Special Issue "TCR Gene Therapy: Challenges, Opportunities and Future Directions"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 April 2020).

Special Issue Editors

Prof. Hans Stauss
Website
Guest Editor
Institute of Immunity and Transplantation, UCL Division of Infection and Immunity, University College London, Royal Free Hospital, London, UK
Interests: immunology—cancer-immunology, onco-immunology, gene therapy, and immunotherapy; T-cells—CD8 T-cells, CD4 T-cells, and Tregs; vector—lentivirus and retrovirus; antigen: neo-antigen and tumor-antigen; effector function—cytotoxicity, cytokine production, T-cell receptor, affinity, and avidity
Assoc. Prof. Maxine Tran
Website
Co-Guest Editor
Department of Surgical Biotechnology, Division of Surgery and Interventional Science, University College London, London, UK
Interests: cancer immunology; immuno-surveillance; cancer biology; inherited kidney cancer syndromes; early kidney cancer; von-Hippel Lindau syndrome; hereditary leiomyomatosis renal cell carcinoma; metabolic kidney cancer; clinical trials

Special Issue Information

Dear Colleagues,

In the past years, adoptive immunotherapy with gene-engineered T-cells has provided new treatment options for cancer patients. The most successful strategies have involved the engineering of T cells expressing chimeric antigen receptors (CARs) directed against differentiation antigens expressed in hematological malignancies. To date, clinical trials with TCR gene engineered T cells have not yet shown the impressive benefits seen with CAR constructs targeting CD19-positive blood cancers. In this Special Issue, we will discuss the opportunity to use the TCR technology to target cancer antigens, including mutated proteins, that cannot be reached by CAR technology. We will explore how TCR modifications and T-cell editing can improve the functional profile of engineered T cells, and review our current understanding of the TCR signaling mechanisms that enable T cell activation at exceedingly low concentrations of peptide antigens. This Issue provides detailed insight into the TCR biology and how it may enable the development of highly specific immunotherapies for the treatment of cancer.

Prof. Hans Stauss
Assoc. Prof. Maxine Tran
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cancer immunotherapy
  • TCR gene therapy
  • Gene editing
  • Neo-antigens
  • T-cells
  • Adoptive cell therapy

Published Papers (7 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

Open AccessArticle
MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo
Cells 2020, 9(7), 1581; https://doi.org/10.3390/cells9071581 - 29 Jun 2020
Abstract
In this study we report the functional comparison of T cell receptor (TCR)-engineered major histocompatibility complex (MHC) class I-restricted CD4+ versus CD8+ T cells targeting a peptide from six transmembrane epithelial antigen of the prostate 1 (STEAP1) in the context of [...] Read more.
In this study we report the functional comparison of T cell receptor (TCR)-engineered major histocompatibility complex (MHC) class I-restricted CD4+ versus CD8+ T cells targeting a peptide from six transmembrane epithelial antigen of the prostate 1 (STEAP1) in the context of HLA-A*02:01. STEAP1 is a tumor-associated antigen, which is overexpressed in many cancers, including Ewing sarcoma (EwS). Based on previous observations, we postulated strong antitumor potential of tumor-redirected CD4+ T cells transduced with an HLA class I-restricted TCR against a STEAP1-derived peptide. We compared CD4+ T cell populations to their CD8+ counterparts in vitro using impedance-based xCELLigence and cytokine/granzyme release assays. We further compared antitumor activity of STEAP130-TCR transgenic (tg) CD4+ versus CD8+ T cells in tumor-bearing xenografted Rag2−/−γc−/− mice. TCR tgCD4+ T cells showed increased cytotoxic features over time with similar functional avidity compared to tgCD8+ cells after 5–6 weeks of culture. In vivo, local tumor control was equal. Assessing metastatic organotropism of intraveniously (i.v.) injected tumors, only tgCD8+ cells were associated with reduced metastases. In this analysis, EwS-redirected tgCD4+ T cells contribute to local tumor control, but fail to control metastatic outgrowth in a model of xenografted EwS. Full article
(This article belongs to the Special Issue TCR Gene Therapy: Challenges, Opportunities and Future Directions)
Show Figures

