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Emerging Cellular Therapies: T Cells and Beyond

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

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 27409

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Special Issue Editors

Prof. Dr. Stephen Todryk

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Guest Editor

1. Faculty of Health & Life Sciences, Northumbria University, Newcastle upon Tyne NE1 8ST, UK
2. Translational & Clinical Research Institute, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
Interests: T cells; anti-microbial immunity; immune memory; biomarkers
Special Issues, Collections and Topics in MDPI journals

Dr. Agnieszka Jozwik

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Guest Editor

Division of Cancer Studies, King's College London, London, UK
Interests: CAR T cells; anti-tumour T cells

Dr. Julian De Havilland

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Guest Editor

Newcastle Biomedicine Cellular Therapies Facility, Newcastle University, Newcastle upon Tyne, UK
Interests: cell manufacture; quality control

Dr. Joanna Hester

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Guest Editor

Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
Interests: regulatory T cells; transplantation

Special Issue Information

Dear Colleagues,

Cellular Therapies are fast becoming a viable option for the treatment of numerous diseases, due to the progress of technologies that enhance capabilities and reduce costs. They are typically used only when standard treatments have failed, since they are intensive in terms of skilled labour, reagents, and facilities; are often tailored or patient-specific; and, thus, remain expensive and limited in availability. This is in sharp contrast to off-the-shelf drugs. Therapies that have their basis in immune cells benefit from the potency of such cells, together with a mechanistic understanding of their often-complex action. Immunologists have always recognized the key role of T cells in health and disease. Their importance clinically is highlighted when they are absent or dysfunctional, such as in certain primary (genetic) or secondary (induced) immunodeficiencies, where viral infections predominate. Less obvious is their beneficial role as effector T cells in anti-cancer immunity, and their role as regulatory T cells in ameliorating inflammatory immune responses when not needed, such as in autoimmunity, transplantation, cancer therapy (graft vs host with haematopoietic stem cells), and allergy. Current T cell therapies involve manipulation of T cells in all these contexts, mainly ex-vivo, using a range of technological approaches, and are at various stages of clinical development. This Special Issue of Cells aims to highlight these approaches and applications, explain their technical and mechanistic bases, and update their current status and efficacy. Future paths that such “Cell Therapies” will take shall also be discussed.

Prof. Dr. Stephen Todryk
Dr. Agnieszka Jozwik
Dr. Julian de Havilland
Dr. Joanna Hester
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

T cell therapy
adoptive transfer
anti-viral immunity
transplantation
regulatory T cells
anti-tumour immunity

Published Papers (4 papers)

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Editorial

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4 pages, 200 KiB

Open AccessEditorial

Emerging Cellular Therapies: T Cells and Beyond

by Stephen Todryk, Agnieszka Jozwik, Julian de Havilland and Joanna Hester

Cells 2019, 8(3), 284; https://doi.org/10.3390/cells8030284 - 26 Mar 2019

Cited by 7 | Viewed by 3533

Abstract

Cellular therapies, including those based on T cells, are becoming approved options for clinicians treating a range of diseases. Cytotoxic T lymphocytes (CTLs) can be modified ex vivo to express receptors such as chimeric antigen receptors (CARs) or T cell receptors, allowing them to target tumour cells when infused back into patients with particular cancers. CTLs specific for viruses can be purified ex vivo and reinfused into patients transplanted with haematopoietic stem cells to help combat viral reactivation. Regulatory T cells (Tregs) can be expanded ex vivo for infusion into patients with autoimmunity or allergy, or into those at risk of rejecting transplanted cells or tissues, or suffering graft versus host disease. Effector and regulatory T cells can also be generated by infusion of patient-derived dendritic cells (DCs) conditioned in ways to elicit anti-tumour immunity (CTLs) or Tregs. All such therapies are resource-heavy (particularly in process regulation) and so must be initially targeted to patients that have limited treatment options, but also where they have a chance of being effective. Full article

(This article belongs to the Special Issue Emerging Cellular Therapies: T Cells and Beyond)

Review

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12 pages, 547 KiB

Open AccessFeature PaperReview

Adoptive T Cell Therapy Strategies for Viral Infections in Patients Receiving Haematopoietic Stem Cell Transplantation

by Giorgio Ottaviano, Robert Chiesa, Tobias Feuchtinger, Mark A. Vickers, Anne Dickinson, Andrew R. Gennery, Paul Veys and Stephen Todryk

