scholarly journals γδ T Cells: The Ideal Tool for Cancer Immunotherapy

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1305 ◽  
Author(s):  
Mahboubeh Yazdanifar ◽  
Giulia Barbarito ◽  
Alice Bertaina ◽  
Irma Airoldi
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Third Party ◽  
Allogeneic Cell Therapy ◽  
Cell Immunotherapy ◽  
Engineered T Cells ◽  
Ideal Tool ◽  
Adoptive Cell Immunotherapy

γδ T cells have recently gained considerable attention as an attractive tool for cancer adoptive immunotherapy due to their potent anti-tumor activity and unique role in immunosurveillance. The remarkable success of engineered T cells for the treatment of hematological malignancies has revolutionized the field of adoptive cell immunotherapy. Accordingly, major efforts are underway to translate this exciting technology to the treatment of solid tumors and the development of allogeneic therapies. The unique features of γδ T cells, including their major histocompatibility complex (MHC)-independent anti-cancer activity, tissue tropism, and multivalent response against a broad spectrum of the tumors, render them ideal for designing universal ‘third-party’ cell products, with the potential to overcome the challenges of allogeneic cell therapy. In this review, we describe the crucial role of γδ T cells in anti-tumor immunosurveillance and we summarize the different approaches used for the ex vivo and in vivo expansion of γδ T cells suitable for the development of novel strategies for cancer therapy. We further discuss the different transduction strategies aiming at redirecting or improving the function of γδ T cells, as well as, the considerations for the clinical applications.

scholarly journals Vγ9Vδ2 T cells as a promising innovative tool for immunotherapy of hematologic malignancies

2011 ◽  
Vol 4 (4) ◽  
pp. 211
Author(s):  
Serena Meraviglia ◽  
Carmela La Mendola ◽  
Valentina Orlando ◽  
Francesco Scarpa ◽  
Giuseppe Cicero ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Hematologic Malignancies ◽  
Cytolytic Activity ◽  
Cell Therapies ◽  
Stressed Cells

The potent anti-tumor activities of γδ T cells, their ability to produce pro-inflammatory cytokines, and their strong cytolytic activity have prompted the development of protocols in which γδ agonists or ex vivo-expanded γδ cells are administered to tumor patients. γδ T cells can be selectively activated by either synthetic phosphoantigens or by drugs that enhance their accumulation into stressed cells as aminobisphosphonates, thus offering new avenues for the development of γδ T cell-based immunotherapies. The recent development of small drugs selectively activating Vγ9Vδ2 T lymphocytes, which upregulate the endogenous phosphoantigens, has enabled the investigators to design the experimental approaches of cancer immunotherapies; several ongoing phase I and II clinical trials are focused on the role of the direct bioactivity of drugs and of adoptive cell therapies involving phosphoantigen- or aminobisphosphonate-activated Vγ9Vδ2 T lymphocytes in humans. In this review, we focus on the recent advances in the activation/expansion of γδ T cells in vitro and in vivo that may represent a promising target for the design of novel and highly innovative immunotherapy in patients with hematologic malignancies.<br />

scholarly journals In vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
N. N. Parayath ◽  
S. B. Stephan ◽  
A. L. Koehne ◽  
P. S. Nelson ◽  
M. T. Stephan
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Human Leukemia ◽  
Antigen Receptors ◽  
Wide Range ◽  
Engineered T Cells ◽  
Circulating T Cells ◽  
The Cost

AbstractEngineering chimeric antigen receptors (CAR) or T cell receptors (TCR) helps create disease-specific T cells for targeted therapy, but the cost and rigor associated with manufacturing engineered T cells ex vivo can be prohibitive, so programing T cells in vivo may be a viable alternative. Here we report an injectable nanocarrier that delivers in vitro-transcribed (IVT) CAR or TCR mRNA for transiently reprograming of circulating T cells to recognize disease-relevant antigens. In mouse models of human leukemia, prostate cancer and hepatitis B-induced hepatocellular carcinoma, repeated infusions of these polymer nanocarriers induce sufficient host T cells expressing tumor-specific CARs or virus-specific TCRs to cause disease regression at levels similar to bolus infusions of ex vivo engineered lymphocytes. Given their ease of manufacturing, distribution and administration, these nanocarriers, and the associated platforms, could become a therapeutic for a wide range of diseases.

scholarly journals Induction of tolerance to bone marrow allografts by donor-derived host nonreactive ex vivo–induced central memory CD8 T cells