Figure 1

Open AccessArticle
HLA-DPB1 Reactive T Cell Receptors for Adoptive Immunotherapy in Allogeneic Stem Cell Transplantation
Cells 2020, 9(5), 1264; https://doi.org/10.3390/cells9051264 - 20 May 2020
Abstract
HLA-DPB1 antigens are mismatched in about 80% of allogeneic hematopoietic stem cell transplantations from HLA 10/10 matched unrelated donors and were shown to be associated with a decreased risk of leukemia relapse. We recently developed a reliable in vitro method to generate HLA-DPB1 [...] Read more.
HLA-DPB1 antigens are mismatched in about 80% of allogeneic hematopoietic stem cell transplantations from HLA 10/10 matched unrelated donors and were shown to be associated with a decreased risk of leukemia relapse. We recently developed a reliable in vitro method to generate HLA-DPB1 mismatch-reactive CD4 T-cell clones from allogeneic donors. Here, we isolated HLA-DPB1 specific T cell receptors (TCR DP) and used them either as wild-type or genetically optimized receptors to analyze in detail the reactivity of transduced CD4 and CD8 T cells toward primary AML blasts. While both CD4 and CD8 T cells showed strong AML reactivity in vitro, only CD4 T cells were able to effectively eliminate leukemia blasts in AML engrafted NOD/SCID/IL2Rγc−/− (NSG) mice. Further analysis showed that optimized TCR DP and under some conditions wild-type TCR DP also mediated reactivity to non-hematopoietic cells like fibroblasts or tumor cell lines after HLA-DP upregulation. In conclusion, T cells engineered with selected allo-HLA-DPB1 specific TCRs might be powerful off-the-shelf reagents in allogeneic T-cell therapy of leukemia. However, because of frequent (common) cross-reactivity to non-hematopoietic cells with optimized TCR DP T cells, safety mechanisms are mandatory. Full article
(This article belongs to the Special Issue TCR Gene Therapy: Challenges, Opportunities and Future Directions)
Show Figures

Figure 1

Review

Jump to: Research

Open AccessReview
T-Cell Gene Therapy in Cancer Immunotherapy: Why It Is No Longer Just CARs on The Road
Cells 2020, 9(7), 1588; https://doi.org/10.3390/cells9071588 - 30 Jun 2020
Abstract
T-cells have a natural ability to fight cancer cells in the tumour microenvironment. Due to thymic selection and tissue-driven immunomodulation, these cancer-fighting T-cells are generally low in number and exhausted. One way to overcome these issues is to genetically alter T-cells to improve [...] Read more.
T-cells have a natural ability to fight cancer cells in the tumour microenvironment. Due to thymic selection and tissue-driven immunomodulation, these cancer-fighting T-cells are generally low in number and exhausted. One way to overcome these issues is to genetically alter T-cells to improve their effectiveness. This process can involve introducing a receptor that has high affinity for a tumour antigen, with two promising candidates known as chimeric-antigen receptors (CARs), or T-cell receptors (TCRs) with high tumour specificity. This review focuses on the editing of immune cells to introduce such novel receptors to improve immune responses to cancer. These new receptors redirect T-cells innate killing abilities to the appropriate target on cancer cells. CARs are modified receptors that recognise whole proteins on the surface of cancer cells. They have been shown to be very effective in haematological malignancies but have limited documented efficacy in solid cancers. TCRs recognise internal antigens and therefore enable targeting of a much wider range of antigens. TCRs require major histocompatibility complex (MHC) restriction but novel TCRs may have broader antigen recognition. Moreover, there are multiple cell types which can be used as targets to improve the “off-the-shelf” capabilities of these genetic engineering methods. Full article
(This article belongs to the Special Issue TCR Gene Therapy: Challenges, Opportunities and Future Directions)
Show Figures

Figure 1

Open AccessReview
Engineering Strategies to Enhance TCR-Based Adoptive T Cell Therapy
Cells 2020, 9(6), 1485; https://doi.org/10.3390/cells9061485 - 18 Jun 2020
Abstract
T cell receptor (TCR)-based adoptive T cell therapies (ACT) hold great promise for the treatment of cancer, as TCRs can cover a broad range of target antigens. Here we summarize basic, translational and clinical results that provide insight into the challenges and opportunities [...] Read more.
T cell receptor (TCR)-based adoptive T cell therapies (ACT) hold great promise for the treatment of cancer, as TCRs can cover a broad range of target antigens. Here we summarize basic, translational and clinical results that provide insight into the challenges and opportunities of TCR-based ACT. We review the characteristics of target antigens and conventional αβ-TCRs, and provide a summary of published clinical trials with TCR-transgenic T cell therapies. We discuss how synthetic biology and innovative engineering strategies are poised to provide solutions for overcoming current limitations, that include functional avidity, MHC restriction, and most importantly, the tumor microenvironment. We also highlight the impact of precision genome editing on the next iteration of TCR-transgenic T cell therapies, and the discovery of novel immune engineering targets. We are convinced that some of these innovations will enable the field to move TCR gene therapy to the next level. Full article
(This article belongs to the Special Issue TCR Gene Therapy: Challenges, Opportunities and Future Directions)
Show Figures

