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https://www.readbyqxmd.com/read/28076863/adverse-renal-effects-of-immune-checkpoint-inhibitors-a-narrative-review
#1
Rimda Wanchoo, Sabine Karam, Nupur N Uppal, Valerie S Barta, Gilbert Deray, Craig Devoe, Vincent Launay-Vacher, Kenar D Jhaveri
BACKGROUND: Cancer immunotherapy, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death 1 (PD-1), has revolutionized the treatment of malignancies by engaging the patient's own immune system against the tumor rather than targeting the cancer directly. These therapies have demonstrated a significant benefit in the treatment of melanomas and other cancers. SUMMARY: In order to provide an extensive overview of the renal toxicities induced by these agents, a Medline search was conducted of published literature related to ipilimumab-, pembrolizumab-, and nivolumab-induced kidney toxicity...
January 12, 2017: American Journal of Nephrology
https://www.readbyqxmd.com/read/28062513/metastatic-melanoma-patient-had-complete-response-with-clonal-expansion-after-whole-brain-radiation-and-pd-1-blockade
#2
Cara L Haymaker, DaeWon Kim, Marc Uemura, Luis M Vence, Ann Phillip, Natalie McQuail, Paul D Brown, Irina Fernandez, Courtney W Hudgens, Caitlin Creasy, Wen-Jen Hwu, Padmanee Sharma, Michael T Tetzlaff, James P Allison, Patrick Hwu, Chantale Bernatchez, Adi Diab
We report here on a patient with metastatic melanoma who had extensive brain metastases. After being treated with the sequential combination of whole brain radiation therapy (WBRT) followed by the PD-1 inhibitory antibody, pembrolizumab, the patient had a durable complete response. Retrospective laboratory studies of T cells revealed that, after treatment with anti-PD-1 commenced, effector CD8(+) T cells in the blood expanded and the ratio of CD8(+):Treg T cells increased. A CD8(+) T-cell clone present in the initial brain metastases was expanded in the blood after anti-PD-1 treatment, which suggested an antitumor role for this clone...
January 6, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28057179/biomarqueurs-pr%C3%A3-dictifs-de-r%C3%A3-ponse-aux-traitements-bloquant-les-voies-de-costimulation-inhibitrices
#3
Franck Pagès, Clémence Granier, Amos Kirilovsky, Carine Elsissy, Eric Tartour
Immunotherapies targeting co-inhibitory receptors recently open a new promising approach of cancer treatment. Indeed, an objective clinical response was observed after treatment by anti-CTLA-4 and anti-PD-1 in many indications but the treatment still failed in 70 to 80 % of cases treated. Given the adverse effects and the high cost of these therapies, there is a need for the development of biomarkers. This review focus on potential predictive biomarkers. In peripheral blood, high level of Il-2 soluble receptor at baseline and absence of ICOS+ CD4-T lymphocytes induction may be associated with the absence of clinical response for melanoma patients treated by ipilimumab (anti-CTLA-4)...
November 2016: Bulletin du Cancer
https://www.readbyqxmd.com/read/28057176/immunoth%C3%A3-rapie-et-m%C3%A3-lanome-l%C3%A2-exemple-des-anticorps-immunomodulateurs
#4
Cécile Pagès, Barouyr Baroudjian, Celeste Lebbé
Recently, metastatic melanoma has known real therapeutic improvement. Since 2011, 8 drugs have been approved for advanced melanoma such as immunotherapy checkpoint inhibitors. Chemotherapy is no longer used in the first setting of metastatic melanoma treatment. In 2010, the advent of ipilimumab, an anti CTLA 4 inhibitor, changed the scenario and in the following years, many studies confirmed the efficacy of nivolumab and pembrolizumab, two anti PD 1 inhibitors, as a first line treatment. Furthermore, the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma...
November 2016: Bulletin du Cancer
https://www.readbyqxmd.com/read/28055269/targeting-pd-1-pathway-a-new-hope-for-gastrointestinal-cancers
#5
Burak Bilgin, Mehmet An Sendur, Muhammed Bülent Akıncı, Didem Şener Dede, Bülent Yalçın
BACKGROUND: VEGF, HER2 and EGFR targeted agents are currently used in gastric, esophageal and colorectal cancers. However, treatment outcomes are still poor in most of the Gastrointestinal (GI) cancers. Immune checkpoints are one of the most promising immunotherapy approaches. In this review article, we aimed to discuss the efficacy and safety of anti-PD-1/PD-L1 therapies in GI cancers, including gastric, esophageal and colorectal cancer in the era of published or reported recent studies...
