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Gregory S Alexander, Joshua D Palmer, Madalina Tuluc, Jianqing Lin, Adam P Dicker, Voichita Bar-Ad, Larry A Harshyne, Jennifer Louie, Colette M Shaw, D Craig Hooper, Bo Lu
BACKGROUND: Pembrolizumab is a monoclonal antibody that is designed against programmed cell death protein 1 (PD-1). Pembrolizumab and other immunocheckpoint-blocking monoclonal antibodies work by modulating a patient's own immune system to increase anti-tumor activity. While immunocheckpoint blockade has shown promising results, only 20-40 % of patients experience objective clinical benefit. Differences in individual tumor biology and the presence multiple immune checkpoints present a challenge for treatment...
2016: Journal of Hematology & Oncology
T Mok, Y-L Wu, S Sadowski, J Zhang, R Rangwala, D Kush, G de Lima Lopes
No abstract text is available yet for this article.
April 2016: Journal of Thoracic Oncology
Toshio Shimizu, Takashi Seto, Fumihiko Hirai, Mitsuhiro Takenoyama, Kaname Nosaki, Junji Tsurutani, Hiroyasu Kaneda, Tsutomu Iwasa, Hisato Kawakami, Kazuo Noguchi, Takashi Shimamoto, Kazuhiko Nakagawa
Background This phase I study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of pembrolizumab in Japanese patients with advanced solid tumors. Methods Following an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W) until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1...
June 2016: Investigational New Drugs
Lajos Pusztai, Andrea Ladányi, Borbála Székely, Magdolna Dank
The prognostic value of tumor infiltrating lymphocytes in breast cancer has long been recognized by histopathologists. These observations were reaffirmed by recent immunohistochemistry and gene expression profiling studies that also revealed an association between greater chemotherapy sensitivity and extensive lymphocytic infiltration in early stage breast cancers treated with neoadjuvant chemotherapy. These results suggest that local anti-tumor immune response can at least partially control cancer growth and may mediate the antitumor effects of chemotherapy...
March 2, 2016: Magyar Onkologia
Safiya Karim, Natasha Leighl
New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit...
January 2016: Future Oncology
M Tan, L Quintal
WHAT IS KNOWN AND OBJECTIVE: To review the pharmacology, efficacy, safety, formulary and economic considerations of pembrolizumab, a novel, first-in-class, anti-PD-1 monoclonal antibody for treatment of advanced melanoma. METHODS: A literature search was conducted using PubMed (July 2013-December 2014) with search terms: pembrolizumab, MK-3475 and lambrolizumab. Additional sources were identified through a subsequent review of all relevant papers, clinicaltrials...
June 29, 2015: Journal of Clinical Pharmacy and Therapeutics
Meagan S Barbee, Adebayo Ogunniyi, Troy Z Horvat, Thu-Oanh Dang
OBJECTIVE: To provide the clinician with an update and the current status and future direction of approved immune checkpoint inhibitors (ICIs) in oncology. DATA SOURCES: A PubMed search from January 1, 1966 to March 13, 2015 was performed using the key terms ipilimumab, pembrolizumab, lambrolizumab, nivolumab, immune checkpoint inhibitor, MDX-010, MDX-101, BMS-734016, MK-3475, SCH 900475, MDX-1106, BMS-936558, ONO-4538, CTLA-4, PD-1, or PD-L1 and cancer, oncology, or neoplasm...
August 2015: Annals of Pharmacotherapy
Amita Patnaik, S Peter Kang, Drew Rasco, Kyriakos P Papadopoulos, Jeroen Elassaiss-Schaap, Muralidhar Beeram, Ronald Drengler, Cong Chen, Lon Smith, Guillermo Espino, Kevin Gergich, Liliana Delgado, Adil Daud, Jill A Lindia, Xiaoyun Nicole Li, Robert H Pierce, Jennifer H Yearley, Dianna Wu, Omar Laterza, Manfred Lehnert, Robert Iannone, Anthony W Tolcher
PURPOSE: This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0...
October 1, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Katelyn T Byrne, Robert H Vonderheide, Elizabeth M Jaffee, Todd D Armstrong
The overall objective of the fifth American Association for Cancer Research Special Conference, "Tumor Immunology and Immunotherapy: A New Chapter," organized by the Cancer Immunology Working Group, was to highlight multidisciplinary approaches of immunotherapy and mechanisms related to the ability of immunotherapy to fight established tumors. With the FDA approval of sipuleucel-T, ipilimumab (anti-CTLA-4; Bristol-Myers Squibb), and the two anti-PD-1 antibodies, pembrolizumab (formerly MK-3475 or lambrolizumab; Merck) and nivolumab (Bristol-Myers Squibb), immunotherapy has become a mainstream treatment option for some cancers...
May 12, 2015: Cancer Immunology Research
Blanca Homet Moreno, Giulia Parisi, Lidia Robert, Antoni Ribas
Immune-regulatory mechanisms are used by cancer to hide from the immune system. Advances and in-depth understanding of the biology of melanoma and its interaction with the immune system have led to the development of some of antagonistic antibodies to the programmed death 1 pathway (PD-1) and one of its ligands, programmed death ligand 1 (PD-L1), which are demonstrating high clinical benefit rates and tolerability. Blocking the immune-regulatory checkpoints that limit T-cell responses to melanoma upon PD-1/PD-L1 modulation has provided clinically validated targets for cancer immunotherapy...
