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Immunotherapy ctla-4

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https://www.readbyqxmd.com/read/29775689/biomarkers-for-checkpoint-inhibition-in-hematologic-malignancies
#1
REVIEW
Djordje Atanackovic, Tim Luetkens
In the past few years we have seen remarkable paradigm shifts in the treatment of many solid tumors due to the introduction of inhibitors targeting immune checkpoints such as PD-1/PD-L1 and CTLA-4. Recent results indicate that checkpoint inhibition also represents a very promising approach for certain types of hematologic malignancies. Unfortunately, treatment with checkpoint inhibitors is also associated with substantial toxicities and high costs and only a subset of patients appears to derive clinical benefit from these treatments...
May 15, 2018: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29769148/current-landscape-and-future-of-dual-anti-ctla4-and-pd-1-pd-l1-blockade-immunotherapy-in-cancer-lessons-learned-from-clinical-trials-with-melanoma-and-non-small-cell-lung-cancer-nsclc
#2
REVIEW
Young Kwang Chae, Ayush Arya, Wade Iams, Marcelo R Cruz, Sunandana Chandra, Jaehyuk Choi, Francis Giles
Immunotherapy is among the most rapidly evolving treatment strategies in oncology. The therapeutic potential of immune-checkpoint inhibitors is exemplified by the recent hail of Food and Drug Administration (FDA) approvals for their use in various malignancies. Continued efforts to enhance outcomes with immunotherapy agents have led to the formulation of advanced treatment strategies. Recent evidence from pre-clinical studies evaluating immune-checkpoint inhibitors in various cancer cell-lines has suggested that combinatorial approaches may have superior survival outcomes compared to single-agent immunotherapy regimens...
May 16, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29755699/sequential-immunotherapy-in-a-patient-with-primary-refractory-hodgkin-lymphoma-and-novel-mutations
#3
Richard Greil, Lisa Pleyer, Bettina Jansko, Carmen Feierabend, Lukas Rettenbacher, Olga Stiefel, Christoph Rass, Patrick Morre, Daniel Neureiter, Sigrun Greil-Ressler
Primary resistant Hodgkin lymphoma is an aggressive disease with few treatment options and short survival. Neoplastic cells of classical Hodgkin lymphoma are heavily dependent on microenvironmental stimuli, regularly express PD-L1, and a relevant proportion of relapsed patients is sensitive to blocking of the PD1/PD-L1 axis. However, response duration is limited and further treatment options are unknown but urgently needed. We report a case of a patient without relevant response to five subsequent chemotherapy regimens who immediately and dramatically responded to an anti-PD1 mab...
April 17, 2018: Oncotarget
https://www.readbyqxmd.com/read/29750176/adoptive-cell-therapy-with-tumor-infiltrating-lymphocytes-in-advanced-melanoma-patients
#4
Mélanie Saint-Jean, Anne-Chantal Knol, Christelle Volteau, Gaëlle Quéreux, Lucie Peuvrel, Anabelle Brocard, Marie-Christine Pandolfino, Soraya Saiagh, Jean-Michel Nguyen, Christophe Bedane, Nicole Basset-Seguin, Amir Khammari, Brigitte Dréno
Immunotherapy for melanoma includes adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TILs). This monocenter retrospective study was undertaken to evaluate the efficacy and safety of this treatment of patients with advanced melanoma. All advanced melanoma patients treated with TILs using the same TIL expansion methodology and same treatment interleukin-2 (IL-2) regimen between 2009 and 2012 were included. After sterile intralesional excision of a cutaneous or subcutaneous metastasis, TILs were produced according to a previously described method and then infused into the patient who also received a complementary subcutaneous IL-2 regimen...
2018: Journal of Immunology Research
https://www.readbyqxmd.com/read/29743521/e2f1-inhibition-mediates-cell-death-of-metastatic-melanoma
#5
Florian Rouaud, Nedra Hamouda-Tekaya, Michaël Cerezo, Patricia Abbe, Joséphine Zangari, Veronique Hofman, Mickaël Ohanna, Baharia Mograbi, Najla El-Hachem, Zohra Benfodda, Alexandre Lebeau, Meri K Tulic, Paul Hofman, Corine Bertolotto, Thierry Passeron, Jean-Sébastien Annicotte, Robert Ballotti, Stéphane Rocchi
Melanoma is one of the most lethal cancers when it reaches a metastatic stage. Despite advancements in targeted therapies (BRAF inhibitors) or immunotherapies (anti-CTLA-4 or anti-PD1), most patients with melanoma will need additional treatment. Thus, there is an urgent need to develop new therapeutical approaches to bypass resistance and achieve more prolonged responses. In this context, we were interested in E2F1, a transcription factor that plays a major role in the control of cell cycle under physiological and pathological conditions...
