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TCR Gene Therapy: Challenges, Opportunities and Future Directions
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TCR Gene Therapy: Challenges, Opportunities and Future Directions

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

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 69243

Special Issue Editors

Prof. Hans Stauss

E-Mail 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

E-Mail 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 submissions that pass pre-check are 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 semimonthly 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 2700 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 (12 papers)

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Editorial

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4 pages, 181 KiB  
Editorial
TCR Gene Therapy: Challenges, Opportunities, and Future Directions
by Hans J. Stauss and Maxine G. B. Tran
Cells 2020, 9(12), 2567; https://doi.org/10.3390/cells9122567 - 01 Dec 2020
Cited by 6 | Viewed by 2045
Abstract
Adoptive immunotherapy with gene-engineered T cells has provided new treatment options for cancer patients [...] Full article
(This article belongs to the Special Issue TCR Gene Therapy: Challenges, Opportunities and Future Directions)

Research

Jump to: Editorial, Review

15 pages, 1363 KiB  
Article
MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo
by Sebastian J. Schober, Melanie Thiede, Hendrik Gassmann, Carolin Prexler, Busheng Xue, David Schirmer, Dirk Wohlleber, Stefanie Stein, Thomas G. P. Grünewald, Dirk H. Busch, Guenther H. S. Richter, Stefan E. G. Burdach and Uwe Thiel
Cells 2020, 9(7), 1581; https://doi.org/10.3390/cells9071581 - 29 Jun 2020
Cited by 21 | Viewed by 3398
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)
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15 pages, 3856 KiB  
Article
HLA-DPB1 Reactive T Cell Receptors for Adoptive Immunotherapy in Allogeneic Stem Cell Transplantation
by Sebastian Klobuch, Kathrin Hammon, Sarah Vatter-Leising, Elisabeth Neidlinger, Michael Zwerger, Annika Wandel, Laura Maria Neuber, Bernhard Heilmeier, Regina Fichtner, Carina Mirbeth, Wolfgang Herr and Simone Thomas
Cells 2020, 9(5), 1264; https://doi.org/10.3390/cells9051264 - 20 May 2020
Cited by 10 | Viewed by 2774
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)
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Review

