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CAR Treg

Angela C Boroughs, Rebecca C Larson, Bryan D Choi, Amanda A Bouffard, Lauren S Riley, Erik Schiferle, Anupriya S Kulkarni, Curtis L Cetrulo, David Ting, Bruce R Blazar, Shadmehr Demehri, Marcela V Maus
Regulatory T cells (Tregs) are key modulators of inflammation and are important for the maintenance of peripheral tolerance. Adoptive immunotherapy with polyclonal Tregs holds promise in organ transplantation, graft-versus-host disease, and autoimmune diseases, but may be enhanced by antigen-specific, long-lived Treg cells. We modified primary human Tregs with chimeric antigen-receptors (CARs) bearing different costimulatory domains and performed in vitro analyses of their phenotype and function. While neither the presence of a CAR nor the type of costimulation domain influenced Foxp3 expression in Tregs, the costimulation domain of the CARs affected CAR Treg surface phenotype and functions such as cytokine production...
March 14, 2019: JCI Insight
Shweta Joshi, Donald L Durden
Cancer immunotherapy, including immune checkpoint blockade and adoptive CAR T-cell therapy, has clearly established itself as an important modality to treat melanoma and other malignancies. Despite the tremendous clinical success of immunotherapy over other cancer treatments, this approach has shown substantial benefit to only some of the patients while the rest of the patients have not responded due to immune evasion. In recent years, a combination of cancer immunotherapy together with existing anticancer treatments has gained significant attention and has been extensively investigated in preclinical or clinical studies...
2019: Journal of Oncology
Stephen Lai, Carly E Starke, Jacob K Flynn, Carol L Vinton, Alexandra M Ortiz, Joseph C Mudd, Jason M Brenchley
Among the numerous immunological abnormalities observed in chronically HIV-infected individuals, perturbations in memory CD4 T cells are thought to specifically contribute to disease pathogenesis. Among these, functional imbalance in the frequencies of T-regulatory (Tregs) and Interleukin-17/22 (IL-17/IL-22) producing T-helper cells (Th17/Th22) from mucosal sites, and T-follicular helper cells (Tfh) in lymph nodes, are thought to facilitate specific aspects of disease pathogenesis. However, while preferential infection of Tfh cells is widely believed to create an important viral reservoir in an immunologically privileged site in vivo , whether immunological perturbations among memory CD4 T cell populations are attributable to their relative infectivity by the virus in vivo is unclear...
February 20, 2019: Journal of Virology
José Manuel Marín Morales, Nadine Münch, Katja Peter, Daniel Freund, Uta Oelschlägel, Kristina Hölig, Thea Böhm, Anne-Christine Flach, Jörg Keßler, Ezio Bonifacio, Martin Bornhäuser, Anke Fuchs
Adoptive transfer of T regulatory cells (Treg) has been successfully exploited in the context of graft-versus-host disease, transplantation, and autoimmune disease. For the majority of applications, clinical administration of Treg requires laborious ex vivo expansion and typically involves open handling for culture feeds and repetitive sampling. Here we show results from our approach to translate manual Treg manufacturing to the fully closed automated CliniMACS Prodigy® system reducing contamination risk, hands-on time, and quality variation from human intervention...
2019: Frontiers in Immunology
Nicholas Aj Dawson, Caroline Lamarche, Romy E Hoeppli, Peter Bergqvist, Vivian Fung, Emma McIver, Qing Huang, Jana Gillies, Madeleine Speck, Paul C Orban, Jonathan W Bush, Majid Mojibian, Megan K Levings
Chimeric antigen receptor (CAR) technology can be used to engineer the antigen-specificity of regulatory T cells (Tregs) and improve their potency as an adoptive cell therapy in multiple disease models. As synthetic receptors, CARs carry the risk of immunogenicity, particularly when derived from non-human antibodies. Using an HLA-A*02:01-specific CAR (A2-CAR) encoding a single-chain Fv derived from a mouse antibody, we developed a panel of 20 humanized (h)A2-CARs. Systematic testing demonstrated variations in expression, ability to bind HLA-A*02:01, and stimulate human Treg suppression in vitro...
