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Melanoma immunotherapy

Ammar Sukari, Nadine Abdallah, Misako Nagasaka
Adoptive cellular therapy (ACT) is an immunotherapy which involves the passive transfer of lymphocytes into a lymphodepleted host after ex vivo stimulation and expansion. Tumor-infiltrating lymphocytes (TILs) have shown objective tumor responses mainly restricted to melanoma and rely on a laborious manufacturing process. These limitations led to emergence of engineered cells, where normal peripheral blood lymphocytes are modified to express T cell receptors (TCRs) or chimeric antigen receptors (CARs) specific for tumor-associated antigens (TAAs)...
April 2019: Critical Reviews in Oncology/hematology
Victoria Grätz, Ewan A Langan, Alexander Neumann, Detlef Zillikens, Patrick Terheyden
The common adverse effects of immune checkpoint blockade therapy are well recognised. However, neurological adverse effects of checkpoint inhibitor therapy are less widely appreciated, and their clinical management remains challenging. Therefore, we report our experience of managing acute, life-threatening neurological toxicity during immune checkpoint inhibitor therapy. Five male patients with stage IV melanoma underwent anti-programmed cell death protein 1 therapy (monotherapy or combination therapy with anti-cytotoxic T-lymphocyte antigen-4 antibodies) and developed severe neurological symptoms and signs including headache, hemiparesis and dysarthria...
March 11, 2019: Melanoma Research
Hannah Yejin Kim, Parth J Upadhyay, Alia Fahmy, Xiaoman Liu, Janna K Duong, Alan V Boddy
Targeted therapies, based on identification of common oncogenic mutations such as BRAF V600E/K and monoclonal antibody immunotherapies, have transformed the treatment of melanoma. Dual mitogen-activated protein kinase (MAPK) pathway inhibition of BRAF V600E/K and MEK 1/2 kinases with BRAF-MEK inhibitors using dabrafenib-trametinib, vemurafenib-cobimetinib and encorafenib-binimetinib is now the standard of care for BRAF V600E/K tumours. Monoclonal antibodies, such as pembrolizumab and nivolumab, against programmed cell death protein (PD-1) on T cells, as well as ipilimumab against cytotoxic T lymphocyte antigen-4 (CTLA-4), enable restoration of suppressed T-cell antitumour response, and have also shown improved clinical benefit compared with traditional chemotherapy...
March 13, 2019: Clinical Pharmacokinetics
Anna Gajos-Michniewicz, Malgorzata Czyz
Tumour metastasis is a multistep process. Melanoma is a highly aggressive cancer and metastasis accounts for the majority of patient deaths. microRNAs (miRNAs) are non-coding RNAs that affect the expression of their target genes. When aberrantly expressed they contribute to the development of melanoma. While miRNAs can act locally in the cell where they are synthesized, they can also influence the phenotype of neighboring melanoma cells or execute their function in the direct tumour microenvironment by modulating ECM (extracellular matrix) and the activity of fibroblasts, endothelial cells, and immune cells...
March 7, 2019: Cancers
Avinash Das Sahu, Joo S Lee, Zhiyong Wang, Gao Zhang, Ramiro Iglesias-Bartolome, Tian Tian, Zhi Wei, Benchun Miao, Nishanth Ulhas Nair, Olga Ponomarova, Adam A Friedman, Arnaud Amzallag, Tabea Moll, Gyulnara Kasumova, Patricia Greninger, Regina K Egan, Leah J Damon, Dennie T Frederick, Livnat Jerby-Arnon, Allon Wagner, Kuoyuan Cheng, Seung Gu Park, Welles Robinson, Kevin Gardner, Genevieve Boland, Sridhar Hannenhalli, Meenhard Herlyn, Cyril Benes, Keith Flaherty, Ji Luo, J Silvio Gutkind, Eytan Ruppin
Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interac tions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer ). Here, we perform a genome-wide in silico prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients...
March 11, 2019: Molecular Systems Biology
Shweta Joshi, Donald L Durden
Cancer immunotherapy, including immune checkpoint blockade and adoptive CAR T-cell therapy, has clearly established itself as an important modality to treat melanoma and other malignancies. Despite the tremendous clinical success of immunotherapy over other cancer treatments, this approach has shown substantial benefit to only some of the patients while the rest of the patients have not responded due to immune evasion. In recent years, a combination of cancer immunotherapy together with existing anticancer treatments has gained significant attention and has been extensively investigated in preclinical or clinical studies...
2019: Journal of Oncology
Abdullah Al Emran, Aniruddha Chatterjee, Euan J Rodger, Jessamy C Tiffen, Stuart J Gallagher, Michael R Eccles, Peter Hersey
Methylation of DNA at CpG sites is the most common and stable of epigenetic changes in cancer. Hypermethylation acts to limit immune checkpoint blockade immunotherapy by inhibiting endogenous interferon responses needed for recognition of cancer cells. By contrast, global hypomethylation results in the expression of programmed death ligand 1 (PD-L1) and inhibitory cytokines, accompanied by epithelial-mesenchymal changes that can contribute to immunosuppression. The drivers of these contrasting methylation states are not well understood...
