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Memory t cell cancer

Marco A Moro-García, Juan C Mayo, Rosa M Sainz, Rebeca Alonso-Arias
T lymphocytes, from their first encounter with their specific antigen as naïve cell until the last stages of their differentiation, in a replicative state of senescence, go through a series of phases. In several of these stages, T lymphocytes are subjected to exponential growth in successive encounters with the same antigen. This entire process occurs throughout the life of a human individual and, earlier, in patients with chronic infections/pathologies through inflammatory mediators, first acutely and later in a chronic form...
2018: Frontiers in Immunology
David A Schaer, Richard P Beckmann, Jack A Dempsey, Lysiane Huber, Amelie Forest, Nelusha Amaladas, Yanxia Li, Ying Cindy Wang, Erik R Rasmussen, Darin Chin, Andrew Capen, Carmine Carpenito, Kirk A Staschke, Linda A Chung, Lacey M Litchfield, Farhana F Merzoug, Xueqian Gong, Philip W Iversen, Sean Buchanan, Alfonso de Dios, Ruslan D Novosiadly, Michael Kalos
Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control...
March 13, 2018: Cell Reports
Claudia Fumarola, Pier Giorgio Petronini, Roberta Alfieri
Cell metabolic reprogramming is one of the main hallmarks of cancer and many oncogenic pathways that drive the cancer-promoting signals also drive the altered metabolism. This review focuses on recent data on the use of oncogene-targeting agents as potential modulators of deregulated metabolism in different solid cancers. Many drugs, originally designed to inhibit a specific target, then have turned out to have different effects involving also cell metabolism, which may contribute to the mechanisms underlying the growth inhibitory activity of these drugs...
March 9, 2018: Biochemical Pharmacology
Wei Li, Xiujun Song, Huijie Yu, Manze Zhang, Fengsheng Li, Cheng Cao, Qisheng Jiang
Pancreatic cancer (PC) is a lethal disease and remains one of the most resistant cancers to traditional therapies. New therapeutic modalities are urgently needed, particularly immunotherapy, which has shown promise in numerous animal model studies. Dendritic cell (DC)-based immunotherapy has been used in clinical trials for various cancers, including PC, because DCs are the most potent antigen-presenting cell (APC), which are capable of priming naive T cells and stimulating memory T cells to generate antigen-specific responses...
March 8, 2018: Arab Journal of Gastroenterology: the Official Publication of the Pan-Arab Association of Gastroenterology
Maile K Hollinger, Valentina Giudice, Nicole A Cummings, Guillermo Rivell, Hansheng Zhang, Sachiko Kajigaya, Keyvan Keyvanfar, Jichun Chen, Xingmin Feng, Neal S Young
While PD-1 blockade has revolutionized cancer immunotherapy, immune-related adverse events (irAEs) present life-threatening complications. Recent reports of aplastic anemia (AA) as irAEs implicate PD-1/PD-L1 as important in preventing immune-mediated destruction of the hematopoietic niche. Infusion of PD-1-deficient (PD-1 KO) lymph node (LN) cells into minor-antigen mismatched mice resulted in early mortality, as well as more severe BM hypoplasia, anemia, and BM microarchitecture disruption in PD-1 KO LN-infused mice relative to mice that received B6 LN cell infusion...
March 7, 2018: Experimental Hematology
Ciprian Tomuleasa, Shigeo Fuji, Cristian Berce, Anca Onaciu, Sergiu Chira, Bobe Petrushev, Wilhelm-Thomas Micu, Vlad Moisoiu, Ciprian Osan, Catalin Constantinescu, Sergiu Pasca, Ancuta Jurj, Laura Pop, Ioana Berindan-Neagoe, Delia Dima, Shigehisa Kitano
Chimeric antigen receptor (CAR) T-cell technology has seen a rapid development over the last decade mostly due to the potential that these cells may have in treating malignant diseases. It is a generally accepted principle that very few therapeutic compounds deliver a clinical response without treatment-related toxicity, and studies have shown that CAR T-cells are not an exception to this rule. While large multinational drug companies are currently investigating the potential role of CAR T-cells in hematological oncology, the potential of such cellular therapies are being recognized worldwide as they are expected to expand in the patient to support the establishment of the immune memory, provide a continuous surveillance to prevent and/or treat a relapse, and keep the targeted malignant cell subpopulation in check...
2018: Frontiers in Immunology
Denis R Beckford Vera, Christof C Smith, Lisa M Bixby, Dylan M Glatt, Stuart S Dunn, Ryoichi Saito, William Y Kim, Jonathan S Serody, Benjamin G Vincent, Matthew C Parrott
The ability to non-invasively monitor tumor-infiltrating T cells in vivo could provide a powerful tool to visualize and quantify tumor immune infiltrates. For non-invasive evaluations in vivo, an anti-CD3 mAb was modified with desferrioxamine (DFO) and radiolabeled with zirconium-89 (Zr-89 or 89Zr). Radiolabeled 89Zr-DFO-anti-CD3 was tested for T cell detection using positron emission tomography (PET) in both healthy mice and mice bearing syngeneic bladder cancer BBN975. In vivo PET/CT and ex vivo biodistribution demonstrated preferential accumulation and visualization of tracer in the spleen, thymus, lymph nodes, and bone marrow...