January 5, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28039358/stromal-senescence-by-prolonged-cdk4-6-inhibition-potentiates-tumor-growth
#6
Xiangnan Guan, Kyle M LaPak, Rebecca C Hennessey, Christina Y Yu, Reena Shakya, Jianying Zhang, Christin E Burd
: Senescent cells within the tumor microenvironment (TME) adopt a pro-inflammatory, senescence-associated secretory phenotype (SASP) that promotes cancer initiation, progression and therapeutic resistance. Here, exposure to Palbociclib (PD-0332991), a CDK4/6 inhibitor, induces senescence and a robust SASP in normal fibroblasts. Senescence caused by prolonged CDK4/6 inhibition is DNA damage-independent and associated with Mdm2 downregulation, whereas the SASP elicited by these cells is largely reliant upon NF-kappaB activation...
December 30, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28003187/angiopoietin-2-as-a-biomarker-and-target-for-immune-checkpoint-therapy
#7
Xinqi Wu, Anita Giobbie-Hurder, Xiaoyun Liao, Courtney Connelly, Erin M Connolly, Jingjing Li, Michael P Manos, Donald Lawrence, David McDermott, Mariano Severgnini, Jun Zhou, Evisa Gjini, Ana Lako, Mikel Lipschitz, Christine J Pak, Sara Abdelrahman, Scott Rodig, F Stephen Hodi
Immune checkpoint therapies targeting CTLA-4 and PD-1 have proven effective in cancer treatment. However, the identification of biomarkers for predicting clinical outcomes and mechanisms to overcome resistance remain as critical needs. Angiogenesis is increasingly appreciated as an immune modulator with potential for combinatorial use with checkpoint blockade. Angiopoietin-2 (ANGPT2) is an immune target in patients and is involved in resistance to anti-VEGF treatment with the monoclonal antibody bevacizumab...
January 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28000240/epidermal-anti-programmed-cell-death-ligand-1-expression-in-ten-associated-with-nivolumab-therapy
#8
Karina L Vivar, Maria Deschaine, Jane Messina, Jennifer M Divine, Alejandro Rabionet, Nishit Patel, Michael A Harrington, Lucia Seminario-Vidal
BACKGROUND: Nivolumab is an anti-programmed cell death receptor-1 (PD-1) antibody used in the treatment of metastatic or unresectable melanoma. Cutaneous reactions are the most common adverse events reported with these agents and are rarely severe or life-threatening. METHODS: Case report describing the clinicopathological findings of a patient with a fatal toxic epidermal necrolysis (TEN) eruption associated with use of nivolumab for treatment of metastatic melanoma...
December 21, 2016: Journal of Cutaneous Pathology
https://www.readbyqxmd.com/read/27999741/characterization-of-nivolumab-associated-skin-reactions-in-patients-with-metastatic-non-small-cell-lung-cancer
#9
Omar Hasan Ali, Stefan Diem, Eva Markert, Wolfram Jochum, Katrin Kerl, Lars E French, Daniel E Speiser, Martin Früh, Lukas Flatz
Immune checkpoint inhibitors have led to considerable therapy improvement in cancer patients. Autoimmune side effects including skin reactions are frequently observed. In melanoma, those include rash and vitiligo and were shown to be associated with a prolonged overall survival. Little is known about skin reactions in non-small cell lung cancer (NSCLC) patients during immunotherapy. Here, we retrospectively investigated immune-related adverse skin reactions (irAEs) in 40 patients with metastatic NSCLC treated with the anti-PD-1 antibody nivolumab...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27989216/the-safety-of-talimogene-laherparepvec-for-the-treatment-of-advanced-melanoma
#10
Alexandra Gangi, Jonathan S Zager
Talimogene laherparepvec (T-VEC, IMLYGIC) is an oncolytic herpes virus type I used as intralesional therapy for the treatment of unresectable metastatic melanoma in a cutaneous, subcutaneous, or nodal location. Talimogene laherparepvec selectively replicates within and lyses tumor cells while producing granulocyte macrophage colony-stimulating factor (GM-CSF), which may promote an immune mediated antitumor response. Areas covered: The US Food and Drug Administration approved Talimogene laherparepvec in late 2015 following the completion of phase I, II and III trials that demonstrated safety and efficacy...
