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immune-checkpoint blockers

Antonin Levy, Christophe Massard, Jean-Charles Soria, Eric Deutsch
PURPOSE: To assess preliminary safety and efficacy results of the anti-programmed cell death ligand-1 (anti-PD-L1) durvalumab in combination with radiotherapy (RT) in an expansion cohort of patients included in a phase 1/2 trial at our institution. PATIENTS AND METHODS: Data from patients who received concurrent palliative RT with durvalumab (10 mg/kg every 2 weeks via intravenous infusion) were analysed in terms of safety (CTCAE v4.0) and efficacy (RECIST v1.1 and tumour growth rate [TGR])...
October 17, 2016: European Journal of Cancer
Erika Vacchelli, Norma Bloy, Fernando Aranda, Aitziber Buqué, Isabelle Cremer, Sandra Demaria, Alexander Eggermont, Silvia Chiara Formenti, Wolf Hervé Fridman, Jitka Fucikova, Jérôme Galon, Radek Spisek, Eric Tartour, Laurence Zitvogel, Guido Kroemer, Lorenzo Galluzzi
Malignant cells succumbing to some forms of radiation therapy are particularly immunogenic and hence can initiate a therapeutically relevant adaptive immune response. This reflects the intrinsic antigenicity of malignant cells (which often synthesize a high number of potentially reactive neo-antigens) coupled with the ability of radiation therapy to boost the adjuvanticity of cell death as it stimulates the release of endogenous adjuvants from dying cells. Thus, radiation therapy has been intensively investigated for its capacity to improve the therapeutic profile of several anticancer immunotherapies, including (but not limited to) checkpoint blockers, anticancer vaccines, oncolytic viruses, Toll-like receptor (TLR) agonists, cytokines, and several small molecules with immunostimulatory effects...
2016: Oncoimmunology
Naoshi Nishida, Masatoshi Kudo
Accumulation of genetic and epigenetic alterations is a hallmark of cancer genomes, including those in hepatocellular carcinoma (HCC). Particularly, in human HCC, epigenetic changes are more frequently observed than genetic changes in a variety of cancer-related genes, suggesting a potential role for epigenetic alterations during hepatocarcinogenesis. Several environmental factors, such as inflammation, obesity, and steatosis, are reported to affect the epigenetic status in hepatocytes, which could play a role in HCC development...
2016: Digestive Diseases
Laurence Zitvogel, Jonathan M Pitt, Romain Daillère, Mark J Smyth, Guido Kroemer
Fundamental cancer research and the development of efficacious antineoplastic treatments both rely on experimental systems in which the relationship between malignant cells and immune cells can be studied. Mouse models of transplantable, carcinogen-induced or genetically engineered malignancies - each with their specific advantages and difficulties - have laid the foundations of oncoimmunology. These models have guided the immunosurveillance theory that postulates that evasion from immune control is an essential feature of cancer, the concept that the long-term effects of conventional cancer treatments mostly rely on the reinstatement of anticancer immune responses and the preclinical development of immunotherapies, including currently approved immune checkpoint blockers...
September 30, 2016: Nature Reviews. Cancer
U Leiter, R Gutzmer, M Alter, C Ulrich, A S Lonsdorf, M M Sachse, U Hillen
Squamous cell carcinoma (SCC) of the skin accounts for 20 % of non-melanoma skin cancer and is one of the most frequent types of cancer in Caucasian populations. Diagnosis is based on the clinical features and should be histopathologically confirmed to adequately address the prognosis and treatment. Complete surgical excision with histopathological control of excision margins is the gold standard in the treatment of primary SCC. Sentinel lymph node biopsies (SLNB) can be considered in SCC with a tumor thickness of >6 mm but there is currently no evidence concerning prognostic and therapeutic effects...
September 28, 2016: Der Hautarzt; Zeitschrift Für Dermatologie, Venerologie, und Verwandte Gebiete
Florence T H Wu, Shan Man, Ping Xu, Annabelle Chow, Marta Paez-Ribes, Christina R Lee, Steven R Pirie-Shepherd, Urban Emmenegger, Robert S Kerbel
Antiangiogenic tyrosine kinase inhibitors (TKIs) that target VEGF receptor-2 (VEGFR2) have not been effective as adjuvant treatments for micrometastatic disease in phase III trials. Angiopoietin-2 (Ang2) is a pro-angiogenic and pro-inflammatory vascular destabilizer that cooperates with VEGF. The purpose of this study was to test whether CVX-060 (an Ang2-specific CovX-body) can be combined with VEGFR2-targeting TKIs (sunitinib or regorafenib) to successfully treat postsurgical metastatic disease in multiple orthotopically implanted human tumor xenograft and syngeneic murine tumor models...