2018: PloS One
Aileen Weiwei Li, Miguel C Sobral, Soumya Badrinath, Youngjin Choi, Amanda Graveline, Alexander G Stafford, James C Weaver, Maxence O Dellacherie, Ting-Yu Shih, Omar A Ali, Jaeyun Kim, Kai W Wucherpfennig, David J Mooney
Existing strategies to enhance peptide immunogenicity for cancer vaccination generally require direct peptide alteration, which, beyond practical issues, may impact peptide presentation and result in vaccine variability. Here, we report a simple adsorption approach using polyethyleneimine (PEI) in a mesoporous silica microrod (MSR) vaccine to enhance antigen immunogenicity. The MSR-PEI vaccine significantly enhanced host dendritic cell activation and T-cell response over the existing MSR vaccine and bolus vaccine formulations...
March 5, 2018: Nature Materials
Debora Vignali, Elisa Cantarelli, Carlotta Bordignon, Adriana Canu, Antonio Citro, Andrea Annoni, Lorenzo Piemonti, Paolo Monti
Stem memory T cells (Tscm) constitute the earliest developmental stage of memory T cells, displaying stem cell-like properties such as self-renewal capacity. Their superior immune reconstitution potential has sparked interest in cancer immune-therapy, vaccine development and immune reconstitution, whereas their role in autoimmunity is largely unexplored. Here we show that autoreactive CD8+ Tscm specific for β cell antigens GAD65, insulin and IGRP are present in patients with type 1 diabetes (T1D). In vitro, generation of autoreactive Tscm from naïve precursors required the presence of the homeostatic cytokine interleukin-7 (IL-7)...
March 5, 2018: Diabetes
Emily Z Keung, Esosa U Ukponmwan, Alexandria P Cogdill, Jennifer A Wargo
Unprecedented advances in the treatment of cancer have occurred through the use of immunotherapy, with several agents currently approved by the Food and Drug Administration (FDA) for the treatment of widespread metastatic disease across cancer types. Immune checkpoint blockade represents a particularly promising class of agents that block inhibitory molecules on the surface of T cells, resulting in their activation and propagation of an immune response. Treatment with these agents may re-invigorate anti-tumor immunity, resulting in therapeutic responses, and use of these agents currently is being studied in the adjuvant setting...
March 2, 2018: Annals of Surgical Oncology
Karlo Perica, Kevin J Curran, Renier J Brentjens, Sergio A Giralt
Two commercial Chimeric Antigen Receptor (CAR) T cell therapies for CD19 expressing B cell malignancies, Kymriah and Yescarta, have recently been approved by the FDA. The administration of CAR T cells is a complex endeavor involving cell manufacture, tracking and shipping of apheresis products, and management of novel and severe toxicities. At Memorial Sloan Kettering Cancer Center, we have identified eight essential tasks that define the CAR T cell workflow. In this review, we discuss practical aspects of CAR T cell program development, including clinical, administrative, and regulatory challenges for successful implementation...
February 27, 2018: Biology of Blood and Marrow Transplantation
Elizabeth Q Littauer, Lisa K Mills, Nicole Brock, E Stein Esser, Andrey Romanyuk, Joanna A Pulit-Penaloza, Elena V Vassilieva, Jacob T Beaver, Olivia Antao, Florian Krammer, Richard W Compans, Mark R Prausnitz, Ioanna Skountzou
The widely used influenza subunit vaccine would benefit from increased protection rates in vulnerable populations. Skin immunization by microneedle (MN) patch can increase vaccine immunogenicity, as well as increase vaccination coverage due to simplified administration. To further increase immunogenicity, we used granulocyte-macrophage colony stimulating factor (GM-CSF), an immunomodulatory cytokine already approved for skin cancer therapy and cancer support treatment. GM-CSF has been shown to be upregulated in skin following MN insertion...
February 26, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Tadej Dovšak, Alojz Ihan, Vojko Didanovič, Andrej Kansky, Miha Verdenik, Nataša Ihan Hren
BACKGROUND: The immune system has a known role in the aetiology, progression and final treatment outcome of oral squamous cell cancers. The aim of this study was to evaluate the influence of radical surgery and radiotherapy on advanced oral squamous cell carcinoma blood counts, lymphocyte subsets and levels of acute inflammatory response markers. METHODS: Blood samples were obtained from 56 patients 5 days before and 10 days after surgery, 30 days and 1 year after radiotherapy...
March 1, 2018: BMC Cancer
Fabian Schlott, Dominik Steubl, Stefanie Ameres, Andreas Moosmann, Stefan Dreher, Uwe Heemann, Volker Hösel, Dirk H Busch, Michael Neuenhahn
Human Cytomegalovirus (CMV) reactivation remains a major source of morbidity in patients after solid organ and hematopoietic stem cell transplantation (HSCT). Adoptive T cell therapy (ACT) with CMV-specific T cells is a promising therapeutic approach for HSCT recipients, but might be counteracted by CMV's immune evasion strategies. HLA-C*07:02 is less susceptible to viral immune evasion suggesting HLA-C*07:02-restricted viral epitopes as promising targets for ACT. For a better understanding of HLA-C*07:02-restricted CMV-specific T cells we used recently generated reversible HLA-C*07:02/IE-1 multimers (Streptamers) recognizing a CMV-derived Immediate-Early-1 (IE-1) epitope and analyzed phenotypic and functional T cell characteristics...