December 28, 2016: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/27951441/resistance-to-pd1-pdl1-checkpoint-inhibition
#11
REVIEW
Jake S O'Donnell, Georgina V Long, Richard A Scolyer, Michele W L Teng, Mark J Smyth
For the first time in decades, patients with difficult-to-treat cancers such as advanced stage metastatic melanoma are being offered a glimpse of hope in the form of immunotherapies. By targeting factors that foster the development and maintenance of an immunosuppressive microenvironment within tumors, these therapies release the brakes on the host's own immune system; allowing cure of disease. Indeed, phase III clinical trials have revealed that therapies such as ipilimumab and pembrolizumab which target the CTLA4 and PD-1 immune checkpoints, respectively, have raised the three-year survival of patients with melanoma to ∼70%, and overall survival (>5years) to ∼30%...
January 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/27940380/biomimetic-biodegradable-artificial-antigen-presenting-cells-synergize-with-pd-1-blockade-to-treat-melanoma
#12
A K Kosmides, R A Meyer, J W Hickey, K Aje, K N Cheung, J J Green, J P Schneck
Biomimetic materials that target the immune system and generate an anti-tumor responses hold promise in augmenting cancer immunotherapy. These synthetic materials can be engineered and optimized for their biodegradability, physical parameters such as shape and size, and controlled release of immune-modulators. As these new platforms enter the playing field, it is imperative to understand their interaction with existing immunotherapies since single-targeted approaches have limited efficacy. Here, we investigate the synergy between a PLGA-based artificial antigen presenting cell (aAPC) and a checkpoint blockade molecule, anti-PD1 monoclonal antibody (mAb)...
February 2017: Biomaterials
https://www.readbyqxmd.com/read/27903500/primary-resistance-to-pd-1-blockade-mediated-by-jak1-2-mutations
#13
Daniel Sanghoon Shin, Jesse M Zaretsky, Helena Escuin-Ordinas, Angel Garcia-Diaz, Siwen Hu-Lieskovan, Anusha Kalbasi, Catherine S Grasso, Willy Hugo, Salemiz Sandoval, Davis Y Torrejon, Nicolaos Palaskas, Gabriel Abril Rodriguez, Giulia Parisi, Ariel Azhdam, Bartosz Chmielowski, Grace Cherry, Elizabeth Seja, Beata Berent-Maoz, I Peter Shintaku, Dung Thi Le, Drew M Pardoll, Luis A Diaz, Paul C Tumeh, Thomas G Graeber, Roger S Lo, Begoña Comin-Anduix, Antoni Ribas
Loss of function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned they may also be involved in primary resistance to anti-PD-1 therapy. JAK1/2 inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to lack of PD-L1 expression upon interferon gamma exposure mediated by inability to signal through the interferon gamma receptor pathway...
November 30, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27895920/pd1-pd-l1-inhibition-as-a-potential-radiosensitizer-in-head-and-neck-squamous-cell-carcinoma-a-case-report
#14
Misako Nagasaka, Mark Zaki, Harold Kim, S Naweed Raza, George Yoo, Ho-Sheng Lin, Ammar Sukari
BACKGROUND: Immunotherapy targeting the checkpoint PD1 (programmed cell death protein 1) or PDL1 (programmed death ligand 1) has led to advances in the treatment of melanoma and non-small cell lung cancer (NSCLC). The use of such therapies has also been introduced into the treatment of other malignancies, including head and neck cancer. The combined effects of checkpoint inhibitors and anti-PD1(L1) antibodies and radiation therapy have not yet been sufficiently investigated. CASE PRESENTATION: We report a case of locally relapsed non-resectable oral cavity squamous cell carcinoma, with excellent local control after pembrolizumab (MK3475) followed by radiotherapy...
2016: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/27892744/evaluation-of-efficacy-and-safety-of-different-pembrolizumab-dose-schedules-in-treatment-of-non-small-cell-lung-cancer-and-melanoma-a-systematic-review
#15
Omar Abdel-Rahman
AIM: Pembrolizumab is a fully humanized anti-PD-1 agent currently approved for the treatment of advanced melanoma and pretreated non-small-cell lung cancer (NSCLC). OBJECTIVE: To assess the efficacy and safety of different dose schedules of pembrolizumab in the treatment of patients with advanced NSCLC and melanoma. Search method: MEDLINE database has been searched. Reference lists of original studies and review articles were checked for other related articles. SELECTION CRITERIA: Prospective clinical trials reporting the outcomes of more than one dose schedule of pembrolizumab in the treatment of advanced NSCLC and melanoma...
