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Immunotherapy ctla-4

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https://www.readbyqxmd.com/read/28729154/tremelimumab-as-second-line-or-third-line-treatment-in-relapsed-malignant-mesothelioma-determine-a-multicentre-international-randomised-double-blind-placebo-controlled-phase-2b-trial
#1
Michele Maio, Arnaud Scherpereel, Luana Calabrò, Joachim Aerts, Susana Cedres Perez, Alessandra Bearz, Kristiaan Nackaerts, Dean A Fennell, Dariusz Kowalski, Anne S Tsao, Paul Taylor, Federica Grosso, Scott J Antonia, Anna K Nowak, Maria Taboada, Martina Puglisi, Paul K Stockman, Hedy L Kindler
BACKGROUND: New therapeutic strategies for malignant mesothelioma are urgently needed. In the DETERMINE study, we investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma. METHODS: DETERMINE was a double-blind, placebo-controlled, phase 2b trial done at 105 study centres across 19 countries in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease...
July 17, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28721449/role-of-regulatory-t-cells-in-acute-myeloid-leukemia-patients-undergoing-relapse-preventive-immunotherapy
#2
Frida Ewald Sander, Malin Nilsson, Anna Rydström, Johan Aurelius, Rebecca E Riise, Charlotta Movitz, Elin Bernson, Roberta Kiffin, Anders Ståhlberg, Mats Brune, Robin Foà, Kristoffer Hellstrand, Fredrik B Thorén, Anna Martner
Regulatory T cells (Tregs) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov ) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3(+)CD25(high)CD4(+) Tregs during immunotherapy and to determine the potential impact of Tregs on relapse risk and survival...
July 18, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28716652/toxicity-profiles-of-immunotherapy
#3
REVIEW
Sophie Cousin, Antoine Italiano
Immunotherapies are changing the landscape of advanced solid tumor treatment. These therapies have different mechanisms of action and include oncolytic viruses, checkpoint inhibitors, such as CTLA-4 or PD1/PD-L1 monoclonal antibodies, and CSF-1R antibodies. Given the growing therapeutic impact of these agents in oncology, it is important to better understand their properties. Immunotherapies generate new toxicity profiles that are called immune-related adverse events and require specific management. This review focuses on the mechanisms of action of such side effects, as well as their description and their general management...
July 14, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28714866/ibrutinib-treatment-improves-t-cell-number-and-function-in-cll-patients
#4
Meixiao Long, Kyle Beckwith, Priscilla Do, Bethany L Mundy, Amber Gordon, Amy M Lehman, Kami J Maddocks, Carolyn Cheney, Jeffrey A Jones, Joseph M Flynn, Leslie A Andritsos, Farrukh Awan, Joseph A Fraietta, Carl H June, Marcela V Maus, Jennifer A Woyach, Michael A Caligiuri, Amy J Johnson, Natarajan Muthusamy, John C Byrd
BACKGROUND: Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS: Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially...
July 17, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28693793/biomarkers-of-response-to-pd-1-pd-l1-inhibition
#5
REVIEW
Saman Maleki Vareki, Carmen Garrigós, Ignacio Duran
Immunotherapy is a promising treatment strategy for cancer that has recently shown unprecedented survival benefits in selected patients. A number of immunomodulatory agents that target immune system checkpoints such as the cytotoxic T-lymphocyte antigen 4 (CTLA-4), the programmed death-1 (PD-1) or its ligand (PD-L1), have received regulatory approval for the treatment of multiple cancers including malignant melanoma, non-small cell lung cancer, renal cell carcinoma, classical Hodgkin lymphoma, and recurrent or metastatic head and neck squamous cell carcinoma...
August 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28690075/tumor-microenvironment-changes-leading-to-resistance-of-immune-checkpoint-inhibitors-in-metastatic-melanoma-and-strategies-to-overcome-resistance
#6
REVIEW
Bhargavi Pulluri, Abhijeet Kumar, Montaser Shaheen, Joanne Jeter, Srinath Sundararajan
Immunotherapy with checkpoint inhibitors targeting CTLA-4 and/or PD-1 receptors independent of the BRAF mutational status and targeted therapy with BRAF and MEK inhibitors in BRAF V600 mutated patients have taken the forefront of advanced melanoma treatment. The main advantage of immunotherapy is its ability to provide durable responses in a subset of patients. However, significant proportions of patients either do not respond or have progression after initial response to immunotherapies. Multiple changes in the tumor microenvironment, such as down regulation of immune checkpoint ligands by tumor, alteration in interferon signaling, and activation of alternate immune suppressive pathways, have been identified as possible reasons for failure of immune checkpoint therapy...
