10 results on '"Papa, Sophie"'
Search Results
2. Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2.
- Author
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Pellizzari G, Martinez O, Crescioli S, Page R, Di Meo A, Mele S, Chiaruttini G, Hoinka J, Batruch I, Prassas I, Grandits M, López-Abente J, Bugallo-Blanco E, Ward M, Bax HJ, French E, Cheung A, Lombardi S, Figini M, Lacy KE, Diamandis EP, Josephs DH, Spicer J, Papa S, and Karagiannis SN
- Subjects
- Animals, Humans, Mice, Fusion Regulatory Protein 1, Heavy Chain immunology, Immunoglobulin E metabolism, Immunotherapy methods, Receptors, Chimeric Antigen immunology
- Abstract
Background: Cancer immunotherapy with monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapies can benefit from selection of new targets with high levels of tumor specificity and from early assessments of efficacy and safety to derisk potential therapies., Methods: Employing mass spectrometry, bioinformatics, immuno-mass spectrometry and CRISPR/Cas9 we identified the target of the tumor-specific SF-25 antibody. We engineered IgE and CAR T cell immunotherapies derived from the SF-25 clone and evaluated potential for cancer therapy., Results: We identified the target of the SF-25 clone as the tumor-associated antigen SLC3A2, a cell surface protein with key roles in cancer metabolism. We generated IgE monoclonal antibody, and CAR T cell immunotherapies each recognizing SLC3A2. In concordance with preclinical and, more recently, clinical findings with the first-in-class IgE antibody MOv18 (recognizing the tumor-associated antigen Folate Receptor alpha), SF-25 IgE potentiated Fc-mediated effector functions against cancer cells in vitro and restricted human tumor xenograft growth in mice engrafted with human effector cells. The antibody did not trigger basophil activation in cancer patient blood ex vivo, suggesting failure to induce type I hypersensitivity, and supporting safe therapeutic administration. SLC3A2-specific CAR T cells demonstrated cytotoxicity against tumor cells, stimulated interferon-γ and interleukin-2 production in vitro. In vivo SLC3A2-specific CAR T cells significantly increased overall survival and reduced growth of subcutaneous PC3-LN3-luciferase xenografts. No weight loss, manifestations of cytokine release syndrome or graft-versus-host disease, were detected., Conclusions: These findings identify efficacious and potentially safe tumor-targeting of SLC3A2 with novel immune-activating antibody and genetically modified cell therapies., Competing Interests: Competing interests: SNK and JS are founders and shareholders of Epsilogen Ltd., and HJB is now employed through a fund provided by Epsilogen Ltd., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2021
- Full Text
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3. Setting the scene - a future 'epidemic' of immune-related adverse events in association with checkpoint inhibitor therapy.
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Bermudez MV and Papa S
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- Antineoplastic Agents, Immunological therapeutic use, CTLA-4 Antigen antagonists & inhibitors, Humans, Immunologic Factors therapeutic use, Immunotherapy methods, Immunotherapy trends, Ipilimumab adverse effects, Ipilimumab therapeutic use, Melanoma drug therapy, Prognosis, Programmed Cell Death 1 Receptor antagonists & inhibitors, Antineoplastic Agents, Immunological adverse effects, Immunologic Factors adverse effects, Immunotherapy adverse effects, Neoplasms drug therapy
- Abstract
Cancer immune therapy with checkpoint inhibitors (CPIs) has changed the landscape of treatment for a growing number of indications. These drugs are associated with a specific mechanism of action that has profound implications for both immunology and inflammatory disease. This article looks to set the scene covering the history of CPI therapy to date and outlining the likely future developments., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2019
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4. Design of a phase I clinical trial to evaluate intratumoral delivery of ErbB-targeted chimeric antigen receptor T-cells in locally advanced or recurrent head and neck cancer.