March 7, 2019: Trends in Immunology
Michael B Atkins, Ahmad Tarhini, Michael Rael, Komal Gupte-Singh, Elliott O'Brien, Corey Ritchings, Sumati Rao, David F McDermott
AIM: Comparison of clinical outcomes of nivolumab + ipilimumab versus BRAF + MEK inhibitors (dabrafenib + trametinib or vemurafenib + cobimetinib) in BRAF-mutant advanced melanoma. METHODS: Matching-adjusted indirect comparisons were conducted between nivolumab + ipilimumab (CheckMate 067/069 studies) and BRAF + MEK inhibitors (COMBI-d, COMBI-v and coBRIM studies). Overall survival (OS), progression-free survival and objective response rates were assessed...
March 11, 2019: Immunotherapy
Biswajit Podder, Cristiano Guttà, Jan Rožanc, Elke Gerlach, Maria Feoktistova, Diana Panayotova-Dimitrova, Leonidas G Alexopoulos, Martin Leverkus, Markus Rehm
Melanoma cells are highly resistant to conventional genotoxic agents, and BRAFV600/MEK-targeted therapies as well as immunotherapies frequently remain inefficient. Alternative means to treat melanoma, in particular through the induction of programmed cell death modalities such as apoptosis or necroptosis, therefore still need to be explored. Here, we report that melanoma cell lines expressing notable amounts of RIPK1, RIPK3 and MLKL, the key players of necroptosis signal transduction, fail to execute necroptotic cell death...
March 8, 2019: Cell Death and Differentiation
Joachim Torrano, Abdullah Al Emran, Heinz Hammerlindl, Helmut Schaider
BACKGROUND: A multitude of recent studies has observed common epigenetic changes develop in tumour cells of multiple lineages following exposure to stresses such as hypoxia, chemotherapeutics, immunotherapy or targeted therapies. A significant increase in the transcriptionally repressive mark trimethylated H3K9 (H3K9me3) is becoming associated with treatment-resistant phenotypes suggesting upstream mechanisms may be a good target for therapy. We have reported that the increase in H3K9me3 is derived from the methyltransferases SETDB1 and SETDB2 following treatment in melanoma, lung, breast and colorectal cancer cell lines, as well as melanoma patient data...
March 8, 2019: Clinical Epigenetics
Sherise D Ferguson, Shivani Bindal, Roland L Bassett, Lauren E Haydu, Ian E McCutcheon, Amy B Heimberger, Jing Li, Barbara J O'Brien, Nandita Guha-Thakurta, Michael T Tetzlaff, Hussein Tawbi, Michael A Davies, Isabella C Glitza
PURPOSE: Although the survival of most melanoma patients diagnosed with leptomeningeal disease (LMD) is short, some patients can have better outcomes and prolonged survival. A large retrospective cohort of patients was analyzed to identify features associated with survival with LMD from melanoma. METHODS: Clinical characteristics, treatments and survival were collected for melanoma patients diagnosed with LMD from 1999 to 2015. The Kaplan-Meier method was used to estimate overall survival (OS) and Cox proportional hazards regression was used to test statistical significance of associations with survival...
March 7, 2019: Journal of Neuro-oncology
Annika Krückel, Alvaro Moreira, Waltraud Fröhlich, Gerold Schuler, Lucie Heinzerling
BACKGROUND: The role of eosinophils in cancer is not yet completely understood, but patients with eosinophilia show a trend towards longer survival in several types of cancer, including melanoma. However, eosinophil count at initial diagnosis of metastatic melanoma does not predict survival. Since eosinophil cationic protein (ECP) mediates anticancer effects, such as tissue remodelling and cytotoxic activity, we investigated this marker as an early prognostic marker in metastatic melanoma...
March 7, 2019: BMC Cancer
Viola Franke, Alexander C J van Akkooi
Since the first documented lymph node dissection in 1892, many trials have investigated the potential effect of this surgical procedure on survival in patients with melanoma. Two randomised controlled trials were unable to demonstrate improved survival with completion lymph node dissection versus nodal observation in patients with sentinel node-positive disease, although patients with larger sentinel node metastases (>1 mm) might benefit more from observation than from dissection, and could potentially be considered for adjuvant systemic therapy instead of complete dissection...
