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Hamid O.,Angeles Clinic and Research Institute | Goldenberg G.,Mount Sinai School of Medicine
Journal of Drugs in Dermatology | Year: 2013

Basal cell carcinoma (BCC) is a common skin cancer and its incidence is on the rise worldwide. Clinical presentation and histologic examination are used for diagnosis and to stratify BCCs as either low- or high-risk for recurrence or development of advanced disease. A number of surgical and nonsurgical options are available for BCC. BCC is most often managed with a surgical approach, but not all tumors and patients are suitable for surgery. Vismodegib is a recently approved first-in-class hedgehog pathway inhibitor that has expanded options for patients who have locally advanced or metastatic BCC. Copyright © 2013. Source


Hamid O.,Angeles Clinic and Research Institute | Carvajal R.D.,Sloan Kettering Cancer Center
Expert Opinion on Biological Therapy | Year: 2013

Introduction: Multiple agents targeting the immune "checkpoint" programmed death-1 (PD-1) pathway have demonstrated early evidence of durable clinical activity and an encouraging safety profile in patients with various tumor types, including some cancers, such as non-small-cell lung cancer, historically perceived as non-immunogenic and thus nonresponsive to immunotherapy. Areas covered: Functions of the PD-1 pathway in normal immune responses are reviewed, along with the significance of expression of PD-1 and its ligands in malignant settings. Rationale for the development of PD-1 pathway-targeted therapies and associated clinical data are presented. Finally, efforts to date to identify and develop partner predictive or prognostic biomarkers for these new PD-1 pathway-targeted immunotherapies are discussed. Expert opinion: Rather than targeting the tumor directly, immunotherapies inhibiting PD-1 pathway signaling modulate the antitumor immune response. Indeed, these agents have already demonstrated promising antitumor activity and manageable toxicity in various cancers. If future data continue to support encouraging clinical profiles of anti-PD-1 and anti-programmed death-ligand 1 antibodies, the current paradigm of cancer therapy may shift. In select patient populations (ideally identified by a predictive biomarker), PD-1 pathway-targeted immunotherapy has the potential to serve as the backbone of cancer treatment, and trials evaluating combinations with chemotherapy and/or molecularly targeted therapies will determine whether additive or even synergistic responses can be achieved. © 2013 Informa UK, Ltd. Source


Ledezma B.,University of California at Los Angeles | Heng A.,Angeles Clinic and Research Institute
Cancer Management and Research | Year: 2014

After decades without promising new treatments for advanced and metastatic melanoma, ipilimumab was the first systemic therapy approved for use in this patient population. A fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4) to augment antitumor T-cell responses, ipilimumab significantly extended overall survival in clinical trials. Because ipilimumab is associated with a set of immune-related adverse events that likely reflect the agent's mechanism of action, a management guide has been established. Nurses play a significant role in initially identifying these adverse reactions and assisting in patient education, treatment, and follow-up. Herein, we discuss commonly asked questions related to ipilimumab therapy and treatment of adverse events, and how nurses can be prepared to answer these questions as they arise from patients and caregivers. © 2014 Ledezma and Heng, This work is published by Dove Medical Press Limited. Source


Herbst R.S.,Yale University | Soria J.-C.,Gustave Roussy South Paris University | Kowanetz M.,Genentech | Fine G.D.,Genentech | And 18 more authors.
Nature | Year: 2014

The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system1-4. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment5. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing6-10. The PD-L1-PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections11. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH 1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment. © 2014 Macmillan Publishers Limited. All rights reserved. Source


Garon E.B.,University of California at Los Angeles | Rizvi N.A.,Columbia University | Hui R.,University of Sydney | Leighl N.,Princess Margaret Cancer Center | And 23 more authors.
New England Journal of Medicine | Year: 2015

BACKGROUND: We assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non-small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. METHODS: We assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review. RESULTS: Common side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all the patients, the objective response rate was 19.4%, and the median duration of response was 12.5 months. The median duration of progression-free survival was 3.7 months, and the median duration of overall survival was 12.0 months. PD-L1 expression in at least 50% of tumor cells was selected as the cutoff from the training group. Among patients with a proportion score of at least 50% in the validation group, the response rate was 45.2%. Among all the patients with a proportion score of at least 50%, median progression-free survival was 6.3 months; median overall survival was not reached. CONCLUSIONS: Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab. Copyright © 2015 Massachusetts Medical Society. Source

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