- Author
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van Schalkwyk MC, Papa SE, Jeannon JP, Guerrero Urbano T, Spicer JF, and Maher J
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- Adult, Female, Humans, Male, Receptors, Antigen genetics, Receptors, Antigen immunology, Receptors, Cytokine genetics, Receptors, Cytokine immunology, Recombinant Proteins administration & dosage, Recombinant Proteins adverse effects, Recombinant Proteins pharmacokinetics, Research Design, T-Lymphocytes immunology, T-Lymphocytes transplantation, Carcinoma, Squamous Cell therapy, Genes, erbB, Genetic Therapy, Head and Neck Neoplasms therapy, Immunotherapy
- Abstract
Despite several advances, 5-year survival in patients with head and neck squamous cell carcinoma (HNSCC) remains unchanged at only 50%. The commonest cause of death is locally advanced/recurrent disease. Consequently, there is an unmet need for new approaches to improve local control in HNSCC. T4 immunotherapy is an autologous cell therapy in which peripheral blood T-cells are genetically engineered using a retroviral vector to coexpress two chimeric receptors: (i) T1E28z is a chimeric antigen receptor that engages multiple ErbB dimers that are commonly upregulated in HNSCC; (ii) 4αβ is a chimeric cytokine receptor that converts the weak mitogenic stimulus provided by interleukin (IL)-4 into a strong and selective growth signal, allowing preferential expansion and enrichment of T4(+) T-cells ex vivo. T4 immunotherapy exerts antitumor activity against HNSCC cell lines and tumors in vivo, without significant toxicity. Human T4(+) T-cells also engage mouse ErbB receptors, permitting safety testing in SCID Beige mice. Severe toxicity caused by cytokine release syndrome ensues when human T4(+) T-cells are administered at high doses to mice, particularly with advanced tumor burdens. However, such toxicity is not required for efficacy and is never seen if T-cells are administered by the intratumoral route. To exploit this, we have designed a first-in-man clinical trial in which T4(+) T-cells are administered to patients with locally advanced/recurrent HNSCC. Cells will be administered at a single sitting to multiple sites around the viable tumor circumference. A 3+3 dose escalation design will be used, starting at 10(7) cells (cohort 1), escalating to 10(9) cells (cohort 5). If maximum tolerated dose remains undefined, cohorts 6/7 will receive either low- or high-dose cyclophosphamide before 10(9) T4(+) T-cells. A panel of routine/in-house assays and imaging techniques will be used to monitor safety, efficacy, perturbation of endogenous antitumor immunity, immunogenicity, and T-cell trafficking.
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- 2013
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5. Acute kidney injury in patients treated with immune checkpoint inhibitors
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Gupta, Shruti, Short, Samuel AP, Sise, Meghan E, Prosek, Jason M, Madhavan, Sethu M, Soler, Maria Jose, Ostermann, Marlies, Herrmann, Sandra M, Abudayyeh, Ala, Anand, Shuchi, Glezerman, Ilya, Motwani, Shveta S, Murakami, Naoka, Wanchoo, Rimda, Ortiz-Melo, David I, Rashidi, Arash, Sprangers, Ben, Aggarwal, Vikram, Malik, A Bilal, Loew, Sebastian, Carlos, Christopher A, Chang, Wei-Ting, Beckerman, Pazit, Mithani, Zain, Shah, Chintan V, Renaghan, Amanda D, De Seigneux, Sophie, Campedel, Luca, Kitchlu, Abhijat, Shin, Daniel Sanghoon, Rangarajan, Sunil, Deshpande, Priya, Coppock, Gaia, Eijgelsheim, Mark, Seethapathy, Harish, Lee, Meghan D, Strohbehn, Ian A, Owen, Dwight H, Husain, Marium, Garcia-Carro, Clara, Bermejo, Sheila, Lumlertgul, Nuttha, Seylanova, Nina, Flanders, Lucy, Isik, Busra, Mamlouk, Omar, Lin, Jamie S, Garcia, Pablo, Kaghazchi, Aydin, Khanin, Yuriy, Kansal, Sheru K, Wauters, Els, Chandra, Sunandana, Schmidt-Ott, Kai M, Hsu, Raymond K, Tio, Maria C, Mothi, Suraj Sarvode, Singh, Harkarandeep, Schrag, Deborah, Jhaveri, Kenar D, Reynolds, Kerry L, Cortazar, Frank B, Leaf, David E, Salem, Joe-Elie, Bagnis, Corinne Isnard, Rahma, Osama E, Mothi, Suraj S, Selamet, Umut, Chang, Weiting, Hirsch, Jamie S, Sakhiya, Vipulbhai, Stalbow, Daniel, Wu, Sylvia, Cennamo, Armando, Papa, Sophie, Rigg, Anne, Shaunak, Nisha, Kibbelaar, Zoe A, and Benesova, Karolina
- Subjects
Kidney Disease ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Renal and urogenital ,Good Health and Well Being ,Acute Kidney Injury ,Aged ,Cohort Studies ,Female ,Humans ,Immune Checkpoint Inhibitors ,Immunotherapy ,Male ,Middle Aged ,Risk Factors ,immunotherapy ,CTLA-4 antigen ,programmed cell death 1 receptor ,ICPi-AKI Consortium Investigators - Abstract
BackgroundImmune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer.MethodsWe collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI.ResultsICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI.ConclusionsPatients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.