September 20, 2016: Cancer Research
Saskia Herz, Thomas Höfer, Matina Papapanagiotou, Julia Christina Leyh, Sarah Meyenburg, Dirk Schadendorf, Selma Ugurel, Alexander Roesch, Elisabeth Livingstone, Bastian Schilling, Cindy Franklin
BACKGROUND: Immune-checkpoint inhibitors have been approved for the treatment of metastatic melanoma based on several phase III trials. Patients after organ transplantation and patients with impaired renal function were excluded from these studies. Recently, allograft rejections were reported in organ transplant recipients receiving PD-1 blocking antibodies. PATIENTS AND FINDINGS: Four patients with metastatic melanoma and impaired kidney function (baseline serum creatinine 1...
November 2016: European Journal of Cancer
Satoru Senju
Antibody-based anti-cancer immunotherapy was recently recognized as one of the truly effective therapies for cancer patients. Antibodies against cell surface cancer antigens, such as CD20, and also those against immune-inhibitory molecules called "immune checkpoint blockers", such as CTLA4 or PD1, have emerged. Large-scale clinical trials have confirmed that, in some cases, antibody-based drugs are superior to conventional chemotherapeutic agents. These antibody-based drugs are now being manufactured employing a mass-production system by pharmaceutical companies...
August 2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Michael B Atkins, George K Philips
INTRODUCTION: Advanced renal cell carcinoma (RCC) was considered refractory to most cancer therapies until the 1980s, after which immune modulating agents and targeted agents were developed. Recently the rapid development of therapeutic monoclonal antibodies targeting immune checkpoint pathways has provided significant clinical benefit in patients with many distinct cancer types. Nivolumab, an anti-PD1 monoclonal antibody showed improvement in response rate and overall survival in patients with previously treated RCC and received US FDA approval in late 2015...
September 2016: Expert Opinion on Emerging Drugs
Maria Del Castillo, Fabian A Romero, Esther Argüello, Chrisann Kyi, Michael A Postow, Gil Redelman-Sidi
The risk of infection among patients receiving immune checkpoint blockade is unknown. We retrospectively reviewed medical records of 740 melanoma patients who received immune checkpoint blockers. Serious infection occurred in 54 patients (7.3%). The main risk factors were receipt of corticosteroids and/or infliximab.
August 7, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Ilinca Popp, Anca Ligia Grosu, Gabriele Niedermann, Dan G Duda
Stereotactic body radiation therapy (SBRT) has become an attractive treatment modality and a safe, non-invasive alternative to surgery to control primary or secondary malignant tumors. While emphasis has been on the local tumor control as a treatment objective for SBRT, the rare but intriguing observations of abscopal (or out-of-field) effects have pointed to the exciting possibility of activating anti-tumor immunity by using high-dose radiation. This review summarizes the available evidence supporting immune modulation by SBRT alone, as well as its potential combination with immunotherapy...
August 2016: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
Christine Mateus, Cristina Libenciuc, Caroline Robert
ANTI-PD1 ROLE IN TREATMENT OF CUTANEOUS MELANOMA: The treatment of metastatic melanoma dramatically changed over the last years. Two therapeutic revolutions emerged in parallel, targeted anti-BRAF and anti-MEK therapies, for patients BRAFV600 mutated and immunotherapy with immune checkpoint blockers using anti-CTLA-4 then anti-PD1 monoclonal antibodies. Indeed, melanoma immunotherapy was a golden objective for many years but in spite of important efforts using cytokines (interferon, interleukin) and different vaccine approaches no objective improvement of patients 'prognosis was obtained...
June 2016: Bulletin du Cancer
Guido Kroemer, Lorenzo Galluzzi, Laurence Zitvogel
A paper recently published in Science Translational Medicine describes a next-generation antisense oligonucleotide that specifically downregulates the expression of human signal transducer and activator of transcription 3 (STAT3). Such an oligonucleotide, AZD9150, exerts antineoplastic effects on a selected panel of STAT3-dependent human cancer cells growing in vitro and in vivo (as xenografts in immunodeficient mice). Moreover, preliminary data from a Phase I clinical trial indicate that AZD9150 may cause partial tumor regression in patients with chemorefractory lymphoma and non-small cell lung carcinoma...
