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allogeneic immune therapy

Krzysztof Giannopoulos
The modest successes of targeted therapies along with the curative effects of allogeneic hematopoietic stem cell transplantation (alloHSCT) in acute myeloid leukemia (AML) stimulate the development of new immunotherapies. One of the promising methods of immunotherapy is the activation of immune response by the targeting of negative control checkpoints. The two best-known inhibitory immune checkpoints are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed cell death protein 1 receptor (PD-1). In AML, PD-1 expression is observed in T-cell subpopulations, including T regulatory lymphocytes...
February 12, 2019: Journal of Clinical Medicine
Alex B Blair, Jennifer Kleponis, Dwayne L Thomas Ii, Stephen T Muth, Adrian G Murphy, Victoria Kim, Lei Zheng
Pancreatic ductal adenocarcinoma (PDAC) represents an immune quiescent tumor that is resistant to immune checkpoint inhibitors. Previously, our group has shown that a GM-CSF secreting allogenic pancreatic tumor cell vaccine (GVAX), may prime the tumor microenvironment by inducing intratumoral T-cell infiltration. Here, we show that untreated PDACs express minimal indoleamine-2, 3-dioxygenase (IDO1); however, GVAX therapy induced IDO1 expression on tumor epithelia as well as vaccine-induced tertiary lymphoid aggregates...
February 12, 2019: Journal of Clinical Investigation
Wendy W Pang, Agnieszka Czechowicz, Aaron C Logan, Rashmi Bhardwaj, Jessica Poyser, Christopher Y Park, Irving L Weissman, Judith A Shizuru
The myelodysplastic syndromes (MDS) represent a group of clonal disorders that result in ineffective hematopoiesis and are associated with an increased risk of transformation into acute leukemia. MDS arises from hematopoietic stem cells (HSCs); therefore, successful elimination of MDS HSCs is an important part of any curative therapy. However, current treatment options, including allogeneic hematopoietic cell transplantation (HCT), often fail to ablate disease-initiating MDS HSCs, and thus have low curative potential and high relapse rates...
February 11, 2019: Blood
Mohammed Alnaggar, Yan Xu, Jingxia Li, Junyi He, Jibing Chen, Man Li, Qingling Wu, Li Lin, Yingqing Liang, Xiaohua Wang, Jiawei Li, Yi Hu, Yan Chen, Kecheng Xu, Yangzhe Wu, Zhinan Yin
BACKGROUND: Cholangiocarcinoma (CCA) is a highly aggressive and fatal tumor. CCA occurs in the epithelial cells of bile ducts. Due to increasing incidences, CCA accounts for 3% of all gastrointestinal malignancies. In addition to comprehensive treatments for cancer, such as surgery, chemotherapy, and radiotherapy, during the past few years, cellular immunotherapy has played an increasingly important role. As a result of our research, we have discovered the γδ T cell-based immunotherapy for CCA...
February 8, 2019: Journal for Immunotherapy of Cancer
Hossein Nejadnik, Jessica Tseng, Heike Daldrup-Link
"Off the shelf" allogeneic stem cell transplants and stem cell nano-composites are being used for the treatment of degenerative bone diseases. However, major and minor histocompatibility antigens of therapeutic cell transplants can be recognized as foreign and lead to their rejection by the host immune system. If a host immune response is identified within the first week post-transplant, immune modulating therapies could be applied to prevent graft failure and support engraftment. Ferumoxytol (Feraheme™) is an FDA approved iron oxide nanoparticle preparation for the treatment of anemia in patients...
February 7, 2019: Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology
Laurens E Franssen, Tuna Mutis, Henk M Lokhorst, Niels W C J van de Donk
The treatment of multiple myeloma (MM) has evolved substantially over the past decades, leading to a significantly improved outcome of MM patients. The introduction of high-dose therapy, especially, and autologous stem cell transplantation, as well as the development of new drugs, such as immunomodulatory drugs (IMiDs) and proteasome inhibitors have contributed to the improvement in survival. However, eventually most MM patients relapse, which indicates that there is a need for new agents and novel treatment strategies...
2019: Therapeutic Advances in Hematology
Sheila A Fisher, Antony Cutler, Carolyn Doree, Susan J Brunskill, Simon J Stanworth, Cristina Navarrete, John Girdlestone
BACKGROUND: Recipients of allogeneic haematopoietic stem cell transplants (HSCT) can develop acute or chronic, or both forms of graft-versus-host disease (a/cGvHD), whereby immune cells of the donor attack host tissues. Steroids are the primary treatment, but patients with severe, refractory disease have limited options and a poor prognosis. Mesenchymal stromal cells (MSCs) exhibit immunosuppressive properties and are being tested in clinical trials for their safety and efficacy in treating many immune-mediated disorders...
