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immune-checkpoint blockade

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https://www.readbyqxmd.com/read/29232467/immunotherapy-in-ovarian-cancer
#1
K Odunsi
Immunological destruction of tumors is a multistep, coordinated process that can be modulated or targeted at several critical points to elicit tumor rejection. These steps in the cancer immunity cycle include: (i) generation of sufficient numbers of effector T cells with high avidity recognition of tumor antigens in vivo; (ii) trafficking and infiltration into the tumor; (iii) overcoming inhibitory networks in the tumor microenvironment; (iv) direct recognition of tumor antigens and generation of an effector anti-tumor response; and (v) persistence of the anti-tumor T cells...
November 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29230210/checkpoint-blockade-toxicity-and-immune-homeostasis-in-the-gastrointestinal-tract
#2
REVIEW
Michael Dougan
Monoclonal antibodies targeting the regulatory immune "checkpoint" receptors CTLA-4, PD-1, and PD-L1 are now standard therapy for diverse malignancies including melanoma, lung cancer, and renal cell carcinoma. Although effective in many patients and able to induce cures in some, targeting these regulatory pathways has led to a new class of immune-related adverse events. In many respects, these immune toxicities resemble idiopathic autoimmune diseases, such as inflammatory bowel disease, autoimmune hepatitis, rheumatoid arthritis, and vitiligo...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29228684/atorvastatin-downregulates-co-inhibitory-receptor-expression-by-targeting-ras-activated-mtor-signalling
#3
Isobel Okoye, Afshin Namdar, Lai Xu, Nicole Crux, Shokrollah Elahi
Regulation of T cell function in the steady state is mediated by co-inhibitory receptors or immune checkpoints such as PD-1, CTLA-4, TIM-3 and LAG-3. Persistent antigen stimulation, during chronic viral infections and cancer, results in sustained expression of multiple co-inhibitory receptors and subsequently poor effector T cell function. Immune checkpoint blockade using monoclonal antibodies against PD-1, PDL-1 and CTLA-4 has been implemented as an immunotherapy strategy- resulting in restoration of T cell function and reduction of viral load or tumour growth...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29225480/role-of-afatinib-in-the-treatment-of-advanced-lung-squamous-cell-carcinoma
#4
REVIEW
Tiziana Vavalà
Lung cancer treatment has considerably changed over the last few years: the identification of druggable oncogenic alterations and innovative immunotherapic approaches granted lung cancer patients the possibility of more efficient and less toxic therapeutic options than chemotherapy. Nowadays, lung squamous cell carcinomas (SqCCs) patients have the chance to benefit from novel treatment alternatives, including immune checkpoint blockade and anti-angiogenic agents and, given positive trial results, from afatinib, a second generation tyrosine kinase inhibitor (TKI) that irreversibly antagonizes ErbB family tyrosine kinase receptors...
2017: Clinical Pharmacology: Advances and Applications
https://www.readbyqxmd.com/read/29224824/circulating-tumour-cell-pd-l1-test-for-head-and-neck-cancers
#5
Arutha Kulasinghe, Liz Kenny, Chamindie Punyadeera
Immune checkpoint inhibitors have gained traction over the last few years in the treatment of metastatic/recurrent head and neck squamous cell carcinoma (HNSCC) patients. Monoclonal antibodies that block the programmed death 1 (PD-1) receptor and its major ligand, PD-L1, have shown durable responses and low toxicity profiles. There are currently no validated predictive biomarkers to select patients likely to respond to anti-PD-1/PD-L1 therapy to avoid unwanted side effects and to reduce healthcare expenditure...