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- 2021
6. A Retrospective Chart Review Study of Real-World Use of Talimogene Laherparepvec in Unresectable Stage IIIB–IVM1a Melanoma in Four European Countries
- Author
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van Akkooi, Alexander C. J., Haferkamp, Sebastian, Papa, Sophie, Franke, Viola, Pinter, Andreas, Weishaupt, Carsten, Huber, Margit A., Loquai, Carmen, Richtig, Erika, Gokani, Priya, Öhrling, Katarina, Louie, Karly S., and Mohr, Peter
- Published
- 2021
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7. CDK Inhibition Primes for Anti-PD-L1 Treatment in Triple-Negative Breast Cancer Models.
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Cheung, Anthony, Chenoweth, Alicia M., Quist, Jelmar, Sow, Heng Sheng, Malaktou, Christina, Ferro, Riccardo, Hoffmann, Ricarda M., Osborn, Gabriel, Sachouli, Eirini, French, Elise, Marlow, Rebecca, Lacy, Katie E., Papa, Sophie, Grigoriadis, Anita, and Karagiannis, Sophia N.
- Subjects
BIOLOGICAL models ,PROTEINS ,GENE expression profiling ,BREAST tumors ,IMMUNOTHERAPY ,ADIPOSE tissues - Abstract
Simple Summary: The cyclin E/CDK2 complex may present a promising target axis for the treatment of triple-negative breast cancers (TNBC); however, therapeutically relevant doses of CDK2 inhibitors have been associated with toxicities. Here, we report that the suboptimal dosing of the CDK 2, 7 and 9 inhibitor SNS-032 reduced the viability of TNBC cells and upregulated the checkpoint ligand PD-L1 expression in surviving cancer cells in vitro and in human orthotopic MDA-MB-231 TNBC xenografts grown in immunodeficient mice. Moreover, in immunodeficient, TNBC xenograft-bearing mice engrafted with human immune cells, SNS-032 treatment was associated with the infiltration of CD45
+ human immune cells in tumors. In these orthotopic MDA-MB-231 TNBC-bearing mice, suboptimal SNS-032 doses given sequentially ahead of dosing with the anti-PD-L1 antibody avelumab significantly restricted tumor growth compared with monotherapy. These findings suggest that surviving cancer cells following suboptimal CDK inhibitor treatment may be responsive to checkpoint immunotherapy. Triple-negative breast cancers (TNBC) expressing PD-L1 qualify for checkpoint inhibitor immunotherapy. Cyclin E/CDK2 is a potential target axis in TNBC; however, small-molecule drugs at efficacious doses may be associated with toxicity, and treatment alongside immunotherapy requires investigation. We evaluated CDK inhibition at suboptimal levels and its anti-tumor and immunomodulatory effects. Transcriptomic analyses of primary breast cancers confirmed higher cyclin E/CDK2 expression in TNBC compared with non-TNBC. Out of the three CDK2-targeting inhibitors tested, the CDK 2, 7 and 9 inhibitor SNS-032 was the most potent in reducing TNBC cell viability and exerted cytotoxicity against all eight TNBC cell lines evaluated in vitro. Suboptimal SNS-032 dosing elevated cell surface PD-L1 expression in surviving TNBC cells. In mice engrafted with human immune cells and challenged with human MDA-MB-231 TNBC xenografts in mammary fat pads, suboptimal SNS-032 dosing partially restricted tumor growth, enhanced the tumor infiltration of human CD45+ immune cells and elevated cell surface PD-L1 expression in surviving cancer cells. In tumor-bearing mice engrafted with human immune cells, the anti-PD-L1 antibody avelumab, given sequentially following suboptimal SNS-032 dosing, reduced tumor growth compared with SNS-032 alone or with avelumab without prior SNS-032 priming. CDK inhibition at suboptimal doses promotes immune cell recruitment to tumors, PD-L1 expression by surviving TNBC cells and may complement immunotherapy. [ABSTRACT FROM AUTHOR]- Published
