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Virus specific car t cells

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https://www.readbyqxmd.com/read/28426845/her2-specific-chimeric-antigen-receptor-modified-virus-specific-t-cells-for-progressive-glioblastoma-a-phase-1-dose-escalation-trial
#1
Nabil Ahmed, Vita Brawley, Meenakshi Hegde, Kevin Bielamowicz, Mamta Kalra, Daniel Landi, Catherine Robertson, Tara L Gray, Oumar Diouf, Amanda Wakefield, Alexia Ghazi, Claudia Gerken, Zhongzhen Yi, Aidin Ashoori, Meng-Fen Wu, Hao Liu, Cliona Rooney, Gianpietro Dotti, Adrian Gee, Jack Su, Yvonne Kew, David Baskin, Yi Jonathan Zhang, Pamela New, Bambi Grilley, Milica Stojakovic, John Hicks, Suzanne Z Powell, Malcolm K Brenner, Helen E Heslop, Robert Grossman, Winfried S Wels, Stephen Gottschalk
Importance: Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited. Objective: To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)-modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity. Design, Setting, and Participants: In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children's Hospital, patients with progressive HER2-positive glioblastoma were enrolled between July 25, 2011, and April 21, 2014...
April 20, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28330372/car-t-cell-therapy-progress-and-prospects
#2
Olivia Wilkins, Allison M Keeler, Terence R Flotte
Lentivirus-mediated transduction of autologous T cells with a chimeric antigen receptor (CAR) to confer a desired epitope specificity as a targeted immunotherapy for cancer has been among the first human gene therapy techniques to demonstrate widespread therapeutic efficacy. Other approaches to using gene therapy to enhance antitumor immunity have been less specific and less effective. These have included amplification, marking, and cytokine transduction of tumor infiltrating lymphocytes, recombinant virus-based expression of tumor antigens as a tumor vaccine, and transduction of antigen-presenting cells with tumor antigens...
April 2017: Human Gene Therapy Methods
https://www.readbyqxmd.com/read/28230645/clinical-scale-rapid-autologous-bk-virus-specific-t-cell-line-generation-from-kidney-transplant-recipients-with-active-viremia-for-adoptive-immunotherapy
#3
Caroline Lamarche, Julie Orio, Victoria Georges-Tobar, Thomas Pincez, Mathieu Goupil, Amina Dahmani, Cedric Carli C, Ann Brasey, Lambert Busque, Jean-Sébastien Delisle
BACKGROUND: Polyomavirus-associated nephropathy (PVAN) following BK virus reactivation in kidney transplant recipients (KTR) can compromise graft survival. Lowering immunosuppression is the only established approach to prevent or treat PVAN but nonspecifically increasing host immune competence also augments rejection risk. Ex vivo T cell stimulation/expansion offers the possibility to generate BK-specific T cell lines for adoptive immunotherapy. The objective of this study was to develop and characterize a clinical scale protocol to generate BK-specific T cell lines from viremic KTR...
February 23, 2017: Transplantation
https://www.readbyqxmd.com/read/28183713/vaccination-targeting-native-receptors-to-enhance-the-function-and-proliferation-of-chimeric-antigen-receptor-car-modified-t-cells
#4
Miyuki Tanaka, Haruko Tashiro, Bilal Omer, Natasha Lapteva, Jun Ando, Minhtran Ngo, Birju Mehta, Gianpietro Dotti, Paul R Kinchington, Ann M Leen, Claudia Rossig, Cliona M Rooney
Purpose: The multiple mechanisms used by solid tumors to suppress tumor-specific immune responses are a major barrier to the success of adoptively transferred tumor-specific T cells. As viruses induce potent innate and adaptive immune responses, we hypothesized that the immunogenicity of viruses could be harnessed for the treatment of solid tumors if virus-specific T cells (VST) were modified with tumor-specific chimeric antigen receptors (CAR). We tested this hypothesis using VZV-specific T cells (VZVST) expressing a CAR for GD2, a disialoganglioside expressed on neuroblastoma and certain other tumors, so that the live-attenuated VZV vaccine could be used for in vivo stimulation...
February 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28143740/engineering-hiv-resistant-anti-hiv-chimeric-antigen-receptor-t-cells
#5
Malika Hale, Taylor Mesojednik, Guillermo S Romano Ibarra, Jaya Sahni, Alison Bernard, Karen Sommer, Andrew M Scharenberg, David J Rawlings, Thor A Wagner
The treatment or cure of HIV infection by cell and gene therapy has been a goal for decades. Recent advances in both gene editing and chimeric antigen receptor (CAR) technology have created new therapeutic possibilities for a variety of diseases. Broadly neutralizing monoclonal antibodies (bNAbs) with specificity for the HIV envelope glycoprotein provide a promising means of targeting HIV-infected cells. Here we show that primary human T cells engineered to express anti-HIV CARs based on bNAbs (HIVCAR) show specific activation and killing of HIV-infected versus uninfected cells in the absence of HIV replication...