January 30, 2019: Cochrane Database of Systematic Reviews
Xuelian Sun, Qiukui Hao, Renjie Tang, Chun Xiao, Meiling Ge, Birong Dong
Frailty, one appealing target for improving successful aging of the elderly population, is a common clinical syndrome based on the accumulation of multisystemic function declines and the increase in susceptibility to stressors during biological aging. The age-dependent senescence, the frailty-related stem cell depletion, chronic inflammation, imbalance of immune homeostasis, and the reduction of multipotent stem cells, collectively suggest the rational hypothesis that it is possible to (partially) cure frailty with stem cells...
January 29, 2019: Rejuvenation Research
Ejlal Abu-El-Rub, Glen Lester Sequiera, Niketa Sareen, Weiang Yan, Meenal Moudgil, Mohammad Golam Sabbir, Sanjiv Dhingra
Bone marrow-derived allogeneic (donor derived) mesenchymal stem cells (MSCs) are immunoprivileged and are considered to be prominent candidates for regenerative therapy for numerous degenerative diseases. Even though the outcome of initial allogeneic MSCs based clinical trials was encouraging, the overall enthusiasm, of late, has dimmed down. This is due to failure of long-term survival of transplanted cells in the recipient. In fact, recent analyses of allogeneic MSC-based studies demonstrated that cells after transplantation turned immunogenic and were subsequently rejected by host immune system...
January 28, 2019: Cell Death & Disease
Lukas Marcelis, Thomas Tousseyn
Post-transplant lymphoproliferative disorders (PTLDs) cover a broad spectrum of lymphoproliferative lesions arising after solid organ or allogeneic hematopoietic stem cell transplantation. The composition and function of the tumor microenvironment (TME), consisting of all non-malignant constituents of a tumor, is greatly impacted in PTLD through a complex interplay between 4 factors: 1) the graft organ causes immune stimulation through chronic antigen presentation; 2) the therapy to prevent organ rejection interferes with the immune system; 3) the oncogenic Epstein-Barr virus (EBV), present in 80% of PTLDs, has a causative role in the oncogenic transformation of lymphocytes and influences immune responses; 4) interaction with the donor-derived immune cells accompanying the graft...
January 24, 2019: Cancer Microenvironment: Official Journal of the International Cancer Microenvironment Society
Wei Wang, Na Zhao, Baozhu Li, Haopeng Gao, Yongjia Yan, Hao Guo
Interleukin-35 (IL-35) is a cytokine recently discovered to play a potent immunosuppressive role by intensifying the functions of regulatory T cells and inhibiting the proliferation and functions of T helper 1 and T helper 17 cells. Mesenchymal stem cells (MSCs) have recently emerged as promising candidates for cell-based immune therapy, and our previous study showed that IL-35 gene modification can effectively enhance the therapeutic effect of MSCs in vitro. In this study, we isolated adipose tissue-derived MSCs in vitro and infected them with lentiviral vectors overexpressing the IL-35 gene, thereby creating IL-35-MSCs...
January 21, 2019: Scandinavian Journal of Immunology
Robert Zeiser, Dietrich W Beelen, Wolfgang Bethge, Martin Bornhäuser, Gesine Bug, Andreas Burchert, Maximilian Christopeit, Justus Duyster, Jürgen Finke, Armin Gerbitz, Jan Henning Klusmann, Guido Kobbe, Michael Lübbert, Carsten Müller-Tidow, Uwe Platzbecker, Wolf Rösler, Martin Sauer, Christoph Schmid, Thomas Schroeder, Mathias Stelljes, Nicolaus Kröger, Lutz P Müller
The curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) relies mainly on the graft-versus-leukemia effect. Relapse after allo-HCT occurs in a considerable proportion of patients and has a dismal prognosis, with still very limited curative potential. This review provides an overview of the established and evolving approaches to preventing or treating relapse of AML and MDS after allo-HCT, in the context of novel insight into the biology of relapse...
January 15, 2019: Biology of Blood and Marrow Transplantation
Giorgio Ottaviano, Robert Chiesa, Tobias Feuchtinger, Mark A Vickers, Anne Dickinson, Andrew R Gennery, Paul Veys, Stephen Todryk
Adverse outcomes following virus-associated disease in patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) have encouraged strategies to control viral reactivation in immunosuppressed patients. However, despite timely treatment with antiviral medication, some viral infections remain refractory to treatment, which hampers outcomes after HSCT, and are responsible for a high proportion of transplant-related morbidity and mortality. Adoptive transfer of donor-derived lymphocytes aims to improve cellular immunity and to prevent or treat viral diseases after HSCT...
January 14, 2019: Cells
Elisa Zaghi, Michela Calvi, Emanuela Marcenaro, Domenico Mavilio, Clara Di Vito
Natural Killer (NK) cells are innate immune cells with a primary role in the immune surveillance against non-self-cells. NK cell recognition of "self" relies on the surface expression on autologous cells of MHC class I (MHC-I) molecules. Either the absence or the down-modulation of MHC-I on target cells "license" NK cells to kill threatening tumor-transformed or virally infected cells. This phenomenon is controlled by a limited repertoire of activating and inhibitory NK receptors (aNKRs and iNKRs) that tunes NK cell activation and effector functions...