July 6, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28683958/-adverse-effects-of-immune-checkpoint-inhibitors-used-to-treat-melanoma-and-other-cancer
#7
Claire Jacquin-Porretaz, Charlée Nardin, Eve Puzenat, Blandine Roche-Kubler, François Aubin
Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers and metastatic renal cancer. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events that may be life threatening if not anticipated and managed appropriately. This new family of dysimmune toxicities remains largely unknown to the broad oncology community...
July 3, 2017: La Presse Médicale
https://www.readbyqxmd.com/read/28680882/immunotherapy-for-patients-with-advanced-urothelial-cancer-current-evidence-and-future-perspectives
#8
REVIEW
Clizia Zichi, Marcello Tucci, Gianmarco Leone, Consuelo Buttigliero, Francesca Vignani, Daniele Pignataro, Giorgio V Scagliotti, Massimo Di Maio
In recent years, immunotherapy has produced encouraging results in a rapidly increasing number of solid tumors. The responsiveness of bladder cancer to immunotherapy was first established in nonmuscle invasive disease in 1976 with intravesical instillations of bacillus Calmette-Guérin (BCG). Very recently immune checkpoint inhibitors demonstrated good activity and significant efficacy in metastatic disease. In particular the best results were obtained with programmed death-ligand-1 (PD-L1) and programmed death-1 (PD-1) inhibitors, but many other immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibodies, are currently under investigation in several trials...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28679955/adoptively-transferred-v%C3%AE-9v%C3%AE-2-t-cells-show-potent-antitumor-effects-in-a-preclinical-b-cell-lymphomagenesis-model
#9
Nicholas A Zumwalde, Akshat Sharma, Xuequn Xu, Shidong Ma, Christine L Schneider, James C Romero-Masters, Amy W Hudson, Annette Gendron-Fitzpatrick, Shannon C Kenney, Jenny E Gumperz
A central issue for adoptive cellular immunotherapy is overcoming immunosuppressive signals to achieve tumor clearance. While γδ T cells are known to be potent cytolytic effectors that can kill a variety of cancers, it is not clear whether they are inhibited by suppressive ligands expressed in tumor microenvironments. Here, we have used a powerful preclinical model where EBV infection drives the de novo generation of human B cell lymphomas in vivo, and autologous T lymphocytes are held in check by PD-1/CTLA-4-mediated inhibition...
July 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28679287/the-safety-of-nivolumab-for-the-treatment-of-metastatic-melanoma
#10
Aine O'Reilly, James Larkin
Nivolumab, a human IgG4 monoclonal antibody directed against PD-1, is a checkpoint inhibitor that is licenced in the treatment of metastatic melanoma either as a monotherapy or in combination with ipilimumab, a CTLA-4 inhibitor. The introduction of immune checkpoint inhibitors to the therapeutic landscape has dramatically altered outcomes in a proportion of patients with metastatic melanoma. Immune checkpoint inhibitors result in a toxicity profile that is distinct from that of chemotherapy or targeted therapy based on their immunomodulatory mechanism and similarly can result in patterns of response that are unique...
July 18, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28674082/intratumoral-sting-activation-with-t-cell-checkpoint-modulation-generates-systemic-antitumor-immunity
#11
Casey R Ager, Matthew J Reilley, Courtney Nicholas, Todd Bartkowiak, Ashvin R Jaiswal, Michael A Curran
Coordinated manipulation of independent immune regulatory pathways in the tumor microenvironment - including blockade of T-cell checkpoint receptors and reversal of suppressive myeloid programs - can render aggressive cancers susceptible to immune rejection. Elevated toxicity associated with combination immunotherapy, however, prevents translation of the most efficacious regimens. We evaluated T-cell checkpoint modulating antibodies targeting CTLA-4, PD-1, and 4-1BB together with myeloid agonists targeting either STING or Flt3 in the TRAMP-C2 model of prostate cancer to determine whether low-dose intratumoral delivery of these agents could elicit systemic control of multi-focal disease...