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21 pages, 2616 KiB  
Review
Breaking Bottlenecks for the TCR Therapy of Cancer
by Lena Gaissmaier, Mariam Elshiaty and Petros Christopoulos
Cells 2020, 9(9), 2095; https://doi.org/10.3390/cells9092095 - 14 Sep 2020
Cited by 38 | Viewed by 5995
Abstract
Immune checkpoint inhibitors have redefined the treatment of cancer, but their efficacy depends critically on the presence of sufficient tumor-specific lymphocytes, and cellular immunotherapies develop rapidly to fill this gap. The paucity of suitable extracellular and tumor-associated antigens in solid cancers necessitates the [...] Read more.
Immune checkpoint inhibitors have redefined the treatment of cancer, but their efficacy depends critically on the presence of sufficient tumor-specific lymphocytes, and cellular immunotherapies develop rapidly to fill this gap. The paucity of suitable extracellular and tumor-associated antigens in solid cancers necessitates the use of neoantigen-directed T-cell-receptor (TCR)-engineered cells, while prevention of tumor evasion requires combined targeting of multiple neoepitopes. These can be currently identified within 2 weeks by combining cutting-edge next-generation sequencing with bioinformatic pipelines and used to select tumor-reactive TCRs in a high-throughput manner for expeditious scalable non-viral gene editing of autologous or allogeneic lymphocytes. “Young” cells with a naive, memory stem or central memory phenotype can be additionally armored with “next-generation” features against exhaustion and the immunosuppressive tumor microenvironment, where they wander after reinfusion to attack heavily pretreated and hitherto hopeless neoplasms. Facilitated by major technological breakthroughs in critical manufacturing steps, based on a solid preclinical rationale, and backed by rapidly accumulating evidence, TCR therapies break one bottleneck after the other and hold the promise to become the next immuno-oncological revolution. Full article
(This article belongs to the Special Issue TCR Gene Therapy: Challenges, Opportunities and Future Directions)
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28 pages, 1695 KiB  
Review
Engineering the Bridge between Innate and Adaptive Immunity for Cancer Immunotherapy: Focus on γδ T and NK Cells
by Fabio Morandi, Mahboubeh Yazdanifar, Claudia Cocco, Alice Bertaina and Irma Airoldi
Cells 2020, 9(8), 1757; https://doi.org/10.3390/cells9081757 - 22 Jul 2020
Cited by 50 | Viewed by 8394
Abstract
Most studies on genetic engineering technologies for cancer immunotherapy based on allogeneic donors have focused on adaptive immunity. However, the main limitation of such approaches is that they can lead to severe graft-versus-host disease (GvHD). An alternative approach would bolster innate immunity by [...] Read more.
Most studies on genetic engineering technologies for cancer immunotherapy based on allogeneic donors have focused on adaptive immunity. However, the main limitation of such approaches is that they can lead to severe graft-versus-host disease (GvHD). An alternative approach would bolster innate immunity by relying on the natural tropism of some subsets of the innate immune system, such as γδ T and natural killer (NK) cells, for the tumor microenvironment and their ability to kill in a major histocompatibility complex (MHC)-independent manner. γδ T and NK cells have the unique ability to bridge innate and adaptive immunity while responding to a broad range of tumors. Considering these properties, γδ T and NK cells represent ideal sources for developing allogeneic cell therapies. Recently, significant efforts have been made to exploit the intrinsic anti-tumor capacity of these cells for treating hematologic and solid malignancies using genetic engineering approaches such as chimeric antigen receptor (CAR) and T cell receptor (TCR). Here, we review over 30 studies on these two approaches that use γδ T and NK cells in adoptive cell therapy (ACT) for treating cancer. Based on those studies, we propose several promising strategies to optimize the clinical translation of these approaches. Full article
(This article belongs to the Special Issue TCR Gene Therapy: Challenges, Opportunities and Future Directions)
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8 pages, 206 KiB  
Review
Engineering CD4+ T Cells to Enhance Cancer Immunity
by Francesca Sillito, Angelika Holler and Hans J. Stauss
Cells 2020, 9(7), 1721; https://doi.org/10.3390/cells9071721 - 18 Jul 2020
Cited by 6 | Viewed by 2949
Abstract
This review presents key advances in combining T cell receptor (TCR) gene transfer to redirect T-cell specificity with gene engineering in order to enhance cancer-protective immune function. We discuss how emerging insights might be applied to CD4+ T cells. Although much attention has [...] Read more.
This review presents key advances in combining T cell receptor (TCR) gene transfer to redirect T-cell specificity with gene engineering in order to enhance cancer-protective immune function. We discuss how emerging insights might be applied to CD4+ T cells. Although much attention has been paid to the role of CD8+ cytotoxic T cells in tumour protection, we provide convincing evidence that CD4+ helper T cells play a critical role in cancer immune responses in animal models and also in patients. We demonstrate that genetic engineering technologies provide exciting opportunities to extend the specificity range of CD4+ T cells from MHC class-II-presented epitopes to include peptides presented by MHC class I molecules. Functional enhancement of tumour immunity can improve the sensitivity of T cells to cancer antigens, promote survival in a hostile tumour microenvironment, boost cancer-protective effector mechanisms and enable the formation of T-cell memory. Engineered cancer-specific CD4+ T cells may contribute to protective immunity by a direct pathway involving cancer cell killing, and by an indirect pathway that boosts the function, persistence and memory formation of CD8+ T cells. Full article
(This article belongs to the Special Issue TCR Gene Therapy: Challenges, Opportunities and Future Directions)
18 pages, 966 KiB  
Review
The Quest for the Best: How TCR Affinity, Avidity, and Functional Avidity Affect TCR-Engineered T-Cell Antitumor Responses
by Diana Campillo-Davo, Donovan Flumens and Eva Lion
Cells 2020, 9(7), 1720; https://doi.org/10.3390/cells9071720 - 18 Jul 2020
Cited by 42 | Viewed by 9280
Abstract
Over the past decades, adoptive transfer of T cells has revolutionized cancer immunotherapy. In particular, T-cell receptor (TCR) engineering of T cells has marked important milestones in developing more precise and personalized cancer immunotherapies. However, to get the most benefit out of this [...] Read more.
Over the past decades, adoptive transfer of T cells has revolutionized cancer immunotherapy. In particular, T-cell receptor (TCR) engineering of T cells has marked important milestones in developing more precise and personalized cancer immunotherapies. However, to get the most benefit out of this approach, understanding the role that TCR affinity, avidity, and functional avidity play on how TCRs and T cells function in the context of tumor-associated antigen (TAA) recognition is vital to keep generating improved adoptive T-cell therapies. Aside from TCR-related parameters, other critical factors that govern T-cell activation are the effect of TCR co-receptors on TCR–peptide-major histocompatibility complex (pMHC) stabilization and TCR signaling, tumor epitope density, and TCR expression levels in TCR-engineered T cells. In this review, we describe the key aspects governing TCR specificity, T-cell activation, and how these concepts can be applied to cancer-specific TCR redirection of T cells. Full article
(This article belongs to the Special Issue TCR Gene Therapy: Challenges, Opportunities and Future Directions)
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18 pages, 1139 KiB  
Review
T-Cell Gene Therapy in Cancer Immunotherapy: Why It Is No Longer Just CARs on The Road
by Michael D. Crowther, Inge Marie Svane and Özcan Met
Cells 2020, 9(7), 1588; https://doi.org/10.3390/cells9071588 - 30 Jun 2020
Cited by 20 | Viewed by 7721
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)
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34 pages, 1749 KiB  
Review
Engineering Strategies to Enhance TCR-Based Adoptive T Cell Therapy
by Jan A. Rath and Caroline Arber
Cells 2020, 9(6), 1485; https://doi.org/10.3390/cells9061485 - 18 Jun 2020
Cited by 47 | Viewed by 10120
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)
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26 pages, 614 KiB  
Review
Chronic Viral Liver Diseases: Approaching the Liver Using T Cell Receptor-Mediated Gene Technologies
by Katie Healy, Anna Pasetto, Michał J. Sobkowiak, Chai Fen Soon, Markus Cornberg, Soo Aleman and Margaret Sällberg Chen
Cells 2020, 9(6), 1471; https://doi.org/10.3390/cells9061471 - 16 Jun 2020
Cited by 6 | Viewed by 3180
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)
13 pages, 1559 KiB  
Review
Redirecting T Cells against Epstein–Barr Virus Infection and Associated Oncogenesis
by Christian Münz
Cells 2020, 9(6), 1400; https://doi.org/10.3390/cells9061400 - 04 Jun 2020
Cited by 23 | Viewed by 7457
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)
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20 pages, 809 KiB  
Review
Orthotopic T-Cell Receptor Replacement—An “Enabler” for TCR-Based Therapies
by Kilian Schober, Thomas R. Müller and Dirk H. Busch
Cells 2020, 9(6), 1367; https://doi.org/10.3390/cells9061367 - 01 Jun 2020
Cited by 13 | Viewed by 4488
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)
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