March 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28129120/targeting-of-aberrant-%C3%AE-v%C3%AE-6-integrin-expression-in-solid-tumors-using-chimeric-antigen-receptor-engineered-t-cells
#6
Lynsey M Whilding, Ana C Parente-Pereira, Tomasz Zabinski, David M Davies, Roseanna M G Petrovic, Y Vincent Kao, Shobhit A Saxena, Alex Romain, Jose A Costa-Guerra, Shelia Violette, Hiroaki Itamochi, Sadaf Ghaem-Maghami, Sabari Vallath, John F Marshall, John Maher
Expression of the αvβ6 integrin is upregulated in several solid tumors. In contrast, physiologic expression of this epithelial-specific integrin is restricted to development and epithelial re-modeling. Here, we describe, for the first time, the development of a chimeric antigen receptor (CAR) that couples the recognition of this integrin to the delivery of potent therapeutic activity in a diverse repertoire of solid tumor models. Highly selective targeting αvβ6 was achieved using a foot and mouth disease virus-derived A20 peptide, coupled to a fused CD28(+)CD3 endodomain...
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28126984/vaccination-to-improve-the-persistence-of-cd19car-gene-modified-t-cells-in-relapsed-pediatric-acute-lymphoblastic-leukemia
#7
C Rossig, M Pule, B Altvater, S Saiagh, G Wright, S Ghorashian, L Clifton-Hadley, K Champion, Z Sattar, B Popova, A Hackshaw, P Smith, T Roberts, E Biagi, B Dreno, R Rousseau, S Kailayangiri, M Ahlmann, R Hough, B Kremens, M G Sauer, P Veys, N Goulden, M Cummins, P J Amrolia
Trials with second generation CD19 chimeric antigen receptors (CAR) T-cells report unprecedented responses but are associated with risk of cytokine release syndrome (CRS). Instead, we studied the use of donor Epstein-Barr virus-specific T-cells (EBV CTL) transduced with a first generation CD19CAR, relying on the endogenous T-cell receptor for proliferation. We conducted a multi-center phase I/II study of donor CD19CAR transduced EBV CTL in pediatric acute lymphoblastic leukaemia (ALL). Patients were eligible pre-emptively if they developed molecular relapse (>5 × 10(-4)) post first stem cell transplant (SCT), or prophylactically post second SCT...
May 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27965307/dual-specific-chimeric-antigen-receptor-t-cells-and-an-indirect-vaccine-eradicate-a-variety-of-large-solid-tumors-in-an-immunocompetent-self-antigen-setting
#8
Clare Y Slaney, Bianca von Scheidt, Alexander J Davenport, Paul A Beavis, Jennifer A Westwood, Sherly Mardiana, David C Tscharke, Sarah Ellis, H Miles Prince, Joseph A Trapani, Ricky W Johnstone, Mark J Smyth, Michele W Teng, Aesha Ali, Zhiya Yu, Steven A Rosenberg, Nicholas P Restifo, Paul Neeson, Phillip K Darcy, Michael H Kershaw
Purpose: While adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors for most cancers. We aimed to develop an immunotherapy approach effective against large tumors in an immunocompetent, self-antigen preclinical mouse model.Experimental Design: In this study, we generated dual-specific T cells expressing both a CAR specific for Her2 and a TCR specific for the melanocyte protein (gp100)...
December 13, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27913506/checkpoint-inhibition-and-cellular-immunotherapy-in-lymphoma
#9
REVIEW
Premal Lulla, Helen E Heslop
Hodgkin and non-Hodgkin lymphoma are both good targets for immunotherapy, as they are accessible to antibodies and cell-based immunotherapy, express costimulatory molecules, and express lineage-restricted, viral, and unique tumor antigens. Blockade of the programmed-death 1 (PD-1) immune checkpoint has produced very encouraging response rates in patients with Hodgkin lymphoma, whereas adoptive transfer of Epstein-Barr Virus (EBV)-specific T cells has shown clinical activity in patients with posttransplant lymphoma and other EBV-associated lymphomas...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27535056/chimeric-antigen-receptor-t-cells-guided-by-the-single-chain-fv-of-a-broadly-neutralizing-antibody-specifically-and-effectively-eradicate-virus-reactivated-from-latency-in-cd4-t-lymphocytes-isolated-from-hiv-1-infected-individuals-receiving-suppressive-combined
#10
Bingfeng Liu, Fan Zou, Lijuan Lu, Cancan Chen, Dalian He, Xu Zhang, Xiaoping Tang, Chao Liu, Linghua Li, Hui Zhang
Despite the advent of combined antiretroviral therapy (cART), the persistence of viral reservoirs remains a major barrier to curing human immunodeficiency virus type 1 (HIV-1) infection. Recently, the shock and kill strategy, by which such reservoirs are eradicated following reactivation of latent HIV-1 by latency-reversing agents (LRAs), has been extensively practiced. It is important to reestablish virus-specific and reliable immune surveillance to eradicate the reactivated virus-harboring cells. In this report, we attempted to reach this goal by using newly developed chimeric antigen receptor (CAR)-T cell technology...