May 9, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29743050/unmasking-of-intracranial-metastatic-melanoma-during-ipilimumab-nivolumab-therapy-case-report-and-literature-review
#6
Marin A McDonald, Parag Sanghvi, Julie Bykowski, Gregory A Daniels
BACKGROUND: While data from several studies over the last decade has demonstrated that introduction of immunologic checkpoint blockage therapy with anti-CTLA-4/PD-1 drugs leads to improved survival in metastatic melanoma patients, relatively little is known about brain-specific therapeutic response and adverse events in the context of immunotherapeutic treatment of intracranial disease. Here we report two independent cases of new intracranial metastases presenting after initiation of combined checkpoint blockade Ipilimumab and Nivolumab for recurrent metastatic melanoma in the context of positive systemic disease response...
May 9, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29740718/combination-immunotherapy-in-non-small-cell-lung-cancer
#7
REVIEW
Melina E Marmarelis, Charu Aggarwal
PURPOSE OF REVIEW: Checkpoint blockade has changed the treatment landscape in non-small cell lung cancer (NSCLC), but single-agent approaches are effective for only a select subset of patients. Here, we will review the evidence for combination immunotherapies in NSCLC and the clinical data evaluating the efficacy of this approach. RECENT FINDINGS: Clinical trials evaluating combination PD-1 and CTLA-4 blockade as well as PD-1 in combination with agents targeting IDO1, B7-H3, VEGF, and EGFR show promising results...
May 8, 2018: Current Oncology Reports
https://www.readbyqxmd.com/read/29735917/cancer-immunotherapy-a-focus-on-the-regulation-of-immune-checkpoints
#8
REVIEW
Tao Shi, Yanyu Ma, Lingfeng Yu, Jiaxuan Jiang, Sunan Shen, Yayi Hou, Tingting Wang
In recent years, the role of cancer immunotherapy has become increasingly important compared to traditional cancer treatments, including surgery, chemotherapy and radiotherapy. Of note, the clinical successes of immune checkpoint blockade, such as PD-1 and CTLA-4, represent a landmark event in cancer immunotherapy development. Therefore, further exploration of how immune checkpoints are regulated in the tumor microenvironment will provide key insights into checkpoint blockade therapy. In this review, we discuss in details about the regulation of immune checkpoints mediated by immune cells, oncolytic viruses, epigenetics, and gut microbiota and mutual regulation by co-expressed checkpoints...
May 7, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29730461/evolution-of-checkpoint-inhibitors-for-the-treatment-of-metastatic-gastric-cancers-current-status-and-future-perspectives
#9
REVIEW
Julien Taieb, Markus Moehler, Narikazu Boku, Jaffer A Ajani, Eduardo Yañez Ruiz, Min-Hee Ryu, Silke Guenther, Vikram Chand, Yung-Jue Bang
BACKGROUND: Standard treatment options for patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC) are associated with limited efficacy and some toxicity. Recently, immunotherapy with antibodies that inhibit the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interaction has emerged as a new treatment option. This manuscript reviews early-phase and late-phase trials of immunotherapy in advanced GC/GEJC. METHODS: Searches for studies of immunotherapy in GC/GEJC were performed using PubMed, ClinicalTrials...
April 22, 2018: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29713453/anti-ctla-4-antibodies-in-cancer-immunotherapy-selective-depletion-of-intratumoral-regulatory-t-cells-or-checkpoint-blockade
#10
Fei Tang, Xuexiang Du, Mingyue Liu, Pan Zheng, Yang Liu
Antibodies to human CTLA-4 have been shown to induce long-lasting protection against melanoma. It is assumed that these antibodies cause tumor rejection by blocking negative signaling from the B7-CTLA-4 interactions to enhance priming of naïve T cells in the lymphoid organs. Recently, we reported that anti-CTLA-4 antibody Ipilimumab effectively induces tumor rejection in vivo although it blocks neither B7 transendocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Using genetic model in which the anti-CTLA-4 antibodies are unable to engage more than 50% of CTLA-4, we demonstrated that saturating binding of CTLA-4 is not necessary for tumor rejection...
