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CAR T regulatory cells

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https://www.readbyqxmd.com/read/30324966/cancer-immunotherapy-the-target-is-precisely-on-the-cancer-and-also-not
#1
Si Lin Koo, Who Whong Wang, Han Chong Toh
In recent years, the impressive number of cancer immunotherapy drugs approved has been unprecedented-building on over a century of understanding on how the immune system combats cancer, and how cancer evades it. Leading the charge are the immune checkpoint inhibitor monoclonal antibodies, and adoptive cell therapy with chimeric- antigen-receptor (CAR)-T cell therapy. These breakthrough therapies have led to improved survival in patients with many advanced cancers. Some of the clinical outcomes have been striking, and may even be potentially curative in some terminal cancer patients...
September 2018: Annals of the Academy of Medicine, Singapore
https://www.readbyqxmd.com/read/30307029/the-landscape-of-car-t-cell-therapy-in-the-united-states-and-china-a-comparative-analysis
#2
Lijuan Gou, Jianchao Gao, Huan Yang, Chenyan Gao
The clinical trials of CAR T-cell therapy are growing fast in recent years, and most of the trials are initiated by sponsors from the United States and China. Exhibiting the distinctions between the clinical trials in the two countries is of great value for understanding the panorama of CAR T-cell clinical trials and forecasting the future of this promising therapy. We analyzed the critical elements of 289 clinical trials posted on the clinicaltrials.gov website by sponsors from the two countries and evaluated the efficacy data in available 50 published CAR T-cell studies...
October 11, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/30253384/chimeric-antigen-receptor-t-cells-with-4-1bb-co-stimulatory-domain-present-a-superior-treatment-outcome-than-those-with-cd28-domain-based-on-bioinformatics
#3
Qi Zhong, Yang-Min Zhu, Li-Ling Zheng, Hui-Juan Shen, Rui-Ming Ou, Zhi Liu, Yan-Ling She, Rui Chen, Cheng Li, Jing Huang, Meng-Dong Yao, Qing Zhang, Shuang Liu
BACKGROUND: The second-generation CD19-chimeric antigen receptor (CAR)-T co-stimulatory domain that is commonly used in clinical practice is CD28 or 4-1BB. Previous studies have shown that the persistence of CAR-T in the 4-1BB co-stimulatory domain appears to be longer. METHODS: The expression profile data of GSE65856 were obtained from GEO database. After data preprocessing, the differentially expressed genes (DEGs) between the mock CAR versus CD19-28z CAR T cells and mock CAR versus CD19-BBz CAR T cells were identified using the limma package...
September 25, 2018: Acta Haematologica
https://www.readbyqxmd.com/read/30232281/4-1bb-enhancement-of-car-t-function-requires-nf-%C3%AE%C2%BAb-and-trafs
#4
Gongbo Li, Justin C Boucher, Hiroshi Kotani, Kyungho Park, Yongliang Zhang, Bishwas Shrestha, Xuefeng Wang, Lawrence Guan, Nolan Beatty, Daniel Abate-Daga, Marco L Davila
Chimeric antigen receptors (CARs) have an antigen-binding domain fused to transmembrane, costimulatory, and CD3ζ domains. Two CARs with regulatory approval include a CD28 or 4-1BB costimulatory domain. While both CARs achieve similar clinical outcomes, biologic differences have become apparent but not completely understood. Therefore, in this study we aimed to identify mechanistic differences between 4-1BB and CD28 costimulation that contribute to the biologic differences between the 2 CARs and could be exploited to enhance CAR T cell function...