November 1, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27375569/cytomegalovirus-infected-cells-resist-t-cell-mediated-killing-in-an-hla-recognition-independent-manner
#11
Julia Proff, Christian Walterskirchen, Charlotte Brey, Rene Geyeregger, Florian Full, Armin Ensser, Manfred Lehner, Wolfgang Holter
In order to explore the potential of HLA-independent T cell therapy for human cytomegalovirus (HCMV) infections, we developed a chimeric antigen receptor (CAR) directed against the HCMV encoded glycoprotein B (gB), which is expressed at high levels on the surface of infected cells. T cells engineered with this anti-gB CAR recognized HCMV-infected cells and released cytokines and cytotoxic granules. Unexpectedly, and in contrast to analogous approaches for HIV, Hepatitis B or Hepatitis C virus, we found that HCMV-infected cells were resistant to killing by the CAR-modified T cells...
2016: Frontiers in Microbiology
https://www.readbyqxmd.com/read/27246312/imaging-of-sleeping-beauty-modified-cd19-specific-t-cells-expressing-hsv1-thymidine-kinase-by-positron-emission-tomography
#12
Amer M Najjar, Pallavi R Manuri, Simon Olivares, Leo Flores, Tiejuan Mi, Helen Huls, Elizabeth J Shpall, Richard E Champlin, Nashaat Turkman, Vincenzo Paolillo, Jason Roszik, Brian Rabinovich, Dean A Lee, Mian Alauddin, Juri Gelovani, Laurence J N Cooper
PURPOSE: We have incorporated a positron emission tomography (PET) functionality in T cells expressing a CD19-specific chimeric antigen receptor (CAR) to non-invasively monitor the adoptively transferred cells. PROCEDURES: We engineered T cells to express CD19-specific CAR, firefly luciferase (ffLuc), and herpes simplex virus type-1 thymidine kinase (TK) using the non-viral-based Sleeping Beauty (SB) transposon/transposase system adapted for human application. Electroporated primary T cells were propagated on CD19(+) artificial antigen-presenting cells...
December 2016: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
https://www.readbyqxmd.com/read/27226366/hiv-1-specific-chimeric-antigen-receptors-based-on-broadly-neutralizing-antibodies
#13
Ayub Ali, Scott G Kitchen, Irvin S Y Chen, Hwee L Ng, Jerome A Zack, Otto O Yang
UNLABELLED: Although the use of chimeric antigen receptors (CARs) based on single-chain antibodies for gene immunotherapy of cancers is increasing due to promising recent results, the earliest CAR therapeutic trials were done for HIV-1 infection in the late 1990s. This approach utilized a CAR based on human CD4 as a binding domain and was abandoned for a lack of efficacy. The growing number of HIV-1 broadly neutralizing antibodies (BNAbs) offers the opportunity to generate novel CARs that may be more active and revisit this modality for HIV-1 immunotherapy...
August 1, 2016: Journal of Virology
https://www.readbyqxmd.com/read/26390167/challenges-and-opportunities-of-allogeneic-donor-derived-car-t-cells
#14
REVIEW
Yinmeng Yang, Elad Jacoby, Terry J Fry
PURPOSE OF REVIEW: As T cells engineered with chimeric antigen receptors (CARs) are entering advanced phases of clinical trial testing with promising results, the potential implications of use in an allogeneic environment are emerging as an important consideration. This review discusses the use of allogeneic CAR therapy, the potential effects of T-cell receptor (TCR) signaling on CAR T-cell efficacy, and the potential for TCR elimination to generate an off-the-shelf product. RECENT FINDINGS: The majority of preclinical and clinical data regarding allogeneic T cells are focused on safety of their use given the potential for graft-versus-host disease (GVHD) mediated by the T-cell receptor expressed with the introduced CAR...
