scholarly journals Regulatory T-Cell Therapy in Liver Transplantation and Chronic Liver Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Angus Hann ◽  
Ye H. Oo ◽  
M. Thamara P. R. Perera
Keyword(s):  
T Cells ◽  
Liver Disease ◽  
T Cell ◽  
Cell Lineage ◽  
Solid Organ ◽  
T Helper 1 ◽  
T Cell Therapy ◽  
Immune Mediated ◽  
And Function ◽  
Type Of Injury

The constant exposure of the liver to gut derived foreign antigens has resulted in this organ attaining unique immunological characteristics, however it remains susceptible to immune mediated injury. Our understanding of this type of injury, in both the native and transplanted liver, has improved significantly in recent decades. This includes a greater awareness of the tolerance inducing CD4+ CD25+ CD127low T-cell lineage with the transcription factor FoxP3, known as regulatory T-Cells (Tregs). These cells comprise 5-10% of CD4+ T cells and are known to function as an immunological “braking” mechanism, thereby preventing immune mediated tissue damage. Therapies that aim to increase Treg frequency and function have proved beneficial in the setting of both autoimmune diseases and solid organ transplantations. The safety and efficacy of Treg therapy in liver disease is an area of intense research at present and has huge potential. Due to these cells possessing significant plasticity, and the potential for conversion towards a T-helper 1 (Th1) and 17 (Th17) subsets in the hepatic microenvironment, it is pre-requisite to modify the microenvironment to a Treg favourable atmosphere to maintain these cells’ function. In addition, implementation of therapies that effectively increase Treg functional activity in the liver may result in the suppression of immune responses and will hinder those that destroy tumour cells. Thus, fine adjustment is crucial to achieve this immunological balance. This review will describe the hepatic microenvironment with relevance to Treg function, and the role these cells have in both native diseased and transplanted livers.

scholarly journals Thymic and Postthymic Regulation of Naïve CD4+T-Cell Lineage Fates in Humans and Mice Models

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
José E. Belizário ◽  
Wesley Brandão ◽  
Cristiano Rossato ◽  
Jean Pierre Peron
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Regulatory Cells ◽  
Transforming Growth Factor ◽  
Cell Lineage ◽  
Lymphoid Tissues ◽  
Regulatory Cells ◽  
T Helper ◽  
Mice Model ◽  
T Helper 1

Our understanding of how thymocytes differentiate into many subtypes has been increased progressively in its complexity. At early life, the thymus provides a suitable microenvironment with specific combination of stromal cells, growth factors, cytokines, and chemokines to induce the bone marrow lymphoid progenitor T-cell precursors into single-positive CD4+and CD8+T effectors and CD4+CD25+T-regulatory cells (Tregs). At postthymic compartments, the CD4+T-cells acquire distinct phenotypes which include the classical T-helper 1 (Th1), T-helper 2 (Th2), T-helper 9 (Th9), T-helper 17 (Th17), follicular helper T-cell (Tfh), and induced T-regulatory cells (iTregs), such as the regulatory type 1 cells (Tr1) and transforming growth factor-β- (TGF-β-) producing CD4+T-cells (Th3). Tregs represent only a small fraction, 5–10% in mice and 1-2% in humans, of the overall CD4+T-cells in lymphoid tissues but are essential for immunoregulatory circuits mediating the inhibition and expansion of all lineages of T-cells. In this paper, we first provide an overview of the major cell-intrinsic developmental programs that regulate T-cell lineage fates in thymus and periphery. Next, we introduce the SV40 immortomouse as a relevant mice model for implementation of new approaches to investigate thymus organogenesis, CD4 and CD8 development, and thymus cells tumorogenesis.

scholarly journals Infection Temperature Affects the Phenotype and Function of Chimeric Antigen Receptor T Cells Produced via Lentiviral Technology

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Jin ◽  
Wenyi Lu ◽  
Meng Zhang ◽  
Xia Xiong ◽  
Rui Sun ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Immune Checkpoints ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
And Function