May 2016: Oncoimmunology
Rémi Fromentin, Wendy Bakeman, Mariam B Lawani, Gabriela Khoury, Wendy Hartogensis, Sandrina DaFonseca, Marisela Killian, Lorrie Epling, Rebecca Hoh, Elizabeth Sinclair, Frederick M Hecht, Peter Bacchetti, Steven G Deeks, Sharon R Lewin, Rafick-Pierre Sékaly, Nicolas Chomont
HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4+ T cells expressing immune checkpoint molecules would be enriched in HIV-infected cells in individuals receiving suppressive ART. Expression levels of 7 immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIGIT, TIM-3, CD160 and 2B4) as well as 4 markers of HIV persistence (integrated and total HIV DNA, 2-LTR circles and cell-associated unspliced HIV RNA) were measured in PBMCs from 48 virally suppressed individuals...
July 2016: PLoS Pathogens
(no author information available yet)
Studying checkpoint blockers and other new immunotherapies is challenging in traditional mouse models because the animals lack B and T cells and have impaired innate immunity. To address these shortcomings, researchers are making progress in reconstituting the human immune system in immunodeficient mouse models.
August 2016: Cancer Discovery
Roman M Chabanon, Marion Pedrero, Céline Lefebvre, Aurélien Marabelle, Jean-Charles Soria, Sophie Postel-Vinay
Immunotherapy is currently transforming cancer treatment. Notably, immune checkpoint blockers (ICB) have shown unprecedented therapeutic successes in numerous tumor types, including cancers that were traditionally considered as nonimmunogenic. However, a significant proportion of patients do not respond to these therapies. Thus, early selection of the most sensitive patients is key, and the development of predictive companion biomarkers constitutes one of the biggest challenges of ICB development. Recent publications have suggested that the tumor genomic landscape, mutational load, and tumor-specific neoantigens are potential determinants of the response to ICB and can influence patients' outcomes upon immunotherapy...
September 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Carole Helissey, Cécile Vicier, Stéphane Champiat
Monoclonal antibodies targeting immune checkpoint molecules CTLA-4, PD-1 or PD-L1 are emerging as promising anticancer therapeutics in multiple cancer subtypes resulting in remarkable and long-lasting clinical responses. These immune checkpoint blockers (ICBs) have already obtained approval for the treatment of patients with metastatic melanoma, advanced/refractory non-small cell lung cancer and renal cell cancer. ICBs enhance immune responses against cancer cells but can also lead to inflammatory side effects called immune-related adverse events (irAEs)...
September 2016: Journal of Geriatric Oncology
Elisa González-Rodríguez, Delvys Rodríguez-Abreu
UNLABELLED: : In recent years, immune checkpoint inhibitors have emerged as effective therapies for advanced neoplasias. As new checkpoint target blockers become available and additional tumor locations tested, their use is expected to increase within a short time. Immune-related adverse events (irAEs) affecting the endocrine system are among the most frequent and complex toxicities. Some may be life-threatening if not recognized; hence, appropriate guidance for oncologists is needed...
July 2016: Oncologist
Masaru Katoh
Fibroblast growth factor (FGF)2, FGF4, FGF7 and FGF20 are representative paracrine FGFs binding to heparan-sulfate proteoglycan and fibroblast growth factor receptors (FGFRs), whereas FGF19, FGF21 and FGF23 are endocrine FGFs binding to Klotho and FGFRs. FGFR1 is relatively frequently amplified and overexpressed in breast and lung cancer, and FGFR2 in gastric cancer. BCR-FGFR1, CNTRL-FGFR1, CUX1-FGFR1, FGFR1OP-FGFR1, MYO18A-FGFR1 and ZMYM2-FGFR1 fusions in myeloproliferative neoplasms are non-receptor-type FGFR kinases, whereas FGFR1-TACC1, FGFR2-AFF3, FGFR2-BICC1, FGFR2-PPHLN1, FGFR3-BAIAP2L1 and FGFR3-TACC3 fusions in solid tumors are transmembrane-type FGFRs with C-terminal alterations...
July 2016: International Journal of Molecular Medicine
Erika Vacchelli, Fernando Aranda, Norma Bloy, Aitziber Buqué, Isabelle Cremer, Alexander Eggermont, Wolf Hervé Fridman, Jitka Fucikova, Jérôme Galon, Radek Spisek, Laurence Zitvogel, Guido Kroemer, Lorenzo Galluzzi
During the past decade, great efforts have been dedicated to the development of clinically relevant interventions that would trigger potent (and hence potentially curative) anticancer immune responses. Indeed, developing neoplasms normally establish local and systemic immunosuppressive networks that inhibit tumor-targeting immune effector cells, be them natural or elicited by (immuno)therapy. One possible approach to boost anticancer immunity consists in the (generally systemic) administration of recombinant immunostimulatory cytokines...
February 2016: Oncoimmunology
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