July 3, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28666979/predicting-the-response-to-ctla-4-blockade-by-longitudinal-noninvasive-monitoring-of-cd8-t-cells
#12
Mohammad Rashidian, Jessica R Ingram, Michael Dougan, Anushka Dongre, Katherine A Whang, Camille LeGall, Juan J Cragnolini, Brian Bierie, Monica Gostissa, James Gorman, Gijsbert M Grotenbreg, Atul Bhan, Robert A Weinberg, Hidde L Ploegh
Immunotherapy using checkpoint-blocking antibodies against targets such as CTLA-4 and PD-1 can cure melanoma and non-small cell lung cancer in a subset of patients. The presence of CD8 T cells in the tumor correlates with improved survival. We show that immuno-positron emission tomography (immuno-PET) can visualize tumors by detecting infiltrating lymphocytes and, through longitudinal observation of individual animals, distinguish responding tumors from those that do not respond to therapy. We used (89)Zr-labeled PEGylated single-domain antibody fragments (VHHs) specific for CD8 to track the presence of intratumoral CD8(+) T cells in the immunotherapy-susceptible B16 melanoma model in response to checkpoint blockade...
June 30, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28666747/combined-immunotherapy-ctla-4-blockade-potentiates-anti-tumor-response-induced-by-transcutaneous-immunization
#13
Johanna Rausch, Pamela Aranda Lopez, Ariane Bialojan, Mark Denny, Peter Langguth, Hans Christian Probst, Hansjörg Schild, Markus P Radsak
BACKGROUND: The epidermal application of the Toll Like Receptor 7 agonist imiquimod and a T-cell peptide epitope (transcutaneous immunization, TCI) mediates systemic peptide-specific cytotoxic T-cell (CTL) responses and leads to tumor protection in a prophylactic tumor setting. However, it does not accomplish memory formation or permanent defiance of tumors in a therapeutic set-up. As a distinct immunologic approach, CTLA-4 blockade augments systemic immune responses and has shown long-lasting effects in preclinical experiments as well as in clinical trials...
June 16, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28658143/efficacy-and-safety-of-anti-pd-1-and-anti-pd-1-combined-with-anti-ctla-4-immunotherapy-to-advanced-melanoma-a-systematic-review-and-meta-analysis-of-randomized-controlled-trials
#14
REVIEW
Chunyan Hao, Jinhui Tian, Huiling Liu, Fei Li, Hongxia Niu, Bingdong Zhu
BACKGROUND: Anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, and anti-CTLA-4 antibody ipilimumab are being in clinic trials to treat melanoma. Here, we performed a meta-analysis to evaluate the efficacy and toxicity of them against advanced melanoma. METHODS: Eleven reports from 6 randomized control trials on treating metastatic melanoma, which were divided into 3 subgroups, nivolumab/pembrolizumab versus chemotherapy, nivolumab versus ipilimumab, and nivolumab-plus-ipilimumab versus ipilimumab, were included and the meta-analysis was performed for each subgroup...
June 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28654899/tumor-reductive-therapies-and-antitumor-immunity
#15
REVIEW
Huiqin Guo, Kangla Tsung
Tumor reductive therapy is to reduce tumor burden through direct killing of tumor cells. So far, there is no report on the connection between antitumor immunity and tumor reductive therapies. In the last few years, a new category of cancer treatment, immunotherapy, emerged and they are categorized separately from classic cytotoxic treatments (chemo and radiation therapy). The most prominent examples include cellular therapies (LAK and CAR-T) and immune checkpoint inhibitors (anti-PD-1 and CTLA-4). Recent advances in clinical immunotherapy and our understanding of the mechanism behind them revealed that these therapies have a closer relationship with classic cancer treatments than we thought...