Chimeric antigen receptor (CAR)-T cell therapy has become an important method for the treatment of hematological tumors. Lentiviruses are commonly used gene transfer vectors for preparing CAR-T cells, and the conditions for preparing CAR-T cells vary greatly. This study reported for the first time the influence of differences in infection temperature on the phenotype and function of produced CAR-T cells. Our results show that infection at 4 degrees produces the highest CAR-positive rate of T cells, infection at 37 degrees produces the fastest proliferation in CAR-T cells, and infection at 32 degrees produces CAR-T cells with the greatest proportion of naive cells and the lowest expression of immune checkpoints. Therefore, infection at 32 degrees is recommended to prepare CAR-T cells. CAR-T cells derived from infection at 32 degrees seem to have a balance between function and phenotype. Importantly, they have increased oncolytic ability. This research will help optimize the generation of CAR-T cells and improve the quality of CAR-T cell products.

scholarly journals Balancing Inflammation: The Link between Th17 and Regulatory T Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Maggie L. Diller ◽  
Ragini R. Kudchadkar ◽  
Keith A. Delman ◽  
David H. Lawson ◽  
Mandy L. Ford
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Th17 Cells ◽  
Cell Lineage ◽  
Effector Functions ◽  
Inflammatory Conditions ◽  
Cell Compartments ◽  
Th17 Cell Differentiation ◽  
And Function

CD4+T cell compartments in mouse and man are composed of multiple distinct subsets each possessing unique phenotypic and functional characteristics. IL-17-producing CD4+T cells (Th17 cells) represent a distinct subset of the CD4+T cell lineage. Recent evidence suggests that Th17 cells carry out effector functions similar to cytotoxic CD8+T cells and play an important role in the clearance of extracellular pathogens and fungi. Th17 cell differentiation and function are closely related to the development and function of regulatory T cells(TREG). The balance between these two cell populations is essential for immune homeostasis and dysregulation of this balance has been implicated in a variety of inflammatory conditions including autoimmunity, allograft rejection, and tumorigenesis. Emerging evidence reports a significant amount of plasticity between the Th17 and regulatory T cell compartments, and the mechanisms by which these cells communicate and influence each other are just beginning to be understood. In this review, we highlight recent findings detailing the mechanisms driving Th17 andTREGplasticity and discuss the biologic consequences of their unique relationship.

Successful In Vitro Priming of EBV-Specific CD8+ T Cells Endowed with Strong Cytotoxic Function for Prophylaxis or Treatment of PTLD in EBV Seronegative Hosts.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1480-1480
Author(s):  
Patrizia Comoli ◽  
Franco Locatelli ◽  
Chiara Frasson ◽  
Sabrina Basso ◽  
Massimo Labirio ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytotoxic Activity ◽  
Cd8 T Cells ◽  
Cultured Cells ◽  
Cytotoxic T Cell ◽  
Solid Organ ◽  
Standard Protocol ◽  
T Cell Therapy ◽  
Hematopoietic Stem