December 2017: Oral Oncology
https://www.readbyqxmd.com/read/29222312/harnessing-the-power-of-the-immune-system-in-non-hodgkin-lymphoma-immunomodulators-checkpoint-inhibitors-and-beyond
#6
REVIEW
Stephen M Ansell
Non-Hodgkin lymphoma is a malignancy of B lymphocytes that typically infiltrate sites of disease, including the lymph nodes, spleen, and bone marrow. Beyond the presence of malignant cells, many immune cells are also present within the tumor microenvironment. Although these immune cells have the potential to regulate the growth of malignant B cells, intratumoral immune cells are unable to eradicate lymphoma cells and most patients with lymphoma have clinical evidence of disease progression. Recent data have identified some of the mechanisms that account for the suppressed antitumor immune response and have created opportunities for treatment to overcome the deficiencies...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29220526/anti-pd-l1-treatment-induced-central-diabetes-insipidus
#7
Chen Zhao, Sri Harsha Tella, Jaydira Del Rivero, Anuhya Kommalapati, Ifechukwude Ebenuwa, James Gulley, Julius Strauss, Isaac Brownell
Context: Immune checkpoint inhibitors, including anti-PD-1, anti-PD-L1 and anti-CTLA4 monoclonal antibodies, have been widely used in cancer treatment. They are known to cause immune-related adverse events (irAEs), which resemble autoimmune diseases. Anterior pituitary hypophysitis with secondary hypopituitarism is a frequently reported irAE, especially in patients receiving anti-CTLA4 treatment. In contrast, posterior pituitary involvement, such as central diabetes insipidus (DI), is relatively rare and is unreported in patients undergoing PD-1/PD-L1 blockade...
December 6, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29220291/emerging-targeted-and-immune-based-therapies-in-sarcoma
#8
Seth M Pollack, Matthew Ingham, Matthew B Spraker, Gary K Schwartz
Soft tissue and bone sarcomas are malignancies of mesenchymal origin, and more than 50 subtypes are defined. For most sarcomas, locally advanced or unresectable disease is still treated with cytotoxic chemotherapy. Recently, our understanding of subtype-specific cancer biology has expanded, and it has revealed distinct molecular alterations responsible for tumor initiation and progression. These findings have motivated the development of targeted therapies that are being evaluated in subtype-specific or biomarker-driven clinical trials...
December 8, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29217585/patient-hla-class-i-genotype-influences-cancer-response-to-checkpoint-blockade-immunotherapy
#9
Diego Chowell, Luc G T Morris, Claud M Grigg, Jeffrey K Weber, Robert M Samstein, Vladimir Makarov, Fengshen Kuo, Sviatoslav M Kendall, David Requena, Nadeem Riaz, Benjamin Greenbaum, James Carroll, Edward Garon, David M Hyman, Ahmet Zehir, David Solit, Michael Berger, Ruhong Zhou, Naiyer A Rizvi, Timothy A Chan
CD8+ T cell-dependent killing of cancer cells requires efficient presentation of tumor antigens by human leukocyte antigen class I (HLA-I) molecules. However, the extent to which patient-specific HLA-I genotype influences response to anti-PD-1 or anti-CTLA-4 is currently unknown. We determined the HLA-I genotype of 1,535 advanced cancer patients treated with immune checkpoint blockade (ICB). Maximal heterozygosity at HLA-I loci (A, B, and C) improved overall survival after ICB compared to patients who were homozygous for at least one HLA locus...
December 7, 2017: Science
https://www.readbyqxmd.com/read/29217528/t-cells-expressing-checkpoint-receptor-tigit-are-enriched-in-follicular-lymphoma-tumors-and-characterized-by-reversible-suppression-of-t-cell-receptor-signaling
#10
Sarah E Josefsson, Kanutte Huse, Arne Kolstad, Klaus Beiske, Daniela Pende, Chloé B Steen, Else Marit Inderberg, Ole Christian Lingjærde, Bjørn Østenstad, Erlend B Smeland, Ronald Levy, Jonathan M Irish, June H Myklebust
PURPOSE: T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing co-inhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets. EXPERIMENTAL DESIGN: Surface expression of 9 co-inhibitory receptors governing T-cell function was characterized in T-cell subsets from FL lymph node tumors and from healthy donor tonsils and peripheral blood samples, using high-dimensional flow cytometry...