November 2015: Current Opinion in Hematology
https://www.readbyqxmd.com/read/26359629/rigorous-optimization-and-validation-of-potent-rna-car-t-cell-therapy-for-the-treatment-of-common-epithelial-cancers-expressing-folate-receptor
#15
Keith Schutsky, D Gang Song, Rachel Lynn, Jenessa B Smith, Mathilde Poussin, Mariangela Figini, Yangbing Zhao, Daniel J Powell
Using lentiviral technology, we recently demonstrated that incorporation of CD27 costimulation into CARs greatly improves antitumor activity and T cell persistence. Still, virus-mediated gene transfer is expensive, laborious and enables long-term persistence, creating therapies which cannot be easily discontinued if toxic. To address these concerns, we utilized a non-integrating RNA platform to engineer human T cells to express FRα-specific, CD27 CARs and tested their capacity to eliminate human FRα(+) cancer...
October 6, 2015: Oncotarget
https://www.readbyqxmd.com/read/26357515/plasmablastic-lymphoma-a-review-of-current-knowledge-and-future-directions
#16
REVIEW
Ghaleb Elyamany, Eman Al Mussaed, Ali Matar Alzahrani
Plasmablastic lymphoma (PBL) is an aggressive subtype of non-Hodgkin's lymphoma (NHL), which frequently arises in the oral cavity of human immunodeficiency virus (HIV) infected patients. PBL shows diffuse proliferation of large neoplastic cells resembling B-immunoblasts/plasmablasts, or with plasmacytic features and an immunophenotype of plasma cells. PBL remains a diagnostic challenge due to its peculiar morphology and an immunohistochemical profile similar to plasma cell myeloma (PCM). PBL is also a therapeutic challenge with a clinical course characterized by a high rate of relapse and death...
2015: Advances in Hematology
https://www.readbyqxmd.com/read/26050990/hiv-specific-immunity-derived-from-chimeric-antigen-receptor-engineered-stem-cells
#17
Anjie Zhen, Masakazu Kamata, Valerie Rezek, Jonathan Rick, Bernard Levin, Saro Kasparian, Irvin Sy Chen, Otto O Yang, Jerome A Zack, Scott G Kitchen
The human immunodeficiency virus (HIV)-specific cytotoxic T lymphocyte (CTL) response is critical in controlling HIV infection. Since the immune response does not eliminate HIV, it would be beneficial to develop ways to enhance the HIV-specific CTL response to allow long-term viral suppression or clearance. Here, we report the use of a protective chimeric antigen receptor (CAR) in a hematopoietic stem/progenitor cell (HSPC)-based approach to engineer HIV immunity. We determined that CAR-modified HSPCs differentiate into functional T cells as well as natural killer (NK) cells in vivo in humanized mice and these cells are resistant to HIV infection and suppress HIV replication...
August 2015: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/25985798/trucks-the-fourth-generation-of-cars
#18
REVIEW
Markus Chmielewski, Hinrich Abken
INTRODUCTION: Adoptive cell therapy of malignant diseases takes advantage of the cellular immune system to recognize and destroy cancer cells. This is impressively demonstrated by redirecting T cells with a chimeric antigen receptor (CAR) towards CD19, inducing complete and lasting remission of leukemia in more than two-thirds of patients in early phase trials. AREAS COVERED: We outline how the CAR strategy is highly specific in redirecting T cells towards pre-defined target cells, however, reaches its limits when targeting solid tumors with a tremendous phenotypic heterogeneity...
2015: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/25925868/defining-novel-parameters-for-the-optimal-priming-and-expansion-of-minor-histocompatibility-antigen-specific-t-cells-in-culture
#19
Valérie Janelle, Cédric Carli, Julie Taillefer, Julie Orio, Jean-Sébastien Delisle
BACKGROUND: Adoptive transfer of minor histocompatibility antigen (MiHA)-specific T cells is a promising therapy for patients with hematological cancers. However, the efficacy of the transferred cells is hampered by the acquisition of terminal effector differentiation and exhaustion features during expansion in vitro thus preventing their function and persistence in vivo. Yet, the factors that induce T-cell differentiation and functional impairment in culture remain poorly defined and are likely to vary depending on the method used for expansion...
2015: Journal of Translational Medicine
https://www.readbyqxmd.com/read/25878112/novel-cd4-based-bispecific-chimeric-antigen-receptor-designed-for-enhanced-anti-hiv-potency-and-absence-of-hiv-entry-receptor-activity
#20
Li Liu, Bhavik Patel, Mustafa H Ghanem, Virgilio Bundoc, Zhili Zheng, Richard A Morgan, Steven A Rosenberg, Barna Dey, Edward A Berger
UNLABELLED: Adoptive transfer of CD8 T cells genetically engineered to express "chimeric antigen receptors" (CARs) represents a potential approach toward an HIV infection "functional cure" whereby durable virologic suppression is sustained after discontinuation of antiretroviral therapy. We describe a novel bispecific CAR in which a CD4 segment is linked to a single-chain variable fragment of the 17b human monoclonal antibody recognizing a highly conserved CD4-induced epitope on gp120 involved in coreceptor binding...
July 2015: Journal of Virology
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