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Melanoma immunotherapy

Fanwen Wang, Tingting Yu, Heng Zheng, Xingzhen Lao
Thymosin alpha 1 (Tα1) is a biological response modifier that has been introduced into markets for treating several diseases. Given the short serum half-life of Tα1 and the rapid development of Fc fusion proteins, we used genetic engineering method to construct the recombinant plasmid to express Tα1-Fc (Fc domain of human IgG4) fusion protein. A single-factor experiment was performed with different inducers of varying concentrations for different times to get the optimal condition of induced expression. Pure proteins higher than 90...
August 17, 2018: Scientific Reports
Robert Roskoski
The Ras-Raf-MEK-ERK signal transduction cascade is arguably the most important oncogenic pathway in human cancers. Ras-GTP promotes the formation of active homodimers or heterodimers of A-Raf, B-Raf, and C-Raf by an intricate process. These enzymes are protein-serine/threonine kinases that catalyze the phosphorylation and activation of MEK1 and MEK2 which, in turn, catalyze the phosphorylation and activation of ERK1 and ERK2. The latter catalyze the regulatory phosphorylation of dozens of cytosolic and nuclear proteins...
August 14, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Koen A Marijt, Laura Blijleven, Els M E Verdegaal, Michel G Kester, Daniel J Kowalewski, Hans-Georg Rammensee, Stefan Stevanović, Mirjam H M Heemskerk, Sjoerd H van der Burg, Thorbald van Hall
Most T cell-based immunotherapies of cancer depend on intact antigen presentation by HLA class I molecules (HLA-I). However, defects in the antigen-processing machinery can cause downregulation of HLA-I, rendering tumor cells resistant to CD8+ T cells. Previously, we demonstrated that a unique category of cancer antigens is selectively presented by tumor cells deficient for the peptide transporter TAP, enabling a specific attack of such tumors without causing immunopathology in mouse models. With a novel combinatorial screening approach, we now identify 16 antigens of this category in humans...
August 16, 2018: Journal of Experimental Medicine
Stefanie Pektor, Lina Hilscher, Kerstin C Walzer, Isabelle Miederer, Nicole Bausbacher, Carmen Loquai, Mathias Schreckenberger, Ugur Sahin, Mustafa Diken, Matthias Miederer
BACKGROUND: [18 F]Fluoro-2-deoxy-2-D-glucose positron emission tomography (FDG-PET) is commonly used in the clinic for diagnosis of cancer and for follow-up of therapy outcome. Additional to the well-established value in tumor imaging, it bears potential to depict immune processes in modern immunotherapies. T cells enhance their glucose consumption upon activation and are crucial effectors for the success of such novel therapies. In this study, we analyzed the T cell immunity in spleen after antigen-specific stimulation of T cells via highly innovative RNA-based vaccines using FDG-PET/MRI...
August 15, 2018: EJNMMI Research
Xiao-Tao Jia, Yanfang Pan, Zhengli Di, Naibing Gu, Zhiqin Liu, Yu-Ming Kang
Anti-γ-aminobutyric acid-B (GABAB ) receptor encephalitis is an autoimmune encephalitis associated with antibodies against neuronal cell surface antigens, which are primarily observed with small-cell lung cancer, melanoma, and thymoma. Here, we first report a case on the association between a relatively frequent cancer, gastric adenocarcinoma (GAC), and a rare GABAB receptor antibody limbic encephalitis. The patient was treated with immunotherapy and combined-drug chemotherapy, which were partially effective in terms of stabilizing the tumor and relieving neurological symptoms...
August 14, 2018: Neurological Sciences
Zijun Zhao, Yu Chen, Ngiambudulu M Francisco, Yuanqing Zhang, Minhao Wu
Chimeric antigen receptor T cell (CAR-T cell) therapy is a novel adoptive immunotherapy where T lymphocytes are engineered with synthetic receptors known as chimeric antigen receptors (CAR). The CAR-T cell is an effector T cell that recognizes and eliminates specific cancer cells, independent of major histocompatibility complex molecules. The whole procedure of CAR-T cell production is not well understood. The CAR-T cell has been used predominantly in the treatment of hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, and multiple myeloma...
July 2018: Acta Pharmaceutica Sinica. B
Matthew C Perez, Hsiang-Hsuan M Yu, Joseph Markowitz
Approximately half of patients with metastatic melanoma develop brain metastasis (MBM) in their disease course. However, patients with MBM were often excluded from early immunotherapy trials, and therefore, the role of immunotherapy in these patients is less clear. We review the case of a patient with widespread metastatic melanoma and symptomatic brain metastases at initial diagnosis. In this case, we have demonstrated that it is reasonable to pursue combination ipilimumab and nivolumab in borderline performance status patients with extensive brain metastases...