Cells 2019, 8(1), 47; https://doi.org/10.3390/cells8010047 - 14 Jan 2019

Cited by 33 | Viewed by 4997

Abstract

Adverse outcomes following virus-associated disease in patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) have encouraged strategies to control viral reactivation in immunosuppressed patients. However, despite timely treatment with antiviral medication, some viral infections remain refractory to treatment, which hampers outcomes after HSCT, and are responsible for a high proportion of transplant-related morbidity and mortality. Adoptive transfer of donor-derived lymphocytes aims to improve cellular immunity and to prevent or treat viral diseases after HSCT. Early reports described the feasibility of transferring nonspecific lymphocytes from donors, which led to the development of cell therapy approaches based on virus-specific T cells, allowing a targeted treatment of infections, while limiting adverse events such as graft versus host disease (GvHD). Both expansion and direct selection techniques have yielded comparable results in terms of efficacy (around 70–80%), but efficacy is difficult to predict for individual cases. Generating bespoke products for each donor–recipient pair can be expensive, and there remains the major obstacle of generating products from seronegative or poorly responsive donors. More recent studies have focused on the feasibility of collecting and infusing partially matched third-party virus-specific T cells, reporting response rates of 60–70%. Future development of this approach will involve the broadening of applicability to multiple viruses, the optimization and cost-control of manufacturing, larger multicentred efficacy trials, and finally the creation of cell banks that can provide prompt access to virus-specific cellular product. The aim of this review is to summarise present knowledge on adoptive T cell manufacturing, efficacy and potential future developments. Full article

(This article belongs to the Special Issue Emerging Cellular Therapies: T Cells and Beyond)

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11 pages, 634 KiB

Open AccessReview

Allogeneic CAR-T Cells: More than Ease of Access?

by Charlotte Graham, Agnieszka Jozwik, Andrea Pepper and Reuben Benjamin

Cells 2018, 7(10), 155; https://doi.org/10.3390/cells7100155 - 01 Oct 2018

Cited by 120 | Viewed by 11306

Abstract

Patient derived anti-CD19 chimeric antigen receptor-T (CAR-T) cells are a powerful tool in achieving a complete remission in a range of B-cell malignancies, most notably B-acute lymphoblastic leukaemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). However, there are limitations, including inability to manufacture CAR-T cells from the patient’s own T cells, disease progression and death prior to return of engineered cells. T cell dysfunction is known to occur in cancer patients, and several groups have recently described differences in CAR-T cells generated from chronic lymphocytic leukaemia (CLL) patients compared with those from a healthy donor. This is thought to contribute to the low response rate in this disease group. Healthy donor, gene-edited CAR-T cells which do not require human leucocyte antigen (HLA) matching have the potential to provide an ‘off the shelf’ product, overcoming the manufacturing difficulties of producing CAR-T cells for each individual patient. They may also provide a more functional, potent product for malignancies such as CLL, where T cell dysfunction is common and frequently cannot be fully reversed during the manufacturing process. Here we review the potential benefits and obstacles for healthy donor, allogeneic CAR-T cells. Full article

(This article belongs to the Special Issue Emerging Cellular Therapies: T Cells and Beyond)

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19 pages, 1269 KiB

Open AccessReview

Chemokine Receptors and Exercise to Tackle the Inadequacy of T Cell Homing to the Tumor Site

by Manja Idorn and Per Thor Straten

Cells 2018, 7(8), 108; https://doi.org/10.3390/cells7080108 - 17 Aug 2018

Cited by 24 | Viewed by 6523

Abstract

While cancer immune therapy has revolutionized the treatment of metastatic disease across a wide range of cancer diagnoses, a major limiting factor remains with regard to relying on adequate homing of anti-tumor effector cells to the tumor site both prior to and after therapy. Adoptive cell transfer (ACT) of autologous T cells have improved the outlook of patients with metastatic melanoma. Prior to the approval of checkpoint inhibitors, this strategy was the most promising. However, while response rates of up to 50% have been reported, this strategy is still rather crude. Thus, improvements are needed and within reach. A hallmark of the developing tumor is the evasion of immune destruction. Achieved through the recruitment of immune suppressive cell subsets, upregulation of inhibitory receptors and the development of physical and chemical barriers (such as poor vascularization and hypoxia) leaves the microenvironment a hostile destination for anti-tumor T cells. In this paper, we review the emerging strategies of improving the homing of effector T cells (TILs, CARs, TCR engineered T cells, etc.) through genetic engineering with chemokine receptors matching the chemokines of the tumor microenvironment. While this strategy has proven successful in several preclinical models of cancer and the strategy has moved into the first phase I/II clinical trial in humans, most of these studies show a modest (doubling) increase in tumor infiltration of effector cells, which raises the question of whether road blocks must be tackled for efficient homing. We propose a role for physical exercise in modulating the tumor microenvironment and preparing the platform for infiltration of anti-tumor immune cells. In a time of personalized medicine and genetic engineering, this “old tool” may be a way to augment efficacy and the depth of response to immune therapy. Full article

(This article belongs to the Special Issue Emerging Cellular Therapies: T Cells and Beyond)

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