December 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29217527/merkel-cell-carcinoma-in-the-age-of-immunotherapy-facts-and%C3%A2-hopes
#11
Aric Colunga, Thomas Pulliam, Paul Nghiem
Merkel cell carcinoma (MCC) is a rare (~2,000 US cases/year) but aggressive neuroendocrine tumor of the skin. For advanced MCC, cytotoxic chemotherapy only infrequently (<10% of cases) offers durable clinical responses (>1 year) suggesting a great need for improved therapeutic options. In 2008, the Merkel cell polyomavirus (MCPyV) was discovered and is clonally integrated in ~80% of MCC tumors. The remaining 20% of MCC tumors have large numbers of UV-associated mutations. Importantly, both the UV-induced-neoantigens in virus-negative tumors and the MCPyV T antigen oncogenes that are required for virus-positive tumor growth are immunogenic...
December 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29216787/mek-inhibitors-under-development-for-treatment-of-non-small-cell-lung-cancer
#12
Chul Kim, Giuseppe Giaccone
The mitogen-activated protein kinase (MAPK) pathway is intimately implicated in the molecular pathogenesis of non-small-cell lung cancer (NSCLC). Aberrant MAPK signaling resulting from the upstream activating mutations converges on mitogen-activated protein kinase kinase 1/2 (MEK1/2), making MEK inhibition an attractive strategy for the treatment of NSCLC. Several MEK inhibitors have demonstrated anticancer activity in patients with NSCLC. Areas covered: In this article, we discuss the biological rationale for the use of MEK inhibitors and summarize the clinical experience with MEK1/2 inhibitors for the treatment of NSCLC, from initial phase I studies to phase II/III studies, both as monotherapy or in combination with other anticancer agents...
December 7, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29216535/nanoantagonists-with-nanophase-segregated-surfaces-for-improved-cancer-immunotherapy
#13
Yang Ma, Sheng-Lin Qiao, Yi Wang, Yao-Xin Lin, Hong-Wei An, Xiao-Chun Wu, Lei Wang, Hao Wang
The blockade of PD-1/PD-L1 interaction by peptide antagonists can unleash and enhance pre-existing anti-cancer immune responses of T cells to eradicate cancer cells. However, low proteolytic stability is the "Achilles' Heel" of peptides. Here, we first report a nanoantagonist with a physiological temperature sensitive nanophase-segregated surface that exhibits significantly enhanced blood circulation, peptide stability and PD-L1 immune checkpoint blockade efficacy. Thermosensitive polymers with different phase transition temperatures (Tt) are used to form the nanophase-segregated surface on an Au nanorod core...
December 1, 2017: Biomaterials
https://www.readbyqxmd.com/read/29213157/immunotherapy-and-gene-therapy-as-novel-treatments-for-cancer
#14
REVIEW
Martha Montserrat Rangel-Sosa, Estuardo Aguilar-Córdova, Augusto Rojas-Martínez
The immune system interacts closely with tumors during the disease development and progression to metastasis. The complex communication between the immune system and the tumor cells can prevent or promote tumor growth. New therapeutic approaches harnessing protective immunological mechanisms have recently shown very promising results. This is performed by blocking inhibitory signals or by activating immunological effector cells directly. Immune checkpoint blockade with monoclonal antibodies directed against the inhibitory immune receptors CTLA-4 and PD-1 has emerged as a successful treatment approach for patients with advanced melanoma...
September 30, 2017: Colombia Médica: CM
https://www.readbyqxmd.com/read/29209782/advances-in-immunotherapeutic-research-for-glioma-therapy
#15
REVIEW
Jeremy Tetsuo Miyauchi, Stella E Tsirka
Gliomas are primary malignancies of the brain. Tumors are staged based on malignancy, nuclear atypia, and infiltration of the surrounding brain parenchyma. Tumors are often diagnosed once patients become symptomatic, at which time the lesion is sizable. Glioblastoma (grade IV glioma) is highly aggressive and difficult to treat. Most tumors are diagnosed de novo. The gold standard of therapy, implemented over a decade ago, consists of fractionated radiotherapy and temozolomide, but unfortunately, chemotherapeutic resistance arises...