February 12, 2019: JCI Insight
Carter M Suryadevara, Rupen Desai, S Harrison Farber, Bryan D Choi, Adam M Swartz, Steven H Shen, Patrick C Gedeon, David J Snyder, James E Herndon, Patrick Healy, Elizabeth A Reap, Gary E Archer, Peter E Fecci, John H Sampson, Luis Sanchez-Perez
PURPOSE: CAR T cells have shown promise against solid tumors, but their efficacy has been limited, due in part, to immunosuppression by CD4+ FoxP3+ regulatory T cells (Tregs). Although lymphodepletion is commonly used to deplete Tregs, these regimens are non-specific, toxic, and provide only a narrow window before Tregs repopulate hosts. Importantly, CARs have also been shown to inadvertently potentiate Tregs by providing a source of IL-2 for Treg consumption. We explored whether disruption of the IL-2 axis would confer efficacy against solid tumors without the need for lymphodepletion...
November 13, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Qunfang Zhang, Weihui Lu, Chun-Ling Liang, Yuchao Chen, Huazhen Liu, Feifei Qiu, Zhenhua Dai
Cellular therapies with polyclonal regulatory T-cells (Tregs) in transplantation and autoimmune diseases have been carried out in both animal models and clinical trials. However, The use of large numbers of polyclonal Tregs with unknown antigen specificities has led to unwanted effects, such as systemic immunosuppression, which can be avoided via utilization of antigen-specific Tregs. Antigen-specific Tregs are also more potent in suppression than polyclonal ones. Although antigen-specific Tregs can be induced in vitro , these iTregs are usually contaminated with effector T cells during in vitro expansion...
2018: Frontiers in Immunology
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
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
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
Markus Chmielewski, Hinrich Abken
Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells has achieved remarkable efficacy in the treatment of hematopoietic malignancies. However, eradicating large solid tumors in advanced stages of the disease remains challenging. We explored augmentation of the anti-tumor immune reaction by establishing an acute inflammatory reaction. Systematic screening indicates that IL-18 polarizes CAR T cells toward T-bethigh FoxO1low effectors with an acute inflammatory response. CAR T cells engineered with inducible IL-18 release exhibited superior activity against large pancreatic and lung tumors that were refractory to CAR T cells without cytokines...
December 12, 2017: Cell Reports
Wen-I Yeh, Howard R Seay, Brittney Newby, Amanda L Posgai, Filipa Botelho Moniz, Aaron Michels, Clayton E Mathews, Jeffrey A Bluestone, Todd M Brusko
The ability to alter antigen specificity by T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene transfer has facilitated personalized cellular immune therapies in cancer. Inversely, this approach can be harnessed in autoimmune settings to attenuate inflammation by redirecting the specificity of regulatory T cells (Tregs). Herein, we demonstrate efficient protocols for lentiviral gene transfer of TCRs that recognize type 1 diabetes-related autoantigens with the goal of tissue-targeted induction of antigen-specific tolerance to halt β-cell destruction...
2017: Frontiers in Immunology
Antonio Pierini, Bettina P Iliopoulou, Heshan Peiris, Magdiel Pérez-Cruz, Jeanette Baker, Katie Hsu, Xueying Gu, Ping-Ping Zheng, Tom Erkers, Sai-Wen Tang, William Strober, Maite Alvarez, Aaron Ring, Andrea Velardi, Robert S Negrin, Seung K Kim, Everett H Meyer
Cellular therapies based on permanent genetic modification of conventional T cells have emerged as a promising strategy for cancer. However, it remains unknown if modification of T cell subsets, such as Tregs, could be useful in other settings, such as allograft transplantation. Here, we use a modular system based on a chimeric antigen receptor (CAR) that binds covalently modified mAbs to control Treg activation in vivo. Transient expression of this mAb-directed CAR (mAbCAR) in Tregs permitted Treg targeting to specific tissue sites and mitigated allograft responses, such as graft-versus-host disease...
October 19, 2017: JCI Insight
Patrick R Adair, Yong Chan Kim, Ai-Hong Zhang, Jeongheon Yoon, David W Scott
Human regulatory CD4(+) T cells (Tregs) are potent immunosuppressive lymphocytes responsible for immune tolerance and homeostasis. Since the seminal reports identifying Tregs, vast research has been channeled into understanding their genesis, signature molecular markers, mechanisms of suppression, and role in disease. This research has opened the doors for Tregs as a potential therapeutic for diseases and disorders such as multiple sclerosis, type I diabetes, transplantation, and immune responses to protein therapeutics, like factor VIII...