June 2015: Seminars in Oncology
Tara C Gangadhar, April Ks Salama
Preclinical work has led to an increased understanding of the immunomodulatory mechanisms involved in the regulation of the antitumor response in a variety of tumor types. PD-1 (programmed death 1) appears to be a key checkpoint involved in immune suppression in the tumor microenvironment, even in diseases not previously thought to be sensitive to immune manipulation. More recently, the subsequent clinical development of PD-1-based therapy has resulted in a major breakthrough in the field of oncology. Pembrolizumab, a humanized highly selective IgG4 anti-PD-1 monoclonal antibody, was recently approved for the treatment of advanced melanoma based on promising early-phase clinical data...
2015: OncoTargets and Therapy
J McDermott, A Jimeno
Programmed cell death protein 1 (PD-1) and its ligands, programmed cell death 1 ligand 1 (PD-L1) and 2 (PD-L2) play an important role in regulating immune response through various mechanisms. This inhibitory action is thought to assist in immune evasion by cancer cells as PD-1, PD-L1 and PD-L2 have been found to be abnormally expressed by tumor cells and lymphocytes in the tumor microenvironment. Preclinical studies described PD-1 blockade resulting in tumor growth suppression and even decreased metastasis...
January 2015: Drugs of Today
Peter Hersey, Kavitha Gowrishankar
Pembrolizumab (MK-3475) is a monoclonal antibody that binds to the PD-1 receptor on T cells and prevents binding to its ligands PD-L1 and PD-L2. Blocking this receptor frees T cells from the inhibitory effects of PD-L1 and allows them to mediate antitumor effects against cancer cells. In a large Phase I study of 411 patients with melanoma, high durable response rates over a range of doses and schedules have been shown with very little toxicity. A Phase III study of pembrolizumab comparing two schedules of administration with the current standard treatment with the anti-CTLA-4 monoclonal antibody is in progress...
2015: Future Oncology
Richard W Joseph, Mark Cappel, Brent Goedjen, Matthew Gordon, Brandon Kirsch, Cheryl Gilstrap, Sanjay Bagaria, Anokhi Jambusaria-Pahlajani
Therapies that activate the immune system through blocking the binding of programmed death ligand 1 (PD-L1) present on tumors and PD-1 (programmed death 1) present on activated immune cells are revolutionizing the care for patients with cancer. These therapies work by inhibiting negative regulators of the immune system, thereby decreasing a tumor's ability to evade the immune system. The side effects of anti-PD-1/PD-L1 therapies are generally mild and as expected are related to autoimmune reactions. Two of the most common side effects of anti-PD-1/PD-L1 therapies are rash and pruritus occurring in approximately 20% of patients...
January 2015: Cancer Immunology Research
Melinda Yushak, Harriet M Kluger, Mario Sznol
Prior to 2011, the only commercially available agents commonly used to treat metastatic melanoma-including dacarbazine, temozolomide (Temodar), fotemustine, carboplatin, paclitaxel, and interleukin-2-demonstrated limited efficacy, and no study involving these agents had shown an improvement in overall survival. The standard of care for the treatment of metastatic melanoma was radically changed by the subsequent approval of two agents, ipilimumab (Yervoy) and vemurafenib (Zelboraf), both of which improved survival in randomized phase III trials...
May 2013: Oncology (Williston Park, NY)
(no author information available yet)
No abstract text is available yet for this article.
August 2014: Cancer Discovery
Jing Lu, Linda Lee-Gabel, Michelle C Nadeau, Thomas M Ferencz, Scott A Soefje
Significant enthusiasm currently exists for new immunotherapeutic strategies: blocking the interaction between programmed death-1 receptor on T-cells and programmed death-ligand 1 on tumor cells to boost immune system stimulation to fight cancer. Immunomodulation with the antiprogrammed death-1/programmed death-ligand 1 monoclonal antibodies has shown to mediate tumor shrinkage and extend overall survival from several pivotal phase I/II studies in melanoma, renal cell carcinoma, and non-small cell lung cancer...
December 2015: Journal of Oncology Pharmacy Practice
(no author information available yet)
No abstract text is available yet for this article.
May 2014: Cancer Discovery
Le Min, F Stephen Hodi
Treatment with fully human monoclonal antibodies against programmed death 1 (PD1) receptor has shown great promise for a number of advanced malignancies. Although inflammatory adverse events have been well described with anti-CTL antigen 4 (CTLA4) therapy, experience with the range of adverse effects of anti-PD1 remains comparatively limited. Here, we report on a patient with advanced mucosal melanoma who received four doses of MK-3475, a fully human monoclonal antibody against PD1, and experienced a durable near-complete response but developed severe hypothyroidism, rhabdomyolysis, and acute kidney injury...
January 2014: Cancer Immunology Research
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