Blood ◽  
2010 ◽  
Vol 115 (10) ◽  
pp. 2095-2104 ◽  
Author(s):  
Eran Ophir ◽  
Yaki Eidelstein ◽  
Ran Afik ◽  
Esther Bachar-Lustig ◽  
Yair Reisner
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Memory Cell ◽  
Central Memory ◽  
Third Party ◽  
High Survival

Abstract Enabling engraftment of allogeneic T cell–depleted bone marrow (TDBM) under reduced-intensity conditioning represents a major challenge in bone marrow transplantation (BMT). Anti–third-party cytotoxic T lymphocytes (CTLs) were previously shown to be endowed with marked ability to delete host antidonor T cells in vitro, but were found to be less effective in vivo. This could result from diminished lymph node (LN) homing caused by the prolonged activation, which induces a CD44+CD62L− effector phenotype, and thereby prevents effective colocalization with, and neutralization of, alloreactive host T cells (HTCs). In the present study, LN homing, determined by imaging, was enhanced upon culture conditions that favor the acquisition of CD44+CD62L+ central memory cell (Tcm) phenotype by anti–third-party CD8+ cells. These Tcm-like cells displayed strong proliferation and prolonged persistence in BM transplant recipients. Importantly, adoptively transferred HTCs bearing a transgenic T-cell receptor (TCR) with antidonor specificity were efficiently deleted only by donor-type Tcms. All these attributes were found to be associated with improved efficacy in overcoming T cell–mediated rejection of TDBM, thereby enabling high survival rate and long-term donor chimerism, without causing graft-versus-host disease. In conclusion, anti–third-party Tcms, which home to recipient LNs and effectively delete antidonor T cells, could provide an effective and novel tool for overcoming rejection of BM allografts.

scholarly journals Adoptively transferred ex vivo expanded γδ-T cells mediate in vivo antitumor activity in preclinical mouse models of breast cancer

2009 ◽  
Vol 122 (1) ◽  
pp. 135-144 ◽  
Author(s):  
Benjamin H. Beck ◽  
Hyung-Gyoon Kim ◽  
Hyunki Kim ◽  
Sharon Samuel ◽  
Zhiyong Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Antitumor Activity ◽  
Mouse Models ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
In Vivo Antitumor Activity

scholarly journals DNA-scaffolded biomaterials enable modular and tunable control of cell-based cancer immunotherapies

2019 ◽  
Author(s):  
Xiao Huang ◽  
Jasper Z. Williams ◽  
Ryan Chang ◽  
Zhongbo Li ◽  
Eric Gai ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cell ◽  
Ex Vivo ◽  
Cell Activity ◽  
Engineered T Cells ◽  
Advanced Biomaterials ◽  
Cancer Immunotherapies ◽  
Biodegradable Particles ◽  
The Impact

Advanced biomaterials provide versatile ways to spatially and temporally control immune cell activity, potentially enhancing their therapeutic potency and safety. Precise cell modulation demands multi-modal display of functional proteins with controlled densities on biomaterials. Here, we develop an artificial immune cell engager (AICE) platform – biodegradable particles onto which multiple proteins are densely loaded with ratiometric control via short nucleic acid tethers. We demonstrate the impact of AICE with varying ratios of anti-CD3 and anti-CD28 antibodies onex vivoexpansion of human primary T cells. We also show that AICE can be used to control the activity of engineered T cellsin vivo. AICE injected intratumorally can provide a local priming signal for systemically administered AND-gate chimeric antigen receptor T cells, driving local tumor clearance while sparing uninjected tumors that model potentially cross-reactive healthy tissues. This modularly functionalized biomaterial thus provides a flexible platform to achieve sophisticated control over cell-based immunotherapies.

scholarly journals Potent ex vivo armed T cells using recombinant bispecific antibodies for adoptive immunotherapy with reduced cytokine release

2021 ◽  
Vol 9 (5) ◽  
pp. e002222
Author(s):  
Jeong A Park ◽  
Brian H Santich ◽  
Hong Xu ◽  
Lawrence G Lum ◽  
Nai-Kong V Cheung
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Cell Number ◽  
Bispecific Antibodies ◽  
Treatment Schedule ◽  
Cytokine Release ◽  
Antitumor Activities