2017: Frontiers in Immunology
Jelena Skuljec, Markus Chmielewski, Christine Happle, Anika Habener, Mandy Busse, Hinrich Abken, Gesine Hansen
Cellular therapy with chimeric antigen receptor (CAR)-redirected cytotoxic T cells has shown impressive efficacy in the treatment of hematologic malignancies. We explored a regulatory T cell (Treg)-based therapy in the treatment of allergic airway inflammation, a model for asthma, which is characterized by an airway hyper-reactivity (AHR) and a chronic, T helper-2 (Th2) cell-dominated immune response to allergen. To restore the immune balance in the lung, we redirected Tregs by a CAR toward lung epithelia in mice upon experimentally induced allergic asthma, closely mimicking the clinical situation...
2017: Frontiers in Immunology
Andreas A Hombach, Hinrich Abken
Evidences are accumulating that CD4⁺ T cells can physiologically mediate antigen specific target cell lysis. By circumventing major histocompatibility complex (MHC)-restrictions through an engineered chimeric antigen receptor (CAR), CD4⁺ T cells lyse defined target cells as efficiently as do CD8⁺ T cells. However, the cytolytic capacity of redirected CD4⁺CD25(-) T cells, in comparison with CD4⁺CD25⁺ regulatory T (Treg) cells was so far not thoroughly defined. Treg cells require a strong CD28 signal together with CD3ζ for activation...
August 29, 2017: Cancers
Nicholas A J Dawson, Megan K Levings
Cellular therapy with T-regulatory cells (Tregs) is a promising strategy to control immune responses and restore immune tolerance in a variety of immune-mediated diseases, such as transplant rejection and autoimmunity. Multiple clinical trials are currently testing this approach, typically by infusing a single dose of polyclonal Tregs that have been expanded in vitro. However, evidence from animal models of Treg therapy has clearly shown that antigen-specific Tregs are vastly superior to polyclonal cells, meaning that fewer cells are needed for the desired therapeutic effect...
September 2017: Translational Research: the Journal of Laboratory and Clinical Medicine
Jeongheon Yoon, Anja Schmidt, Ai-Hong Zhang, Christoph Königs, Yong Chan Kim, David W Scott
Replacement therapy with factor VIII (FVIII) is used in patients with hemophilia A for treatment of bleeding episodes or for prophylaxis. A common and serious problem with this therapy is the patient's immune response to FVIII, because of a lack of tolerance, leading to the formation of inhibitory antibodies. Development of tolerogenic therapies, other than standard immune tolerance induction (ITI), is an unmet goal. We previously generated engineered antigen-specific regulatory T cells (Tregs), created by transduction of a recombinant T-cell receptor (TCR) isolated from a hemophilia A subject's T-cell clone...
January 12, 2017: Blood
D A Boardman, C Philippeos, G O Fruhwirth, M A A Ibrahim, R F Hannen, D Cooper, F M Marelli-Berg, F M Watt, R I Lechler, J Maher, L A Smyth, G Lombardi
Regulatory T cell (Treg) therapy using recipient-derived Tregs expanded ex vivo is currently being investigated clinically by us and others as a means of reducing allograft rejection following organ transplantation. Data from animal models has demonstrated that adoptive transfer of allospecific Tregs offers greater protection from graft rejection compared to polyclonal Tregs. Chimeric antigen receptors (CAR) are clinically translatable synthetic fusion proteins that can redirect the specificity of T cells toward designated antigens...
April 2017: American Journal of Transplantation
F Noyan, K Zimmermann, M Hardtke-Wolenski, A Knoefel, E Schulde, R Geffers, M Hust, J Huehn, M Galla, M Morgan, A Jokuszies, M P Manns, E Jaeckel
CD4+ CD25high FOXP3+ regulatory T cells (Tregs) are involved in graft-specific tolerance after solid organ transplantation. However, adoptive transfer of polyspecific Tregs alone is insufficient to prevent graft rejection even in rodent models, indicating that graft-specific Tregs are required. We developed a highly specific chimeric antigen receptor that recognizes the HLA molecule A*02 (referred to as A2-CAR). Transduction into natural regulatory T cells (nTregs) changes the specificity of the nTregs without alteration of their regulatory phenotype and epigenetic stability...
April 2017: American Journal of Transplantation
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