- 2022
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8. BRAF inhibitors:resistance and the promise of combination treatments for melanoma
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Griffin, Merope, Scotto, Daniele, Josephs, Debra H, Mele, Silvia, Crescioli, Silvia, Bax, Heather J, Pellizzari, Giulia, Wynne, Matthew D, Nakamura, Mano, Hoffmann, Ricarda M, Ilieva, Kristina M, Cheung, Anthony, Spicer, James F, Papa, Sophie, Lacy, Katie E, and Karagiannis, Sophia N
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CTLA-4 ,Immunotherapy ,MAPK ,Melanoma ,BRAF - Abstract
Identification of mutations in the gene encoding the serine/threonine-protein kinase, BRAF, and constitutive activation of the mitogen-activated protein kinase (MAPK) pathway in around 50% of malignant melanomas have led to the development and regulatory approval of targeted pathway inhibitor drugs. A proportion of patients are intrinsically resistant to BRAF inhibitors, and most patients who initially respond, acquire resistance within months. In this review, we discuss pathway inhibitors and their mechanisms of resistance, and we focus on numerous efforts to improve clinical benefits through combining agents with disparate modes of action, including combinations with checkpoint inhibitor antibodies. We discuss the merits of combination strategies based on enhancing immune responses or overcoming tumor-associated immune escape mechanisms. Emerging insights into mechanisms of action, resistance pathways and their impact on host-tumor relationships will inform the design of optimal combinations therapies to improve outcomes for patients who currently do not benefit from recent treatment breakthroughs.
- Published
- 2017
9. Utilizing Immunocytokines for Cancer Therapy.
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Runbeck, Erin, Crescioli, Silvia, Karagiannis, Sophia N., and Papa, Sophie
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CANCER treatment ,CHIMERIC proteins ,CYTOKINES ,CLINICAL trials ,IMMUNOTECHNOLOGY - Abstract
Cytokine therapy for cancer has indicated efficacy in certain diseases but is generally accompanied by severe toxicity. The field of antibody–cytokine fusion proteins (immunocytokines) arose to target these effector molecules to the tumor environment in order to expand the therapeutic window of cytokine therapy. Pre-clinical evidence has shown the increased efficacy and decreased toxicity of various immunocytokines when compared to their cognate unconjugated cytokine. These anti-tumor properties are markedly enhanced when combined with other treatments such as chemotherapy, radiotherapy, and checkpoint inhibitor antibodies. Clinical trials that have continued to explore the potential of these biologics for cancer therapy have been conducted. This review covers the in vitro, in vivo, and clinical evidence for the application of immunocytokines in immuno-oncology. [ABSTRACT FROM AUTHOR]
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- 2021
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10. Development of PSMA-specific immunotherapy for prostate cancer with PIN4 gene-modified T cells.
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Papa, Sophie, Emami-Shahri, Nia, Zhe Liu, Petrausch, Ulf, Mullen, Gregory, Spicer, James, and Maher, John
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IMMUNOTHERAPY , *T cells , *FATTY liver - Abstract
An abstract of the article "Development of PSMA-specific Immunotherapy for Prostate Cancer With PIN4 Gene-modified T Cells," by Sophie Papa, Zhe Liu, and Gregory Mullen is presented.
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- 2014
- Full Text
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