December 5, 2017: Journal of Neurology
https://www.readbyqxmd.com/read/29209327/strategies-to-improve-the-efficacy-of-dendritic-cell-based-immunotherapy-for-melanoma
#16
REVIEW
Kristian M Hargadon
Melanoma is a highly aggressive form of skin cancer that frequently metastasizes to vital organs, where it is often difficult to treat with traditional therapies such as surgery and radiation. In such cases of metastatic disease, immunotherapy has emerged in recent years as an exciting treatment option for melanoma patients. Despite unprecedented successes with immune therapy in the clinic, many patients still experience disease relapse, and others fail to respond at all, thus highlighting the need to better understand factors that influence the efficacy of antitumor immune responses...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29207939/tocilizumab-for-the-management-of-immune-mediated-adverse-events-secondary-to-pd-1-blockade
#17
Chipman Rg Stroud, Aparna Hegde, Cynthia Cherry, Abdul R Naqash, Nitika Sharma, Srikala Addepalli, Sulochana Cherukuri, Teresa Parent, Jessica Hardin, Paul Walker
Background Immune checkpoint inhibitors are poised to revolutionize the management of a growing number of malignancies. Unfortunately, the management of steroid-refractory immune mediated adverse events is based on a paucity of randomized data and limited to single center experiences. Our initial experience with the IL-6 receptor antagonist tocilizumab showed clinical improvement in a wide variety of irAEs. As a result, we adopted the use of tocilizumab for the management of steroid refractory irAEs. Methods The character and clinical course of irAEs were abstracted from the medical record and analyzed...
January 1, 2017: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/29207936/fatal-graft-versus-host-disease-after-allogeneic-stem-cell-transplantation-in-a-patient-recently-exposed-to-nivolumab
#18
Ana Jiménez-Ubieto, Antonia Rodriguez, Pilar Martinez Sánchez, Adolfo Gómez, Yolanda Rodriguez, Gonzalo Carreño-Tarragona, Joaquín Martinez-López, Carlos Grande
Allogeneic hematopoietic stem cell transplantation and checkpoint blockade therapy are immune-based salvage therapies for Hodgkin's lymphoma; however, the use of programmed death 1 blocking agents in the allogeneic stem cell transplantation setting could augment the incidence of steroid refractory graft-versus-host disease. Few studies suggest that that nivolumab is safe in patients previously treated with an allogeneic stem cell transplantation. Likewise, there are very limited data on the use of nivolumab before allogeneic stem cell transplantation...
January 1, 2017: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/29206680/immune-therapies-in-acute-myeloid-leukemia-a-focus-on-monoclonal-antibodies-and-immune-checkpoint-inhibitors
#19
Rita Assi, Hagop Kantarjian, Farhad Ravandi, Naval Daver
PURPOSE OF REVIEW: This review discusses the rationale, efficacy, and toxicity of a variety of immune approaches being evaluated in the therapy of acute myeloid leukemia (AML) including naked and conjugated monoclonal antibodies, bispecific T-cell engager antibodies, and immune checkpoint blockade via antibodies targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed-death 1 (PD-1). RECENT FINDINGS: The stellar success of immune therapies that harness the power of T cells in solid tumors and an improved understanding of the immune system in patients with hematologic malignancies have resulted in major efforts to develop immune therapies for the treatment of patients with AML...
December 4, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/29203894/combining-intratumoral-treg-depletion-with-androgen-deprivation-therapy-adt-preclinical-activity-in-the-myc-cap-model
#20
Ying-Chun Shen, Ali Ghasemzadeh, Christina M Kochel, Thomas R Nirschl, Brian J Francica, Zoila A Lopez-Bujanda, Maria A Carrera Haro, Ada Tam, Robert A Anders, Mark J Selby, Alan J Korman, Charles G Drake
BACKGROUND: Immune checkpoint blockade has shown promising antitumor activity against a variety of tumor types. However, responses in castration-resistant prostate cancer remain relatively rare-potentially due to low baseline levels of infiltration. Using an immunocompetent cMyc-driven model (Myc-CaP), we sought to understand the immune infiltrate induced by androgen deprivation therapy (ADT) and to leverage that infiltration toward therapeutic benefit. METHODS: Using flow cytometry, qPCR and IHC, we quantified ADT-induced immune infiltration in terms of cell type and function...
December 4, 2017: Prostate Cancer and Prostatic Diseases
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