Figure 1

Open AccessReview
Chronic Viral Liver Diseases: Approaching the Liver Using T Cell Receptor-Mediated Gene Technologies
Cells 2020, 9(6), 1471; https://doi.org/10.3390/cells9061471 - 16 Jun 2020
Abstract
Chronic infection with viral hepatitis is a major risk factor for liver injury and hepatocellular carcinoma (HCC). One major contributing factor to the chronicity is the dysfunction of virus-specific T cell immunity. T cells engineered to express virus-specific T cell receptors (TCRs) may [...] Read more.
Chronic infection with viral hepatitis is a major risk factor for liver injury and hepatocellular carcinoma (HCC). One major contributing factor to the chronicity is the dysfunction of virus-specific T cell immunity. T cells engineered to express virus-specific T cell receptors (TCRs) may be a therapeutic option to improve host antiviral responses and have demonstrated clinical success against virus-associated tumours. This review aims to give an overview of TCRs identified from viral hepatitis research and discuss how translational lessons learned from cancer immunotherapy can be applied to the field. TCR isolation pipelines, liver homing signals, cell type options, as well as safety considerations will be discussed herein. Full article
(This article belongs to the Special Issue TCR Gene Therapy: Challenges, Opportunities and Future Directions)
Open AccessReview
Redirecting T Cells against Epstein–Barr Virus Infection and Associated Oncogenesis
Cells 2020, 9(6), 1400; https://doi.org/10.3390/cells9061400 - 04 Jun 2020
Abstract
The Epstein–Barr virus (EBV) is associated with lymphomas and carcinomas. For some of these, the adoptive transfer of EBV specific T cells has been therapeutically explored, with clinical success. In order to avoid naturally occurring EBV specific autologous T cell selection from every [...] Read more.
The Epstein–Barr virus (EBV) is associated with lymphomas and carcinomas. For some of these, the adoptive transfer of EBV specific T cells has been therapeutically explored, with clinical success. In order to avoid naturally occurring EBV specific autologous T cell selection from every patient, the transgenic expression of latent and early lytic viral antigen specific T cell receptors (TCRs) to redirect T cells, to target the respective tumors, is being developed. Recent evidence suggests that not only TCRs against transforming latent EBV antigens, but also against early lytic viral gene products, might be protective for the control of EBV infection and associated oncogenesis. At the same time, these approaches might be more selective and cause less collateral damage than targeting general B cell markers with chimeric antigen receptors (CARs). Thus, EBV specific TCR transgenic T cells constitute a promising therapeutic strategy against EBV associated malignancies. Full article
(This article belongs to the Special Issue TCR Gene Therapy: Challenges, Opportunities and Future Directions)
Show Figures

Figure 1

Open AccessReview
Orthotopic T-Cell Receptor Replacement—An “Enabler” for TCR-Based Therapies
Cells 2020, 9(6), 1367; https://doi.org/10.3390/cells9061367 - 01 Jun 2020
Abstract
Natural adaptive immunity co-evolved with pathogens over millions of years, and adoptive transfer of non-engineered T cells to fight infections or cancer so far exhibits an exceptionally safe and functional therapeutic profile in clinical trials. However, the personalized nature of therapies using virus-specific [...] Read more.
Natural adaptive immunity co-evolved with pathogens over millions of years, and adoptive transfer of non-engineered T cells to fight infections or cancer so far exhibits an exceptionally safe and functional therapeutic profile in clinical trials. However, the personalized nature of therapies using virus-specific T cells, donor lymphocyte infusion, or tumor-infiltrating lymphocytes makes implementation in routine clinical care difficult. In principle, genetic engineering can be used to make T-cell therapies more broadly applicable, but so far it significantly alters the physiology of cells. We recently demonstrated that orthotopic T-cell receptor (TCR) replacement (OTR) by clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein 9 (Cas9) can be used to generate engineered T cells with preservation of near-physiological function. In this review, we present the current status of OTR technology development and discuss its potential for TCR-based therapies. By providing the means to combine the therapeutic efficacy and safety profile of physiological T cells with the versatility of cell engineering, OTR can serve as an “enabler” for TCR-based therapies. Full article
(This article belongs to the Special Issue TCR Gene Therapy: Challenges, Opportunities and Future Directions)
Show Figures

Figure 1

Back to TopTop