June 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28653677/monitoring-immune-checkpoint-blockade-response-evaluation-and-biomarker-development
#16
REVIEW
Mizuki Nishino, Nikhil H Ramaiya, Hiroto Hatabu, F Stephen Hodi
Cancer immunotherapy using immune-checkpoint blockade (ICB) has created a paradigm shift in the treatment of advanced-stage cancers. The promising antitumour activity of monoclonal antibodies targeting the immune-checkpoint proteins CTLA-4, PD-1, and PD-L1 led to regulatory approvals of these agents for the treatment of a variety of malignancies. Patients might experience clinical benefits from treatment with these agents, despite unconventional patterns of tumour response that can be misinterpreted as disease progression, warranting a new, specific approach to evaluate responses to immunotherapy...
June 27, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28653573/the-future-of-immune-checkpoint-cancer-therapy-after-pd-1-and-ctla-4
#17
Andrew W Hahn, David M Gill, Sumanta K Pal, Neeraj Agarwal
The adaptive immune system plays an important role in eradicating malignant cells. Co-stimulatory and co-inhibitory signals to T cells though immune checkpoint receptors are involved in tumorigenesis and metastasis. Exploitation of immune checkpoint inhibitors, PD-1 and CTLA-4, with monoclonal antibodies has created impressive clinical responses. Many other immune checkpoint co-inhibitors and co-stimulators exist, including the B7 superfamily and tumor necrosis factor receptors superfamily. Here, we will examine co-inhibitors and co-stimulators beyond PD-1 and CTLA-4 that are being investigated in active clinical trials...
June 2017: Immunotherapy
https://www.readbyqxmd.com/read/28648699/prognostic-factors-and-outcomes-in-metastatic-uveal-melanoma-treated-with-programmed-cell-death-1-or-combined-pd-1-cytotoxic-t-lymphocyte-antigen-4-inhibition
#18
Markus V Heppt, Lucie Heinzerling, Katharina C Kähler, Andrea Forschner, Michael C Kirchberger, Carmen Loquai, Markus Meissner, Friedegund Meier, Patrick Terheyden, Beatrice Schell, Rudolf Herbst, Daniela Göppner, Felix Kiecker, David Rafei-Shamsabadi, Sebastian Haferkamp, Margit A Huber, Jochen Utikal, Mirjana Ziemer, Irmgard Bumeder, Christiane Pfeiffer, Susanne G Schäd, Christoph Schmid-Tannwald, Julia K Tietze, Thomas K Eigentler, Carola Berking
BACKGROUND: Uveal melanoma (UM) is an ocular malignancy with high potential for metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet shown convincing efficacy in patients with UM. Combined immune checkpoint blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed for UM to date. PATIENTS AND METHODS: Patients with metastatic UM treated with either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer centres...
June 21, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28648302/nephrotic-syndrome-with-cancer-immunotherapies-a-report-of-2-cases
#19
Abhijat Kitchlu, Warren Fingrut, Carmen Avila-Casado, Christopher T Chan, Michael Crump, David Hogg, Heather N Reich
Oncologic immunotherapies use a patient's immune response to eliminate tumor cells by modulation of immune checkpoints, including programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) proteins. Immune-mediated sequelae, including interstitial nephritis, have been reported; however, glomerular disease appears rare. We describe 2 cases of nephrotic syndrome in patients treated with these agents. Patient 1 received the anti-PD-1 antibody pembrolizumab for Hodgkin lymphoma. Following his second dose, he developed nephrotic syndrome and acute kidney injury...
June 22, 2017: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
https://www.readbyqxmd.com/read/28640512/a-major-responder-to-ipilimumab-and-nivolumab-in-metastatic-uveal-melanoma-with-concomitant-autoimmunity
#20
Pui Ying Chan, Peter Hall, Gordon Hay, Victoria M L Cohen, Peter W Szlosarek
The use of immune checkpoint inhibition has led to major improvements in outcome for patients with metastatic cutaneous melanoma. The combination of ipilimumab and nivolumab has demonstrated greater activity over single-agent immunotherapy in phase III trials. Clinical trials of combination CTLA-4 and PD-1 inhibition are underway in uveal melanoma, for which there are currently no data. Here, we present the case of a 74-year-old male patient with metastatic uveal melanoma, who was treated with a combination of ipilimumab and nivolumab...
June 22, 2017: Pigment Cell & Melanoma Research
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