2018: PloS One
Jing Hu, Lu Zheng, Huanle Zhang, Sandian Zhang, Guodong Xu
OBJECTIVE: To investigate the expression and prognostic value of memory T lymphocyte in patients with non-small cell lung cancer(NSCLC) following radiotherapy. METHODS: Forty-six patients with NSCLC receiving radiotherapy in Ningbo Medical Center Lihuili Hospital from February 2010 to May 2012 were enrolled in the study and 50 healthy subjects served as the control group. The central memory T cell (TCM ) and effector memory T cell (TEM ) in peripheral blood CD4+ , CD8+ cells were detected by flow cytometry...
May 25, 2017: Zhejiang da Xue Xue Bao. Yi Xue Ban, Journal of Zhejiang University. Medical Sciences
Jooeun Bae, Teru Hideshima, Yu-Tzu Tai, Yan Song, Paul Richardson, Noopur Raje, Nikhil C Munshi, Kenneth C Anderson
Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138+ MM cells, CD4+ CD25+ FoxP3+ regulatory T cells, and HLA-DRLow/- CD11b+ CD33+ myeloid-derived suppressor cells; and decreases expression of PD1/PD-L1 on CD8+ T cells and of immune checkpoints in bone marrow cells from myeloma patients...
February 22, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Anjum B Khan, Ben Carpenter, Pedro Santos E Sousa, Constandina Pospori, Reema Khorshed, James Griffin, Pedro Veliça, Mathias Zech, Sara Ghorashian, Calum Forrest, Sharyn Thomas, Sara Gonzalez Anton, Maryam Ahmadi, Angelika Holler, Barry Flutter, Zaida Ramirez-Ortiz, Terry K Means, Clare L Bennett, Hans Stauss, Emma Morris, Cristina Lo Celso, Ronjon Chakraverty
A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that re-directing T cells to specialized niches in the bone marrow (BM) that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration towards vascular-associated CXCL12+ cells in the BM and increased their local engraftment...
February 27, 2018: Journal of Clinical Investigation
Hiroaki Tanaka, Tatsuro Tamura, Yoshihiro Okita, Mami Yoshii, Mao Tokumoto, Yukie Go, Chie Sakimura, Soichiro Hiramatsu, Junya Nishimura, Yoshihito Yamagoe, Masakazu Yashiro, Yuichiro Miki, Takahiro Toyokawa, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira
There are many reports on the association between infiltrating immune cells andcancer prognosis. It is generally thought that cancer cells escape from the immune surveillance system in vivo. Cells associatedwith tumor immunosuppressive mechanisms include macrophages, regulatory T cells, bone marrow-derived immunosuppressive cells(MDSC), andneutrophils. These immunosuppressive cells enhance the production of TGF-b andIL -10 andthe expression of PDL-1 by cytokines producedby stromal cells such as cancer cells andfibroblasts, thereby inducing cytotoxic T cells lymphocytes(CTL)...
February 2018: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Jae H Park, F Andres Romero, Ying Taur, Michel Sadelain, Renier J Brentjens, Tobias M Hohl, Susan K Seo
Background: Chimeric antigen receptor (CAR)-modified T cells that target the CD19 antigen present a novel promising therapy for the treatment of relapsed B-cell acute lymphoblastic leukemia (ALL). Although cytokine release syndrome (CRS) and neurotoxicity have emerged as predominant non-infectious complications of CD19 CAR T cell therapy, infections associated with this treatment modality have not been well documented. Methods: We analyzed infectious complications that followed CD19 CAR T cell therapy in 53 adult patients with relapsed ALL enrolled in a phase I clinical trial at Memorial Sloan Kettering Cancer Center (NCT01044069)...
February 22, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Felipe Flores-Santibáñez, Bárbara Cuadra, Dominique Fernández, Mariana V Rosemblatt, Sarah Núñez, Pablo Cruz, Felipe Gálvez-Cancino, J César Cárdenas, Alvaro Lladser, Mario Rosemblatt, María Rosa Bono, Daniela Sauma
Memory CD8+ T cells are ideal candidates for cancer immunotherapy because they can mediate long-term protection against tumors. However, the therapeutic potential of different in vitro -generated CD8+ T cell effector subsets to persist and become memory cells has not been fully characterized. Type 1 CD8+ T (Tc1) cells produce interferon-γ and are endowed with high cytotoxic capacity, whereas IL-17-producing CD8+ T (Tc17) cells are less cytotoxic but display enhanced self-renewal capacity. We sought to evaluate the functional properties of in vitro -generated Tc17 cells and elucidate their potential to become long lasting memory cells...
2018: Frontiers in Immunology
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