Abstract EBV-seronegative solid organ transplant recipients, or recipients of T-cell depleted hematopoietic stem cell from a EBV-seronegative donor, are cohorts at high risk for the development of EBV-associated posttransplant lymphoproliferative disease (PTLD), and would maximally benefit from an EBV-directed T-cell therapy for prevention or treatment of PTLD. Reported experiences have shown that CTL obtained from EBV-seronegative individuals are almost exclusively HLA-class II-restricted CD4+ cytotoxic T cells, and efficiency of this CTL subset in the control of PTLD has not yet been demonstrated in vivo. Conversely, the central role of CD8+ CTL in the cell-mediated containment of EBV infection is well established. Therefore, we endeavoured to develop a protocol of EBV-CTL priming that would allow optimal expansion and high specific cytotoxic activity of CD8+ CTL. We employed naïve lymphocytes obtained from 5 EBV seronegative patients with end-stage renal failure receiving dialysis while listed for a kidney transplantation (4 children, 1 adult). In particular, we compared the CD8+ CTL priming efficiency of three different modified activation protocols, based on LCL stimulation potentially enhanced by either LCL presentation through DC, or selection of IFNg+ cultured cells, or culture in the presence of rhIL-12 and rhIL-7, to the standard protocol for reactivation of EBV-specific CTL from EBV-seropositive individuals. We found that while all protocols employed, with the exception of IFN-g+ T cell selection, allowed for the amplification of CD8+ and CD4+ mediated EBV-specific cytotoxic T cell responses in the EBV-seronegative adult, only specific EBV-transformed lymphoblastoid cell lines (LCL) stimulation in the presence of rhIL-12 and rhIL-7 was able to reproducibly generate and expand EBV-specific CD8+ CTL endowed with strong cytotoxic activity from truly EBV-seronegative children (mean lysis at a E:T ratio of 10:1: 14±10% with the standard protocol vs. 66±30% with the addition of rhIL-7 and rhIL-12). The lines thus activated showed a higher percentage CD8+ T cells, with less than 10% naïve CD8+/CCR7+/CD45RA+ cells. Overall, the total number of CD8+ central memory cells, and of CCR7- T cell effectors was comparable to that observed in healthy EBV-seropositive controls. In conclusion, stimulation with LCL in the presence of IL-12 and IL-7 activates EBV-specific, highly cytotoxic CD8+ CTL from EBV-seronegative subjects, this opening new perspectives for prevention/treatment of PTLD.

HLA and TCR Knockout by Zinc Finger Nucleases: Toward “off-the-Shelf” Allogeneic T-Cell Therapy for CD19+ Malignancies.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3766-3766 ◽  
Author(s):  
Hiroki Torikai ◽  
Andreas Reik ◽  
Carrie Yuen ◽  
Yuanyue Zhou ◽  
Denise Kellar ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Zinc Finger ◽  
Zinc Finger Nucleases ◽  
T Cell Therapy ◽  
Cell Clones ◽  
Immune Mediated ◽  
Paramagnetic Bead

Abstract Abstract 3766 Cell therapy by infusion of T cells can reconstitute immunity to combat pathogens and malignancies. However, the time required to manufacture T cells with the desired properties and in sufficient numbers ex vivo is often incompatible with the treatment window for patients. Furthermore, autologous T cells from patients with advanced disease may have compromised function and be tolerant to desired antigens. A potential solution would be an approach to infuse allogeneic T cells that avoids immune-mediated rejection caused by host T cells recognizing disparate major or minor histocompatibility antigens on the infused cells. To broaden the application of T cell therapy, we investigated whether HLA gene expression can be disrupted by designer zinc-finger nucleases (ZFNs). ZFNs comprise a zinc finger DNA binding domain designed to bind a specific DNA sequence fused to the cleavage domain of Fok I endonuclease. Since FokI dimerization is required to introduce a double strand break (DSB), we generated ZFN pairs that flank the intended DNA target sequences in the required spatial conformation. Cellular repair of the DSB by error-prone non-homologous end joining allows disruption of HLA gene expression. As an initial proof of concept experiment, transfection of ZFN pairs designed to target exon 3 of the HLA-A locus into the human kidney cell line HEK293 resulted in 10% genetic modification of the HLA-A loci. We generated clones of HEK293 cells that showed deletion or insertion mutations within the ZFN binding site of one or both HLA-A alleles leading to early termination of translation. These HLA-Anull HEK293 clones evaded HLA-A-restricted lysis by T cell clones, even after interferon-γ and TNF-α treatment was used to upregulate HLA expression. Since only transient expression of ZFNs is needed to disrupt a target gene, we tested the ability to disrupt HLA-A gene expression by electro-transfer of in vitro-transcribed ZFN mRNA into primary T cells. We show that a single administration of the mRNA encoding the ZFNs targeting HLA-A could render over 40% of primary T cells HLA-A negative. We enriched the HLA-Anull population by paramagnetic bead separation to obtain a pool of T cells >90% of which lack HLA-A expression. An attractive potential clinical application for HLAnull allogeneic T cells is to redirect their specificity independent of HLA via expression of a chimeric antigen receptor (CAR) targeting CD19. Thus, we eliminated HLA-A expression from CD19-specific CAR+ T cells and demonstrated that they (i) evade HLA-A-restricted lysis by T cell clones, and (ii) specifically lysed CD19+ tumor targets. Finally, to further improve this T cell product and eliminate potential deleterious immune mediated recognition by the endogenous T cell receptor (TCR) on allogeneic CAR+ T cells, we used ZFN pairs targeting the TCR α or the TCR β locus. Transient expression of these ZFNs resulted in permanent disruption of endogenous TCR expression and a highly enriched αβ TCRnull cell population could be generated by paramagnetic bead selection. These data support our plans to develop allogeneic T cells as “off-the-shelf” biologics that can be infused on demand as “drugs”. Disclosures: Reik: Sangamo BioSciences: Employment. Zhou:Sangamo BioSciences: Employment. Gregory:Sangamo BioSciences: Employment. Holmes:Sangamo BioSciences: Employment. Rebar:Sangamo BioSciences: Employment.