2018: Cell & Bioscience
https://www.readbyqxmd.com/read/29712685/novel-effector-phenotype-of-tim-3-regulatory-t-cells-leads-to-enhanced-suppressive-function-in-head-and-neck-cancer-patients
#11
Zhuqing Liu, Elizabeth L McMichael, Gulidanna Shayan, Jing Li, Kevin Chen, Raghvendra M Srivastava, Lawrence P Kane, Binfeng Lu, Robert L Ferris
PURPOSE: Regulatory T (Treg) cells are important suppressive cells among tumor infiltrating lymphocytes (TIL). Treg express the well-known immune checkpoint receptor PD-1, which is reported to mark "exhausted" Treg with lower suppressive function. T cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3+ Tregs remains unclear. EXPERIMENTAL DESIGN: CD4+CTLA-4+CD25high Treg were sorted from freshly excised head and neck squamous cell carcinoma (HNSCC) TIL based on Tim-3 expression...
April 30, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29705790/immunotherapy-of-hepatocellular-carcinoma
#12
Bernd Heinrich, Carolin Czauderna, Jens U Marquardt
Hepatocellular carcinoma (HCC) is one of the most deadly and rapidly evolving cancers worldwide. The current systemic treatment strategies in advanced tumor stages remain limited despite promising preclinical and early-phase clinical results for some compounds, highlighting an unmet clinical need. Since the majority of HCCs evolve in the background of a chronic inflammatory liver damage, HCCs can be considered a paradigm for inflammation-induced cancers, which renders immunotherapeutic strategies particularly promising for this tumor entity...
2018: Oncology Research and Treatment
https://www.readbyqxmd.com/read/29705788/immunotherapy-of-colon-cancer
#13
Alexander Stein, Gunnar Folprecht
In contrast to other tumour types inhibitors of PD-1/-L1 or CTLA 4 have not yet shown relevant efficacy in unselected colorectal cancer. Based on the high mutational burden, deficient mismatch repair (dMMR) or microsatellite instable (MSI-H) tumours are yet the only subgroup, which is amenable to checkpoint inhibition. These tumours show relevant and durable responses in the refractory setting by PD-1/-L1 +/- CTLA 4 inhibition. Thus, ongoing phase 3 trials in this subgroup evaluate immunotherapy in the adjuvant setting as well as in the first line metastatic setting with or without chemotherapy...
2018: Oncology Research and Treatment
https://www.readbyqxmd.com/read/29704887/the-sirna-mediated-downregulation-of-pd-1-alone-or-simultaneously-with-ctla-4-shows-enhanced-in-vitro-car-t-cell-functionality-for-further-clinical-development-towards-the-potential-use-in-immunotherapy-of-melanoma
#14
Bianca Simon, Dennis C Harrer, Beatrice Schuler-Thurner, Niels Schaft, Gerold Schuler, Jan Dörrie, Ugur Uslu
Chimeric antigen receptor (CAR)-T cells have been used successfully for cancer immunotherapy. While substantial tumor regression was observed in leukemia and lymphoma, CAR-therapy of solid tumors needs further improvement. A major obstacle to the efficiency of engineered T cells is posed by triggering of inhibitory receptors, e.g. programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), leading to an impaired anti-tumor activity. To boost CAR-T-cell function, we co-electroporated T cells with both, mRNA encoding a CAR specific for chondroitin sulfate proteoglycan 4 (CSPG4) and small-interfering RNAs (siRNAs) to downregulate PD-1 (siPD-1) and CTLA-4 (siCTLA-4)...
April 28, 2018: Experimental Dermatology
https://www.readbyqxmd.com/read/29691200/crispr-cas9-genome-editing-fueling-the-revolution-in-cancer-immunotherapy
#15
REVIEW
Xiaojun Liu, Yangbing Zhao
The development of genomic editing technologies expands the landscape of T cell engineering for adoptive cell therapy. Among the multiple tools that can be used, CRISPR/Cas9 has been shown to be relatively easy to use, simple to design and cost effective with highly efficient multiplex genome engineering capabilities. Allogeneic universal chimeric antigen receptor (CAR) T cells can be produced by disrupting T cell receptor (TCR) and beta-2-microglobulin (B2M) in CAR T cells or by directly knocking in a CAR at the disrupted TRAC locus...