BackgroundT cell-based immunotherapies using chimeric antigen receptors (CAR) or bispecific antibodies (BsAb) have produced impressive responses in hematological malignancies. However, major hurdles remained, including cytokine release syndrome, neurotoxicity, on-target off-tumor effects, reliance on autologous T cells, and failure in most solid tumors. BsAb armed T cells offer a safe alternative.MethodsWe generated ex vivo armed T cells (EATs) using IgG-[L]-scFv-platformed BsAb, where the anti-CD3 (huOKT3) scFv was attached to the light chain of a tumor-binding IgG. BsAb density on EAT, in vitro cytotoxicity, cytokine release, in vivo trafficking into tumors, and their antitumor activities were evaluated in multiple cancer cell lines and patient-derived xenograft mouse models. The efficacy of EATs after cryopreservation was studied, and gamma delta (γδ) T cells were investigated as unrelated alternative effector T cells.ResultsThe antitumor potency of BsAb armed T cells was substantially improved using the IgG-[L]-scFv BsAb platform. When compared with separate BsAb and T cell injection, EATs released less TNF-α, and infiltrated tumors faster, while achieving robust antitumor responses. The in vivo potency of EAT therapy depended on BsAb dose for arming, EAT cell number per injection, total number of EAT doses, and treatment schedule intensity. The antitumor efficacy of EATs was preserved following cryopreservation, and EATs using γδ T cells were safe and as effective as αβ T cell-EATs.ConclusionsEATs exerted potent antitumor activities against a broad spectrum of human cancer targets with remarkable safety. The antitumor potency of EATs depended on BsAb dose, cell number and total dose, and schedule. EATs were equally effective after cryopreservation, and the feasibility of third-party γδ-EATs offered an alternative for autologous T cell sources.

scholarly journals The potential role of γδ T cells after allogeneic HCT for leukemia

Blood ◽  
2018 ◽  
Vol 131 (10) ◽  
pp. 1063-1072 ◽  
Author(s):  
Rupert Handgretinger ◽  
Karin Schilbach
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Large Scale ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Infectious Complications ◽  
Allogeneic Hct

Abstract Allogeneic hematopoetic stem cell transplantation (HCT) offers an option for patients with hematologic malignancies, in whom conventional standard therapies failed or are not effective enough to cure the disease. Successful HCT can restore functional hematopoiesis and immune function, and the new donor-derived immune system can exert a graft-versus-leukemia (GVL) effect. However, allogenic HCT can also be associated with serious risks for transplantation-related morbidities or mortalities such as graft-versus-host disease (GVHD) or life-threatening infectious complications. GVHD is caused by alloreactive T lymphocytes, which express the αβ T-cell receptor, whereas lymphocytes expressing the γδ T-cell receptor are not alloreactive and do not induce GVHD but can exhibit potent antileukemia and anti-infectious activities. Therefore, γδ T cells are becoming increasingly interesting in allogeneic HCT, and clinical strategies to exploit the full function of these lymphocytes have been and are being developed. Such strategies comprise the in vivo activation of γδ T cells or subsets after HCT by certain drugs or antibodies or the ex vivo expansion and manipulation of either patient-derived or donor-derived γδ T cells and their subsets and the adoptive transfer of the ex vivo–activated lymphocytes. On the basis of the absence of dysregulated alloreactivity, such approaches could induce potent GVL effects in the absence of GVHD. The introduction of large-scale clinical methods to enrich, isolate, expand, and manipulate γδ T cells will facilitate future clinical studies that aim to exploit the full function of these beneficial nonalloreactive lymphocytes.

scholarly journals In Situ Programming of CAR T Cells

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Neha N. Parayath ◽  
Matthias T. Stephan
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Annual Review ◽  
Publication Date ◽  
Antigen Receptors ◽  
Car T ◽  
Engineered T Cells ◽  
Long Term Impact

Gene therapy makes it possible to engineer chimeric antigen receptors (CARs) to create T cells that target specific diseases. However, current approaches require elaborate and expensive protocols to manufacture engineered T cells ex vivo, putting this therapy beyond the reach of many patients who might benefit. A solution could be to program T cells in vivo. Here, we evaluate the clinical need for in situ CAR T cell programming, compare competing technologies, review current progress, and provide a perspective on the long-term impact of this emerging and rapidly flourishing biotechnology field. Expected final online publication date for the Annual Review of Biomedical Engineering, Volume 23 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Cancer Immunotherapy: Cytotoxic Activity of γδ T-Cells Expanded Ex Vivo by the Third Generation Bisphosphonate Zoledronate.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1347-1347
Author(s):  
Kiyoshi Sato ◽  
Shinya Kimura ◽  
Takeshi Yuasa ◽  
Hiromi Wada ◽  
Taira Maekawa
Keyword(s):  
T Cells ◽  
Antitumor Activity ◽  
Cytotoxic Activity ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Target Cells ◽  
Third Generation ◽  
Ras Proteins ◽  
Target Cancer