December 2016: Immunotherapy
https://www.readbyqxmd.com/read/27886124/advances-in-cancer-immunotherapy-in-solid-tumors
#16
REVIEW
Smitha Menon, Sarah Shin, Grace Dy
Immunotherapy is heralded as one of the most important advances in oncology. Until recently, only limited immunotherapeutic options were available in selected immunogenic cancers like melanoma and renal cell carcinomas. Nowadays, there is an improved understanding that anti-tumor immunity is controlled by a delicate balance in the tumor microenvironment between immune stimulatory and immune inhibitory pathways. Either by blocking the inhibitory pathways or stimulating the activating pathways that regulate cytotoxic lymphocytes, anti-tumor immunity can be enhanced leading to durable anti-tumor responses...
November 24, 2016: Cancers
https://www.readbyqxmd.com/read/27879972/responses-of-metastatic-basal-cell-and-cutaneous-squamous-cell-carcinomas-to-anti-pd1-monoclonal-antibody-regn2810
#17
Gerald S Falchook, Rom Leidner, Elizabeth Stankevich, Brian Piening, Carlo Bifulco, Israel Lowy, Matthew G Fury
BACKGROUND: Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC) share exposure to UV light as the dominant risk factor, and these tumors therefore harbor high mutation burdens. In other malignancies, high mutation burden has been associated with clinical benefit from therapy with antibodies directed against the Programmed Death 1 (PD-1) immune checkpoint receptor. Highly mutated tumors are more likely to express immunogenic tumor neoantigens that attract effector T cells, which can be unleashed by blockade of the PD-1 immune checkpoint...
2016: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/27873302/ultrasonographic-findings-can-identify-pseudoprogression-under-nivolumab-therapy
#18
K Imafuku, H Hata, S Kitamura, T Yanagi, H Shimizu
'Pseudoprogression' is often seen in patients with melanomas who are treated with immune-checkpoint inhibitors such as nivolumab or ipilimumab. We sometimes evaluate metastatic lesions by imaging tests such as CT or PET-CT. 'Pseudoprogression' usually occurs upon the initial administration, which may make it difficult for the physician to determine the disease condition. In our two cases of metastatic melanoma treated with nivolumab (anti-PD-1 antibody), we examined the ultrasonography (US) of target lesions that could be accessed from the body surface, such as those of the regional lymph node or subcutaneous metastasis...
November 22, 2016: British Journal of Dermatology
https://www.readbyqxmd.com/read/27863197/programmed-death-ligand-1-expression-and-response-to-the-anti-programmed-death-1-antibody-pembrolizumab-in-melanoma
#19
Adil I Daud, Jedd D Wolchok, Caroline Robert, Wen-Jen Hwu, Jeffrey S Weber, Antoni Ribas, F Stephen Hodi, Anthony M Joshua, Richard Kefford, Peter Hersey, Richard Joseph, Tara C Gangadhar, Roxana Dronca, Amita Patnaik, Hassane Zarour, Charlotte Roach, Grant Toland, Jared K Lunceford, Xiaoyun Nicole Li, Kenneth Emancipator, Marisa Dolled-Filhart, S Peter Kang, Scot Ebbinghaus, Omid Hamid
Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks...
December 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27863186/model-based-characterization-of-the-pharmacokinetics-of-pembrolizumab-a-humanized-anti-pd-1-monoclonal-antibody-in-advanced-solid-tumors
#20
M Ahamadi, T Freshwater, M Prohn, C H Li, D P de Alwis, R de Greef, J Elassaiss-Schaap, A Kondic, J A Stone
Pembrolizumab, a potent antibody against programmed death 1 (PD-1) receptor, has shown robust antitumor activity and manageable safety in patients with advanced solid tumors. Its pharmacokinetic (PK) properties were analyzed with population PK modeling using pooled data from the KEYNOTE-001, -002, and -006 studies of patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other solid tumor types. Pembrolizumab clearance was low and the volume of distribution small, as is typical for therapeutic antibodies...
November 14, 2016: CPT: Pharmacometrics & Systems Pharmacology
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