January 15, 2019: Journal of Leukocyte Biology
Katelyn E Masiuk, Jennifer Laborada, Maria Grazia Roncarolo, Roger P Hollis, Donald B Kohn
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a devastating autoimmune disease caused by mutations in FoxP3, a transcription factor required for the development and function of regulatory T cells (Treg cells). Allogeneic hematopoietic stem cell transplant (HSCT) can be curative, but suitable donors are often unavailable. Here, we demonstrate a strategy for autologous HSCT and gene therapy utilizing a lentiviral vector (LV) to restore FoxP3 expression under the control of endogenous human FOXP3 regulatory elements...
February 7, 2019: Cell Stem Cell
Francesco Ceppi, Raffaele Renella, Manuel Diezi, Marc Ansari, Michel A Duchosal, Caroline Arber, Lana Kandalaft, George Coukos, Maja Beck-Popovic
Fighting leukemia using the immune system (antibodies, lymphocytes) is an old idea, which has already been fulfilled in allogeneic bone marrow transplantation. Indeed, the effectiveness of the transplant depends on the action of the donor lymphocytes. To limit the adverse effects on bystander organs (graft-versus-host disease), autologous T cells can be engineered to express synthetic chimeric antigen receptors (CARs) with artificially redirected antigen specificity. Autologous T cells engineered to express a CAR targeting CD19 have shown unprecedented efficacy in clinical trials for relapsed/refractory B-cell leukemias and lymphomas...
January 9, 2019: Revue Médicale Suisse
Michael Scordo, Meier Hsu, Ann A Jakubowski, Gunjan L Shah, Christina Cho, Molly A Maloy, Scott T Avecilla, Esperanza Papadopoulos, Boglarka Gyurkocza, Hugo Castro-Malaspina, Roni Tamari, Richard J O'Reilly, Miguel Angel-Perales, Sergio A Giralt, Brian C Shaffer
Immune mediated cytopenias (IC), such as immune thrombocytopenia (ITP) and immune hemolytic anemia (IHA), are among the adverse events after allogeneic hematopoietic cell transplantation (allo-HCT). Previous reports suggest that in-vivo T-cell depletion may increase the incidence of IC after allo-HCT. We evaluated whether a strategy that reduces functional donor T-cells via ex-vivo CD34+ -selection associates with the development of IC in a cohort of 408 patients who underwent allo-HCT for hematologic malignancy...
January 6, 2019: Biology of Blood and Marrow Transplantation
Takahiro Kobayashi, Yong-Mei Guo, Takaya Yamashita, Miho Nara, Tomoko Yoshioka, Yoshihiro Kameoka, Takahiro Fukuda, Naoto Takahashi
Although programmed cell death (PD)-1 blockade induces immune-related adverse events (irAEs), little is known about the safety of PD-1 blockade after allogeneic hematopoietic stem cell transplantation (HSCT). Here, we describe immune system changes during nivolumab-related myositis in a patient with Hodgkin's lymphoma after allogeneic HSCT; to our knowledge, this is the first such report in the literature. At the onset of myositis, the patient lost lower limb mobility against gravity, and had an activated immune profile with increased cytotoxic CD107a and granzyme B expression, as well as pro-inflammatory cytokines, interferon-γ, tumor necrosis factor-α, interleukin-2 in T and NK cells compared to healthy donor...
January 3, 2019: International Journal of Hematology
Chun-Hui Jin, Jinxing Xia, Sarwish Rafiq, Xin Huang, Zheng Hu, Xianzheng Zhou, Renier J Brentjens, Yong-Guang Yang
BACKGROUND: Adoptive immunotherapy using T cells expressing chimeric antigen receptors (CARs) targeting CD19 has produced remarkable clinical outcomes. However, much of the mechanisms of action, such as the development of memory responses and sources of immune cytokines, remain elusive largely due to the challenge of characterizing human CAR T cell function in vivo. The lack of a suitable in vivo model also hinders the development of new CAR T cell therapies. METHODS: We established a humanized mouse (hu-mouse) model with a functional human immune system and genetically-matched (autologous) primary acute B-lymphoblastic leukemia (B-ALL) that permits modeling of CD19-targeted CAR T cell therapy in immunocompetent hosts without allogeneic or xenogeneic immune responses...
December 20, 2018: EBioMedicine
Simon-David Gauthier, Moutuaata M Moutuou, Francis Daudelin, Dominique Leboeuf, Martin Guimond
Immune reconstitution following allogeneic hematopoietic stem cell transplantation (allo-SCT) relies primarily on homeostatic proliferation (HP) of mature T lymphocytes but this process is typically impaired during graft-versus-host disease (GVHD). We previously showed that low IL-7 levels combined with lack of dendritic cell (DC) regeneration constrain CD4+ T cell HP during GVHD. However, it is not clear whether these alterations to the peripheral CD4+ T cell niche also contribute to impair CD8+ T cell regeneration during GVHD...
December 18, 2018: Biology of Blood and Marrow Transplantation
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