August 14, 2018: BMJ Case Reports
Angus G Dalgleish, Satvinder Mudan, Alberto Fusi
BACKGROUND: The use of checkpoint inhibitors (ipilimumab, pembrolizumab, nivolumab) has revolutionised the treatment of metastatic melanoma. However still more than the half the patients do not respond to single-agent immunotherapy. This has led to the development of combining these agents in an attempt to enhance the anti-cancer activity. More than 300 different studies with 15 different drug doses are currently ongoing. Combining different checkpoint inhibitors (CPIs) does indeed lead to an increase in response rate, but this is associated with significant toxicity...
August 14, 2018: Journal of Translational Medicine
Adi Sharbi-Yunger, Mareike Grees, Cafri Gal, David Bassan, Stefan B Eichmüller, Esther Tzehoval, Jochen Utikal, Viktor Umansky, Lea Eisenbach
For many years, clinicians and scientists attempt to develop methods to stimulate the immune system to target malignant cells. Recent data suggest that effective cancer vaccination requires combination immunotherapies to overcome tumor immune evasion. Through presentation of both MHC-I and II molecules, DCs based vaccine platforms are effective in generating detectable CD4 and CD8 T cell responses against tumor associated antigens. Several platforms include DC transfection with mRNA of the desired tumor antigen...
August 14, 2018: International Journal of Cancer. Journal International du Cancer
Sophie C Cheshire, Ruth E Board, Alexandra R Lewis, Laxminarayan D Gudur, Michael J Dobson
Pembrolizumab is a programmed cell death protein 1, or PD-1, inhibitor therapy immunotherapy for patients with advanced melanoma. This report discusses a series of documented cases of sarcoid-like reactions associated with this therapy. Three patients with malignant melanoma developed metastatic disease and were treated with pembrolizumab immunotherapy. Subsequent imaging showed lymphadenopathy in the mediastinum and hilar regions that was confirmed to represent a sarcoid-like reaction at histologic examination...
August 14, 2018: Radiology
Yuanxuan Xia, Leila A Mashouf, Russell Maxwell, Luke C Peng, Evan J Lipson, William H Sharfman, Chetan Bettegowda, Kristin J Redmond, Lawrence R Kleinberg, Michael Lim
Background: Patients with melanoma can present with a hemorrhagic intracranial lesion. Upon resection, pathology reports may not detect any malignant cells. However, the hemorrhage may obscure their presence and so physicians may still decide whether adjuvant radiotherapy should be applied. Here, we report on the outcomes of a series of patients with melanoma with hemorrhagic brain lesions that returned with no tumor cells. Methods: All melanoma patients who had craniotomies from 2008 to 2017 at a single institution for hemorrhagic brain lesions were identified through retrospective chart review...
2018: Surgical Neurology International
Han Yao, Huanbin Wang, Chushu Li, Jing-Yuan Fang, Jie Xu
Programmed death 1 (PD-1) and its two natural ligands PD-L1 and PD-L2 are responsible for delivering inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. In previous studies, PD-1 was found only expressed on the surface of immune cells, such as T cells and B cells while PD-1's ligands PD-L1 and PD-L2 were found expressed in some tumor cells. However, recent studies revealed intrinsic expression of PD-1 in melanoma and some other cancers. In melanoma cells, PD-1 can be activated by its ligand PD-L1 expressed by tumor cells, modulating downstream mammalian target of rapamycin signaling and promoting tumor growth independent of adaptive immunity...
2018: Frontiers in Immunology
Carlos W Wanderley, David F Colon, Joao Paulo Mesquita Luiz, Francisco F Oliveira, Paula R Viacava, Caio A Leite, Janaina A Pereira, Camila M Silva, Cassia R Silva, Rangel L Silva, Cesar A Speck-Hernandez, Jose M Mota, Jose C Alves-Filho, Roberto C Lima-Júnior, Thiago M Cunha, Fernando Q Cunha
Paclitaxel (PCX) is an antineoplastic agent widely used to treat several solid tumor types. The primary mechanism of action of PCX is based on microtubule stabilization inducing cell cycle arrest. Here, we use several tumor models to show that PCX not only induces tumor cell cycle arrest, but also promotes antitumor immunity. In vitro, PCX reprogrammed M2-polarized macrophages to the M1-like phenotype in a TLR4-dependent manner, similarly to LPS. PCX also modulated the tumor-associated macrophages (TAMs) profile in mouse models of breast and melanoma tumors; gene expression analysis showed that PCX altered the M2-like signature of TAMs toward an M1-like profile...
August 13, 2018: Cancer Research
Joobin Sattar, Adi Kartolo, Wilma M Hopman, Joshua Matthew Lakoff, Tara Baetz
IMPORTANCE: Immunotherapy has emerged as an effective treatment option for the management of advanced cancers. The effects of these immune checkpoint inhibitors in the older patient population has not been adequately assessed. OBJECTIVE: To understand the impact of aging on CTLA-4 and PDL-1 inhibitors efficacy and immune-related adverse events (irAE) in the context of real-world management of advanced solid cancers. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study involved all non-study patients with histologically-confirmed metastatic or inoperable solid cancers receiving immunotherapy at Kingston Health Sciences Centre...