September 20, 2018: JCI Insight
https://www.readbyqxmd.com/read/30180168/the-human-lymph-node-microenvironment-unilaterally-regulates-t-cell-activation-and-differentiation
#5
Konstantin Knoblich, Sara Cruz Migoni, Susan M Siew, Elizabeth Jinks, Baksho Kaul, Hannah C Jeffery, Alfie T Baker, Muath Suliman, Katerina Vrzalikova, Hisham Mehenna, Paul G Murray, Francesca Barone, Ye H Oo, Philip N Newsome, Gideon Hirschfield, Deirdre Kelly, Steven P Lee, Biju Parekkadan, Shannon J Turley, Anne L Fletcher
The microenvironment of lymphoid organs can aid healthy immune function through provision of both structural and molecular support. In mice, fibroblastic reticular cells (FRCs) create an essential T-cell support structure within lymph nodes, while human FRCs are largely unstudied. Here, we show that FRCs create a regulatory checkpoint in human peripheral T-cell activation through 4 mechanisms simultaneously utilised. Human tonsil and lymph node-derived FRCs constrained the proliferation of both naïve and pre-activated T cells, skewing their differentiation away from a central memory T-cell phenotype...
September 2018: PLoS Biology
https://www.readbyqxmd.com/read/30065964/tgf-%C3%AE-responsive-car-t-cells-promote-anti-tumor-immune-function
#6
Andrew J Hou, ZeNan L Chang, Michael H Lorenzini, Eugenia Zah, Yvonne Y Chen
A chimeric antigen receptor (CAR) that responds to transforming growth factor beta (TGF-β) enables the engineering of T cells that convert this immunosuppressive cytokine into a potent T-cell stimulant. However, clinical translation of TGF-β CAR-T cells for cancer therapy requires the ability to productively combine TGF-β responsiveness with tumor-targeting specificity. Furthermore, the potential concern that contaminating, TGF-β?producing regulatory T (Treg) cells may preferentially expand during TGF-β CAR-T cell manufacturing and suppress effector T (Teff) cells demands careful evaluation...
May 2018: Bioengineering & Translational Medicine
https://www.readbyqxmd.com/read/29987406/manipulating-the-tumor-microenvironment-by-adoptive-cell-transfer-of-car-t-cells
#7
REVIEW
Kavitha Gowrishankar, Lucy Birtwistle, Kenneth Micklethwaite
T-cells expressing synthetic chimeric antigen receptors (CARs) have revolutionized immuno-oncology and highlighted the use of adoptive cell transfer, for the treatment of cancer. The phenomenal clinical success obtained in the treatment of hematological malignancies with CAR T-cells has not been reproduced in the treatment of solid tumors, mainly due to the suppressive and hostile tumor microenvironment (TME). This review will address the immunosuppressive features of the TME, which include the stroma, cytokine and chemokine milieu, suppressive regulatory cells and hypoxic conditions, which can all pose formidable barriers for the effective anti-tumor function of CAR T-cells...
July 9, 2018: Mammalian Genome: Official Journal of the International Mammalian Genome Society
https://www.readbyqxmd.com/read/29909913/gmp-car-t-cell-production
#8
REVIEW
Adrian P Gee
The clinical success achieved using CD19-directed CAR-T cells has stimulated many academic institutions to explore the feasibility of manufacturing these, and other CAR-T cells, in-house. This article reviews the issues that must be addressed in order to achieve this goal. It includes the manufacturing infrastructure, the regulatory environment, practical aspects of production, and the costs involved.
June 2018: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29907163/cytokine-release-syndrome
#9
REVIEW
Alexander Shimabukuro-Vornhagen, Philipp Gödel, Marion Subklewe, Hans Joachim Stemmler, Hans Anton Schlößer, Max Schlaak, Matthias Kochanek, Boris Böll, Michael S von Bergwelt-Baildon
During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS)...
June 15, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29904021/overcoming-resistance-of-human-non-hodgkin-s-lymphoma-to-cd19-car-ctl-therapy-by-celecoxib-and-histone-deacetylase-inhibitors
#10
Antoni Xavier Torres-Collado, Ali R Jazirehi
Patients with B-cell non-Hodgkin’s lymphoma (B-NHL) who fail to respond to first-line treatment regimens or develop resistance, exhibit poor prognosis. This signifies the need to develop alternative treatment strategies. CD19-chimeric antigen receptor (CAR) T cell-redirected immunotherapy is an attractive and novel option, which has shown encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. However, the underlying mechanisms of, and approaches to overcome, acquired anti-CD19CAR CD8⁺ T cells (CTL)-resistance in NHL remain elusive...