March 2019: Lancet Oncology
Michele Porcu, Pushpamali De Silva, Cinzia Solinas, Angelo Battaglia, Marina Schena, Mario Scartozzi, Dominique Bron, Jasjit S Suri, Karen Willard-Gallo, Dario Sangiolo, Luca Saba
The broader use of immune checkpoint blockade in clinical routine challenges clinicians in the diagnosis and management of side effects which are caused by inflammation generated by the activation of the immune response. Nearly all organs can be affected by immune-related toxicities. However, the most frequently reported are: fatigue, rash, pruritus, diarrhea, nausea/vomiting, arthralgia, decreased appetite and abdominal pain. Although these adverse events are usually mild, reversible and not frequent, an early diagnosis is crucial...
March 5, 2019: Cancers
Xuan Chen, Rui Wang, Anji Chen, Yongmei Wang, Yiqin Wang, Jialei Zhou, Rongyue Cao
The research of tumor vaccine plays a crucial role in tumor immunotherapy. This study has constructed and prepared a fusion protein vaccine of heat shock protein 65 (HSP65) and the octapeptide epitope 186-193 of the six transmembrane epithelial antigen of the prostate 1 (STEAP1 186-193 ), and investigated the inhibitory effect of the fusion protein on mouse RM-1 prostate cancer and B16F10 melanoma xenografts. The fusion protein His-HSP65-STEAP1 186-193 (HHST1), His-HSP65-2×STEAP1 186-193 (HHST2) and His-HSP65-6×STEAP1 186-193 (HHST6) were obtained by setting different copy number of STEAP1 186-193 and adding His purification tag before HSP65...
March 2019: Biomedicine & Pharmacotherapy
Julien Péron, Alexandre Lambert, Stephane Munier, Brice Ozenne, Joris Giai, Pascal Roy, Stéphane Dalle, Abigirl Machingura, Delphine Maucort-Boulch, Marc Buyse
BACKGROUND: The treatment effect in survival analysis is commonly quantified as the hazard ratio (HR), and tested statistically using the standard log-rank test. Modern anticancer immunotherapies are successful in a proportion of patients who remain alive even after a long-term follow-up. This new phenomenon induces a non-proportionality of the underlying hazards of death. METHODS: The properties of the net survival benefit were illustrated using the dataset from a trial evaluating ipilimumab in metastatic melanoma...
March 5, 2019: Journal of the National Cancer Institute
Ping Han, Qiang Dai, Lilv Fan, Hao Lin, Xiaoqing Zhang, Fanlin Li, Xuanming Yang
Somatic gene mutations play a critical role in immune evasion by tumors. However, there is limited information on genes that confer immunotherapy resistance in melanoma. To answer this question, we established a whole-genome knockout B16/ovalbumin cell line by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease technology, and determined by in vivo adoptive OT-I T-cell transfer and an in vitro OT-I T-cell-killing assay that Janus kinase (JAK)1 deficiency mediates T-cell resistance via a two-step mechanism...
2019: Frontiers in Immunology
Anita Pandey, Maksim Liaukovich, Kishor Joshi, Boris I Avezbakiyev, James E O'Donnell
BACKGROUND Squamous cell carcinoma is one of the most common keratinocytic skin cancers, the other being basal cell carcinoma. It is the second most common skin cancer after melanoma. Cutaneous squamous cell carcinoma is mostly a localized disease. The metastatic presentation is rare even in the presence of invasive disease. The metastatic potential depends on the presence of high-risk features at the time of diagnosis. Lung, liver, and bone are the frequent sites of metastasis. Local and locoregional disease undergoes excision with or without adjuvant radiation...
March 6, 2019: American Journal of Case Reports
Giulia Galli, Stefano Cavalieri, Lorenza Di Guardo, Carolina Cimminiello, Federico Nichetti, Francesca Corti, Monica Alicia Garcia, Brigida Pappalardi, Carlo Fallai, Filippo de Braud, Marco Platania, Michele Del Vecchio
BACKGROUND: Up to 40% of patients with metastatic melanoma (MM) develop brain metastases. Radiotherapy (RT) may potentiate the effects of immunotherapy (IO), even on distant sites (abscopal effect). MATERIAL AND METHODS: We retrospectively analyzed all our MM patients treated with IO within 6 months before/after brain RT between 2012 and 2016. Progression-free (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared with those of controls treated with IO during the same period...
March 5, 2019: Oncology Research and Treatment
Tadahiro Kobayashi, Kyosuke Oishi, Ai Okamura, Maeda Shintaro, Akito Komuro, Yasuhito Hamaguchi, Manabu Fujimoto, Kazuhiko Takehara, Takashi Matsushita
In tumor immunity, the participation of IL-10-producing regulatory B cells (Bregs), which play an important role in suppressing immune responses, is unclear. In this study, we demonstrated an increase in B16F10 melanoma growth and a decrease in the proportion of IFN-γ- and TNF-α-secreting tumor-infiltrating CD8+ T cells in B cell-specific phosphatase and tensin homolog (PTEN)-deficient mice in which Bregs were expanded. The number of tumor-infiltrating Bregs significantly increased in B cell-specific PTEN-deficient mice...
March 2, 2019: Journal of Investigative Dermatology
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