August 10, 2018: Journal of Geriatric Oncology
Anne K Maxwell, Hiroki Takeda, Samuel P Gubbels
OBJECTIVE: To present a case of primary middle ear mucosal melanoma and perform a comprehensive literature review of middle ear and eustachian tube mucosal melanoma. PATIENT: A 61-year-old female presented with no prior history of melanoma and 3 months of aural fullness. A middle ear mass demonstrated primary mucosal melanoma. The mass extended from mesotympanum into hypotympanum, epitympanum, protympanum, eustachian tube, and mastoid antrum. Additionally, a nonenhancing expansile lesion of the petrous apex was noted on magnetic resonance imaging...
August 13, 2018: Annals of Otology, Rhinology, and Laryngology
Bianca Simon, Manuel Wiesinger, Johannes März, Kilian Wistuba-Hamprecht, Benjamin Weide, Beatrice Schuler-Thurner, Gerold Schuler, Jan Dörrie, Ugur Uslu
Natural killer T (NKT) cells represent a cell subpopulation that combines characteristics of natural killer (NK) cells and T cells. Through their endogenous T-cell receptors (TCRs), they reveal a pronounced intrinsic anti-tumor activity. Thus, a NKT cell transfected with a chimeric antigen receptor (CAR), which recognizes a tumor-specific surface antigen, could attack tumor cells antigen-specifically via the CAR and additionally through its endogenous TCR. NKT cells were isolated from peripheral blood mononuclear cells (PBMCs), expanded, and electroporated with mRNA encoding a chondroitin sulfate proteoglycan 4 (CSPG4)-specific CAR...
August 11, 2018: International Journal of Molecular Sciences
Svetomir N Markovic, Filippo Galli, Vera J Suman, Wendy K Nevala, Andrew M Paulsen, Joseph C Hung, Denise N Gansen, Lori A Erickson, Paolo Marchetti, Gregory A Wiseman, Alberto Signore
Early in the course of immunotherapy there is frequently a transient enlargement of tumor masses (pseudo-progression) due to tumor infiltration by TILs. Current clinical imaging modalities are not able to distinguished pseudo-progression from true tumor progression. Thus, patients often remain on treatment 4-8 weeks longer to confirm disease progression. Nuclear medicine offers the possibility to image immune cells and potentially discriminate pseudo-progression and progression. We conducted a pilot study in patients with metastatic melanoma receiving ipilimumab (IPI) or pembrolizumab (PEMBRO) to assess safety and feasibility of SPECT/CT imaging with 99m Tc- interleukin-2 (99m Tc-HYNIC-IL2) to detect TILs and distinguish between true progression from pseudo- progression...
July 13, 2018: Oncotarget
H Taquin, E Fontas, O Massol, P Chevallier, R Balloti, G Beranger, J-P Lacour, T Passeron, H Montaudié
BACKGROUND: Immunotherapies using anti-CTLA4 and anti-PD1 antibodies have revolutionised the management of patients with advanced melanoma. The aim of our study was to analyse the efficacy and safety of immunotherapies in patients with advanced melanoma under real-life conditions. METHODS: We conducted a monocentric, retrospective, observational study that included all patients treated with immunotherapies (ipilimumab, i.e. ipi; nivolumab, i.e. niv and pembrolizumab, i...
August 8, 2018: Annales de Dermatologie et de Vénéréologie
Nausicaa Malissen, Jean-Jacques Grob
The prognosis of patients with metastatic melanoma has dramatically improved in recent years with the introduction of two new therapeutic strategies. BRAF and MEK inhibitors are small molecules that are able to block the mitogen-activated protein kinase (MAPK) pathway, which is constitutively activated by recurrent BRAF V600 mutations in 45% of melanoma patients. These agents were shown to provide a rapid and strong response but are often limited by a high rate of secondary resistance. Monoclonal antibodies against the immune checkpoints cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) can restore an efficient and durable anti-tumor immunity, even following treatment discontinuation...
August 10, 2018: Drugs
Jun Ishihara, Ako Ishihara, Lambert Potin, Peyman Hosseinchi, Kazuto Fukunaga, Martina Damo, Thomas F Gajewski, Melody A Swartz, Jeffrey A Hubbell
CD40 is an immune co-stimulatory receptor expressed by antigen-presenting cells. Agonistic anti-CD40 antibodies have demonstrated considerable anti-tumor effects yet can also elicit serious treatment-related adverse events, such as liver toxicity, including in man. We engineered a variant that binds extracellular matrix through a super-affinity peptide derived from placenta growth factor-2 (PlGF-2123-144) to enhance anti-CD40's effects when administered locally. Peri-tumoral injection of PlGF-2123-144-anti-CD40 antibody showed prolonged tissue retention at the injection site and substantially decreased systemic exposure, resulting in decreased liver toxicity...
August 10, 2018: Molecular Cancer Therapeutics
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