June 14, 2018: Cancers
https://www.readbyqxmd.com/read/29748955/investigational-agents-in-immunotherapy-a-new-horizon-for-the-treatment-of-multiple-myeloma
#11
REVIEW
Cindy Varga, Jacob P Laubach, Kenneth C Anderson, Paul G Richardson
The treatment of multiple myeloma (MM) has gone through several major advances over the last 5 years with the introduction of next generation proteasome inhibitors (PI; carfilzomib, ixazomib) and immunomodulatory derivatives (IMiD; pomalidomide), with these new agents having a substantial impact on patient outcome. However, despite these advances, MM remains a highly resistant disease given its propensity for clonal heterogeneity and its complex interaction with the surrounding bone marrow microenvironment...
May 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29730080/a-decade-of-marketing-approval-of-gene-and-cell-based-therapies-in-the-united-states-european-union-and-japan-an-evaluation-of-regulatory-decision-making
#12
D G M Coppens, S de Wilde, H J Guchelaar, M L De Bruin, H G M Leufkens, P Meij, J Hoekman
There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management...
June 2018: Cytotherapy
https://www.readbyqxmd.com/read/29625832/considerations-pertaining-to-cell-collection-and-administration-of-industry-manufactured-autologous-car-t-cells-in-relation-to-french-healthcare-organization-and-regulations
#13
Christian Chabannon, Jérôme Larghero
Access to treatment with CAR-T Cells at European hospitals in general and at French hospitals in particular remains limited, when compared with the situation that prevails in the USA or in certain Asian countries. Multiple reasons explain why European investigators lag behind their US or Chinese colleagues in this clinical research area. Some of these reasons are related to the European and French regulatory landscapes that hamper the design and rapid implementation of organizational solutions needed for safe and efficient administration of CAR-T Cells...
May 2018: Current Research in Translational Medicine
https://www.readbyqxmd.com/read/29620951/car-t-cells-in-trials-recent-achievements-and-challenges-that-remain-in-the-production-of-modified-t-cells-for-clinical-applications
#14
Ulrike Köhl, Stanislava Arsenieva, Astrid Holzinger, Hinrich Abken
The adoptive transfer of chimeric antigen receptor (CAR)-modified T cells is attracting growing interest for the treatment of malignant diseases. Early trials with anti-CD19 CAR T cells have achieved spectacular remissions in B-cell leukemia and lymphoma, so far refractory, very recently resulting in the Food and Drug Administration approval of CD19 CAR T cells for therapy. With further applications and increasing numbers of patients, the reproducible manufacture of high-quality clinical-grade CAR T cells is becoming an ever greater challenge...
May 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29616042/gene-therapy-with-regulatory-t-cells-a-beneficial-alliance
#15
REVIEW
Moanaro Biswas, Sandeep R P Kumar, Cox Terhorst, Roland W Herzog
Gene therapy aims to replace a defective or a deficient protein at therapeutic or curative levels. Improved vector designs have enhanced safety, efficacy, and delivery, with potential for lasting treatment. However, innate and adaptive immune responses to the viral vector and transgene product remain obstacles to the establishment of therapeutic efficacy. It is widely accepted that endogenous regulatory T cells (Tregs) are critical for tolerance induction to the transgene product and in some cases the viral vector...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29603617/engineering-therapeutic-t-cells-to-suppress-alloimmune-responses-using-tcrs-cars-or-bars
#16
REVIEW
Antoine Sicard, Megan K Levings, David W Scott
Adoptive cell therapy with therapeutic T cells has become one of the most promising strategies to stimulate or suppress immune responses. Using virus-mediated genetic manipulation, the antigen specificity of T cells can now be precisely redirected. Tailored specificity has not only overcome technical limitations and safety concerns but also considerably broadened the spectrum of therapeutic applications. Different T cell-engineering strategies have now become available to suppress alloimmune responses. We first provide an overview of the allorecognition pathways and effector mechanisms that are responsible for alloimmune injuries in the setting of vascularized organ transplantation...