April 21, 2018: Current Research in Translational Medicine
https://www.readbyqxmd.com/read/29688262/t-cells-isolated-from-patients-with-checkpoint-inhibitor-resistant-melanoma-are-functional-and-can-mediate-tumor-regression
#16
R Andersen, T H Borch, A Draghi, A Gokuldass, M A H Rana, M Pedersen, M Nielsen, P Kongsted, J W Kjeldsen, M C W Westergaard, H D Radic, C A Chamberlain, L R Hölmich, H W Hendel, M S Larsen, Ö Met, I M Svane, M Donia
Background: The majority of patients with metastatic melanoma obtain only short-term or no benefit at all from checkpoint inhibitor (CPI) immunotherapy. In this study, we investigated whether the immune system of patients progressing following CPI treatment was able to generate functional tumor-specific immune responses. Materials and methods: Tumor-infiltrating lymphocytes (TILs) were isolated and expanded from metastatic melanoma lesions which progressed during or after anti-PD-1 and anti-CTLA-4 treatment...
April 24, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29672601/expression-of-immune-checkpoint-regulators-cytotoxic-t-lymphocyte-antigen-4-ctla-4-and-programmed-death-ligand-1-pd-l1-in-female-breast-carcinomas
#17
Ari Kassardjian, Peter I Shintaku, Neda A Moatamed
BACKGROUND: Immune checkpoint regulators, cytotoxic T lymphocyte antigen 4 (CTLA-4) and the programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1) have emerged as promising new targets for cancer therapeutics. While tumor expression of PD-L1 has been shown to have objective responses to anti-PD-L1 immunotherapies, the clinical implications of CTLA-4 expression in tumor cells or immune cells in the tumor microenvironment is still controversial. We investigated the expression of CTLA-4 and PD-L1 in human breast tumors and provided a scoring system for the systematic evaluation of CTLA-4 staining...
2018: PloS One
https://www.readbyqxmd.com/read/29669930/tsc2-deficient-tumors-have-evidence-of-t-cell-exhaustion-and-respond-to-anti-pd-1-anti-ctla-4-immunotherapy
#18
Heng-Jia Liu, Patrick H Lizotte, Heng Du, Maria C Speranza, Hilaire C Lam, Spencer Vaughan, Nicola Alesi, Kwok-Kin Wong, Gordon J Freeman, Arlene H Sharpe, Elizabeth P Henske
Tuberous sclerosis complex (TSC) is an incurable multisystem disease characterized by mTORC1-hyperactive tumors. TSC1/2 mutations also occur in other neoplastic disorders, including lymphangioleiomyomatosis (LAM) and bladder cancer. Whether TSC-associated tumors will respond to immunotherapy is unknown. We report here that the programmed death 1 coinhibitory receptor (PD-1) is upregulated on T cells in renal angiomyolipomas (AML) and pulmonary lymphangioleiomyomatosis (LAM). In C57BL/6J mice injected with syngeneic TSC2-deficient cells, anti-PD-1 alone decreased 105K tumor growth by 67% (P < 0...
April 19, 2018: JCI Insight
https://www.readbyqxmd.com/read/29669721/ppar-%C3%AE-contributes-to-immunity-by-cancer-vaccines-that-secrete-gm-csf
#19
Girija Goyal, Karrie Wong, Christopher J Nirschl, Nicholas Souders, Donna Neuberg, Niroshana Anandasabapathy, Glenn Dranoff
Peroxisome proliferator activated receptor-γ (PPARγ) is a lipid-activated nuclear receptor that promotes immune tolerance through effects on macrophages, dendritic cells (DCs), and regulatory T cells (Tregs). Granulocyte-macrophage colony stimulating factor (GM-CSF) induces PPARγ expression in multiple myeloid cell types. GM-CSF contributes to both immune tolerance and protection, but the role of PPARγ in these pathways is poorly understood. Here we reveal an unexpected stimulatory role for PPARγ in the generation of antitumor immunity with irradiated, GM-CSF-secreting tumor-cell vaccines (GVAX)...
April 18, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29667847/cd47-is-a-novel-potent-immunotherapy-target-in-human-malignancies-current-studies-and-future-promises
#20
Bing Tong, Mengzhao Wang
Recently, many immunosuppressive checkpoints such as PD-L1, CTLA-4 and CD47, were identified in succession and serve as potential immunotherapy targets in human cancers. Among them, CD47, a 'marker-of-self' protein that is overexpressed broadly across tumor types, is emerging as a novel potent macrophage immune checkpoint for cancer immunotherapy. In this review, we highlight the prominent role of CD47 as a 'don't-eat-me' signal that inhibits macrophage phagocytosis for immune evasion of a tumor and presents the opportunities and challenges for CD47 inhibitors both as monotherapy and in combination treatments for hematological cancers and solid tumors; some of these agents are currently in clinical trials...
April 18, 2018: Future Oncology
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