentially Hormone Sensitive : The Fuchsia Study

Author

Tuyaerts, Sandra

Abstract

Introduction/BackgroundMany gynaecological malignancies including low-grade uterine sarcomas (LGUS), low-grade endometrial carcinomas (LGEC), sex cord stromal tumours (SCST) and low-grade epithelial serous ovarian cancers (LGSC) express oestrogen receptor (ER). Reports suggest that endocrine therapy can be effective, but due to their rarity, no consensus criteria define which patients would benefit from anti-ER treatment.MethodologyFUCHSia is an open-label, single-arm, prospective, multi-centre, tandem two-stage, phase II study evaluating Fulvestrant (Faslodex) efficacy in women with recurrent/metastatic ER-positive gynaecological malignancies. Tumour types studied are LGUS (all LG endometrial stromal sarcoma, adenosarcoma without sarcomatous overgrowth and leiomyosarcoma), LGEC, SCST and LGSC. Fulvestrant is administered (intramuscular injection, 2x 250 mg) once every 2 weeks for the first month, and monthly until progression. In stage 1, 20 patients will be enrolled per tumour type. When 15 patients per type reach week-24, an interim analysis will be performed. If 1 or more responses are observed per type, 30 additional patients will be recruited in stage 2. Primary endpoint is response rate, determined by RECIST v1.1 criteria.Secondary endpoints are progression-free survival, overall survival, time to progression, clinical benefit, safety and tolerability, and quality of life. Exploratory endpoints are feasibility of sequential 18F-FES PET scans for assessment of ER expression and functional status during treatment, value of 18F-FES PET scans combined with 18F-FDG PET scans in predicting response and patient stratification, and identification of genetic changes in cf-DNA and tumour biopsies potentially predicting response to Fulvestrant.ResultsUZ Leuven is the sponsor and recruitment is ongoing in UZ Ghent, UZ Antwerp and AZ Sint-Maarten. The study will open soon in NKI/AvL Amsterdam. Additional centres in Belgium and The Netherlands will be added later. ConclusionIn this study, we will assess Fulvestrant activity in low-grade gynaecological cancers, while exploratory endpoints will investigate predictors of response and resistance mechanisms.DisclosuresThe authors declare that they have no competing interests.The study obtained funding from u201cKom op tegen Kanker (Stand up to Cancer), the Flemish cancer societyu201d u2028and u201cFWO u2013 Research Fund Flandersu201d.

Published
2017

43. Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer

Author

Tanyi, Janos L., primary, Bobisse, Sara, additional, Ophir, Eran, additional, Tuyaerts, Sandra, additional, Roberti, Annalisa, additional, Genolet, Raphael, additional, Baumgartner, Petra, additional, Stevenson, Brian J., additional, Iseli, Christian, additional, Dangaj, Denarda, additional, Czerniecki, Brian, additional, Semilietof, Aikaterini, additional, Racle, Julien, additional, Michel, Alexandra, additional, Xenarios, Ioannis, additional, Chiang, Cheryl, additional, Monos, Dimitri S., additional, Torigian, Drew A., additional, Nisenbaum, Harvey L., additional, Michielin, Olivier, additional, June, Carl H., additional, Levine, Bruce L., additional, Powell, Daniel J., additional, Gfeller, David, additional, Mick, Rosemarie, additional, Dafni, Urania, additional, Zoete, Vincent, additional, Harari, Alexandre, additional, Coukos, George, additional, and Kandalaft, Lana E., additional

Published
2018
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48. Pilot clinical trial with autologous TriMix-Dendritic cell vaccine in patients with advanced melanoma, preliminary results

Author

Neyns, Bart, Corthals, Jurgen, Van Nuffel, An, Tuyaerts, Sandra, Heirman, Carlo, Roelandts, T., De Coninck, A., Van Riet, Ivan, Bonehill, Aude, Thielemans, Kris, Internal Medicine Specializations, Physiology, Pathology, Dermatology, Skin function and permeability, Vrije Universiteit Brussel, and Immunology and Microbiology

Subjects
melanoma, clinical trial, dendritic cells, Vaccine
Published
2008

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