Abstract Bisphosphonates (BPs), widely used to treat bone diseases, have recently been attracted much interest for their antitumor activity and have been reported to exert direct antitumor effects on several cancer cell lines via the inactivation of Ras proteins. BPs inhibit farnesyl pyrophosphate (FPP) synthetase in the mevalonate pathway and deplete cellular pools of PPs such as farnesyl PP and geranylgeranyl PP which are indispensable for the activation of Ras proteins. In addition to their direct antitumor activity, BPs expand γδ T-cells which are potent effector cells and also induce the accumulation of isopentenyl PP as a tumor antigen in target cancer cells. The purpose of this study was to clarify the cytotoxic activity of γδ T-cells expanded ex vivo by the potent third generation BP zoledronate (ZOL). Peripheral blood mononuclear cells of five healthy donors were incubated with different concentrations of ZOL and interleukin-2. After 14 days incubation, 1 μM ZOL increased the absolute number of γδ T-cells 500–800 fold. Expanded γδ T-cells were of the Vγ9Vδ2 subset and cytokine levels of IL-2, -4, -5, -10, TNF-α and IFN-γ were not elevated at resting i.e. before contact to target cancer cells. In vitro cytotoxic activities of γδ T-cells against the luciferase-labeled small cell lung cancer (SCLC) cell line SBC-5 were examined by a newly developed cytotoxic assay using an in vivo imaging system (Xenogen, Alameda, CA) and video microscopy, Leica AS MDW (Leica Microsystems Inc., Bannockburn, IL). γδ T-cells killed SBC-5 cells pre-treated with 5 μM ZOL for 12 h after 1.5–3.0 h contact with the target cells whereas untreated SBC-5 were rarely killed. SBC-5 cells pretreated with 5 μM ZOL showed a marked increase in their sensitivity to lysis by γδ T-cells, percentages of specific lysis were 42% and 55% at effector/target (E/T) ratios of 5:1 and 10:1, respectively, while those of untreated SBC-5 cells were 8% and 13% at E/T ratios of 5:1 and 10:1, respectively. In vivo efficacy of γδ T-cells was investigated in mice xenografted subcutaneously with SBC-5 cells. Pretreatment with 80 μg/kg ZOL enhanced significantly antitumor activity of γδ T-cells also in vivo. These findings showed that ZOL stimulated the proliferation of γδ T-cells significantly and that the cytotoxic activity of γδ T-cells required pre-treatment of target cells with ZOL, indicating the potential use of autologous ex vivo expanded γδ T-cells for cancer immunotherapy.

scholarly journals β2 Integrins differentially regulate γδ T cell subset thymic development and peripheral maintenance

2020 ◽  
Vol 117 (36) ◽  
pp. 22367-22377
Author(s):  
Claire L. McIntyre ◽  
Leticia Monin ◽  
Jesse C. Rop ◽  
Thomas D. Otto ◽  
Carl S. Goodyear ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Cell Subset ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Γδ T Cell ◽  
Thymic Development ◽  
T Cell Subset

The γδ T cells reside predominantly at barrier sites and play essential roles in immune protection against infection and cancer. Despite recent advances in the development of γδ T cell immunotherapy, our understanding of the basic biology of these cells, including how their numbers are regulated in vivo, remains poor. This is particularly true for tissue-resident γδ T cells. We have identified the β2family of integrins as regulators of γδ T cells. β2-integrin–deficient mice displayed a striking increase in numbers of IL-17–producing Vγ6Vδ1+γδ T cells in the lungs, uterus, and circulation. Thymic development of this population was normal. However, single-cell RNA sequencing revealed the enrichment of genes associated with T cell survival and proliferation specifically in β2-integrin–deficient IL-17+cells compared to their wild-type counterparts. Indeed, β2-integrin–deficient Vγ6+cells from the lungs showed reduced apoptosis ex vivo, suggesting that increased survival contributes to the accumulation of these cells in β2-integrin–deficient tissues. Furthermore, our data revealed an unexpected role for β2integrins in promoting the thymic development of the IFNγ-producing CD27+Vγ4+γδ T cell subset. Together, our data reveal that β2integrins are important regulators of γδ T cell homeostasis, inhibiting the survival of IL-17–producing Vγ6Vδ1+cells and promoting the thymic development of the IFNγ-producing Vγ4+subset. Our study introduces unprecedented mechanisms of control for γδ T cell subsets.

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