EXTH-18. IL-12 ARMORED CAR T CELL THERAPY FOR HETEROGENEOUS GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi167-vi167
Author(s):  
Steven Shen ◽  
Jessica Reedy ◽  
Carter Suryadevara ◽  
Kelly Hotchkiss ◽  
David Snyder ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Cell Activity ◽  
Growth Factor Receptor ◽  
Therapeutic Success ◽  
Term Survival ◽  
T Cell Therapy ◽  
Car T ◽  
And Function

Abstract INTRODUCTION Glioblastoma (GBM) is a lethal primary malignant brain tumor with a median survival of < 20 months. Our next generation immunotherapy utilizes chimeric antigen receptor (CAR) T cells targeted to GBM-specific overexpression of epidermal growth factor receptor variant III (EGFRvIII), “armored” with IL-12, a stimulatory cytokine that enhances T cell persistence and function, to treat orthotopic heterogeneous GBM. METHODS C57Bl/6 mice were intracranially implanted with 5 x 105 of either CT2AvIII tumor cells or a 1:1 mixture of CT2AvIII and CT2A parental tumor cells. Seven days post-implant, mice were treated with 2 x 106 IL-12 CARvIII and monitored for survival. For endogenous T cell activity assessment, TCRα -/- mice were intracranially implanted with either CT2AvIII cells or a 1:1 mixture of CT2AvIII:CT2A parental cells and treated 7 days post implant with intracranial IL-12 CARvIII therapy. RESULTS IL-12 CARvIII therapy was curative in the treatment of CT2AvIII homogeneous tumors and confers a long-term survival in 50% of CT2AvIII:CT2A mice. Furthermore, IL-12 CARvIII therapy successfully eradicated the homogeneous CT2AvIII tumors in TCRα-/- mice but failed to produce any efficacy against the heterogeneous CT2AvIII:CT2A parental tumors, suggesting that endogenous T cells are required for IL-12 CARvIII therapeutic success against heterogeneous tumors. CONCLUSIONS Our findings suggest that IL-12 CARvIII may be an effective treatment against heterogeneous glioma. Furthermore, this data provides insight on treatment against the immunosuppressive tumor microenvironment and applications against other solid tumors. In anticipation of translating this therapy into a phase I clinical trial, we are also investigating adjuvant therapies such irradiation to improve antitumor efficacy of IL-12 CARvIII against heterogeneous glioma.

scholarly journals Enabling T Cell Recruitment to Tumours as a Strategy for Improving Adoptive T Cell Therapy

2017 ◽  
Vol 13 (01) ◽  
pp. 66 ◽  
Author(s):  
Bruno Cadilha ◽  
Klara Dorman ◽  
Felicitas Rataj ◽  
Stefan Endres ◽  
Sebastian Kobold ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Therapeutic Potential ◽  
Cell Activity ◽  
Cell Lineage ◽  
Solid Tumours ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy

Immunotherapy has successfully been implemented as the standard of care in a number of oncologic indications. A hallmark of cancer immunotherapy is the successful activation of T cells against cancer cells, leading to unparalleled efficacy for some tumour entities. However, current approved approaches are not specific, limiting both their activity and their safety. A more tailored way of using the therapeutic potential of T cells is adoptive T cell therapy, which encompasses ex vivo T cell manipulation and reinfusion to patients suffering from cancer. In haematologic malignancies such as acute lymphatic leukaemia of the B cell lineage, T cells modified with a chimeric antigen receptor against the B cell lineage antigen CD19 induce remissions in a high proportion of patients. In contrast, patients suffering from advanced solid tumours have shown little benefit from cell-based approaches. This is partly due to limited access of T cells to the tumour tissue, consequently restricting T cell activity. In this review, we focus on the limitations of T cell trafficking towards solid tumours. We summarise the existing knowledge on lymphocyte migration to understand how this pathway may be used to open therapeutic approaches for a broader range of indications. We also review new strategies targeting the tumour site that aid naturally occurring or gene-engineered T cells to migrate to solid tumours. Finally, we discuss how guiding T cells towards the tumour might contribute in harnessing their full cytolytic potential.

scholarly journals Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Laura Castelletti ◽  
Dannel Yeo ◽  
Nico van Zandwijk ◽  
John E. J. Rasko
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Malignant Mesothelioma ◽  
Oncolytic Viruses ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

AbstractMalignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

scholarly journals Chimeric non-antigen receptors in T cell-based cancer therapy

2021 ◽  
Vol 9 (8) ◽  
pp. e002628
Author(s):  
Jitao Guo ◽  
Andrew Kent ◽  
Eduardo Davila
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Therapy ◽  
Tumor Antigen ◽  
Cell Function ◽  
Antigen Recognition ◽  
Cancer Therapies ◽  
Antigen Receptors ◽  
Natural Ligands ◽  
And Function

Adoptively transferred T cell-based cancer therapies have shown incredible promise in treatment of various cancers. So far therapeutic strategies using T cells have focused on manipulation of the antigen-recognition machinery itself, such as through selective expression of tumor-antigen specific T cell receptors or engineered antigen-recognition chimeric antigen receptors (CARs). While several CARs have been approved for treatment of hematopoietic malignancies, this kind of therapy has been less successful in the treatment of solid tumors, in part due to lack of suitable tumor-specific targets, the immunosuppressive tumor microenvironment, and the inability of adoptively transferred cells to maintain their therapeutic potentials. It is critical for therapeutic T cells to overcome immunosuppressive environmental triggers, mediating balanced antitumor immunity without causing unwanted inflammation or autoimmunity. To address these hurdles, chimeric receptors with distinct signaling properties are being engineered to function as allies of tumor antigen-specific receptors, modulating unique aspects of T cell function without directly binding to antigen themselves. In this review, we focus on the design and function of these chimeric non-antigen receptors, which fall into three broad categories: ‘inhibitory-to-stimulatory’ switch receptors that bind natural ligands, enhanced stimulatory receptors that interact with natural ligands, and synthetic receptor-ligand pairs. Our intent is to offer detailed descriptions that will help readers to understand the structure and function of these receptors, as well as inspire development of additional novel synthetic receptors to improve T cell-based cancer therapy.

scholarly journals HGG-05. REGRESSION OF RECURRENT GLIOBLASTOMA AFTER BORON NEUTRON CAPTURE THERAPY AND CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY IN A CHILD

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii345-iii345
Author(s):  
Hsin-Hung Chen ◽  
Yi-Wei Chen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Boron Neutron Capture Therapy ◽  
Neutron Capture ◽  
Antigen Receptor ◽  
Neutron Capture Therapy ◽  
T Cell Therapy ◽  
Boron Neutron Capture ◽  
Car T

Abstract A 6 y/o girl with recurrent multifocal glioblastoma received 3 times of boron neutron capture therapy (BNCT) and chimeric antigen receptor (CAR)–engineered T cells targeting the tumor-associated antigen HER2. Multiple infusions of CAR T cells were administered over 30 days through intraventricular delivery routes. It was not associated with any toxic effects of grade 3 or higher. After BNCT and CAR T-cell treatment, regression of all existing intracranial lesions were observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid, but new lesions recurred soon after the treatment. This clinical response continued for 14 months after the initiation of first recurrence.

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