June 2018: American Journal of Transplantation
https://www.readbyqxmd.com/read/29552577/the-pharmacology-of-t-cell-therapies
#17
REVIEW
Michael C Milone, Vijay G Bhoj
Adoptive cellular therapy using T cells with tumor specificity derived from either natural T cell receptors (TCRs) or an artificial chimeric antigen receptor (CAR) has reached late phase clinical testing, with two CAR T cell therapies achieving regulatory approval within the United States in 2017. The effective use of these therapies depends upon an understanding of their pharmacology, which is quite divergent from traditional small molecule or biologic drugs. We review the different types of T cell therapy under clinical development, the factors affecting cellular kinetics following infusion, and the relationship between these cellular kinetics and anti-cancer activity...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29546043/overcoming-barriers-of-age-to-enhance-efficacy-of-cancer-immunotherapy-the-clout-of-the-extracellular-matrix
#18
REVIEW
Mark Owyong, Gizem Efe, Michael Owyong, Aamna J Abbasi, Vaishnavi Sitarama, Vicki Plaks
There is a growing list of cancer immunotherapeutics approved for use in a population with an increasing number of aged individuals. Cancer immunotherapy (CIT) mediates tumor destruction by activating anti-tumor immune responses that have been silenced through the oncogenic process. However, in an aging individual, immune deregulation is positively correlated with age. In this context, it is vital to examine the age-related changes in the tumor microenvironment (TME) and specifically, those directly affecting critical players to ensure CIT efficacy...
2018: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/29544719/gene-knocked-out-chimeric-antigen-receptor-car-t-cells-tuning-up-for-the-next-generation-cancer-immunotherapy
#19
Hamid Reza Mirzaei, Hossein Pourghadamyari, Majid Rahmati, Abbas Mohammadi, Javid Sadri Nahand, Abbas Rezaei, Hamed Mirzaei, Jamshid Hadjati
Recently clinical trials utilizing genetically engineered T cells expressing a chimeric antigen receptor (CAR) that is half monoclonal antibody and half T-cell receptor have demonstrated remarkable response in patients with advanced cancers like relapsed or refractory acute lymphoblastic leukemia (ALL) and lymphoma. Moreover, emerging chimeric genome editing tools such as zinc-finger nucleases (ZNFs), transcription activator-like effector nucleases (TALENs) and clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas composed of sequence-specific DNA binding module(s) linked to a non-specific DNA cleavage domain have made possible to dramatically expand the ability to manipulate cells aim to treat and/or study a wide range of diseases including cancer...
June 1, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29503042/engrafting-human-regulatory-t-cells-with-a-flexible-modular-chimeric-antigen-receptor-technology
#20
Stefanie Koristka, Alexandra Kegler, Ralf Bergmann, Claudia Arndt, Anja Feldmann, Susann Albert, Marc Cartellieri, Armin Ehninger, Gerhard Ehninger, Jan Moritz Middeke, Martin Bornhäuser, Marc Schmitz, Jens Pietzsch, Katja Akgün, Tjalf Ziemssen, Jörg Steinbach, Michael P Bachmann
As regulatory T cells (Tregs) play a fundamental role in immune homeostasis their adoptive transfer emerged as a promising treatment strategy for inflammation-related diseases. Preclinical animal models underline the superiority of antigen-specific Tregs compared to polyclonal cells. Here, we applied a modular chimeric antigen receptor (CAR) technology called UniCAR for generation of antigen-specific human Tregs. In contrast to conventional CARs, UniCAR-endowed Tregs are indirectly linked to their target cells via a separate targeting module (TM)...
June 2018: Journal of Autoimmunity
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