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Cells
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Advances in Allogeneic Cell Therapy
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Advances in Allogeneic Cell Therapy

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell and Gene Therapy".

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 21477

Special Issue Editor

Prof. Dr. Kazuhiko Ikeda

E-Mail Website
Guest Editor
Department of Blood Transfusion and Transplantation Immunology, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima 9601295, Japan
Interests: hematopoietic stem cell transplantation; transplantation immunology; myeloproliferative neoplasms; clonal hematopoiesis

Special Issue Information

Dear Colleagues,

Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) is curative for hematologic malignancies. The use of an HLA-matched donor has long been the standard choice for HSCT because of the high incidence of transplant-related mortality due to graft failure and graft-versus-host disease (GVHD) in the HSCT recipients from alternative donors. However, recent advances in T-cell depletion have led to the expansion of donor sources, including HLA-haploidentical donors with a predominant graft-versus-tumor effect. Immune modulation with cellular products such as mesenchymal stem cells has also contributed to controlling GVHD. In addition, treatment with allogeneic immune cells carrying the chimeric antigen receptor (CAR) may have potential advantages over approved autologous CAR-T cell products, in the immediate availability, possible standardization of the product, and combination of CAR-T cells against multiple targets.

In this Special Issue, I invite hematologists, oncologists, and biologists to submit research on the strategies to boost and improve our understanding of the mechanism of allogeneic cell-based treatments. Topics include preclinical and clinical studies for the development, engineering, preparation, and use of allogeneic HSCs, CAR-T cells, stem and progenitor cells, mesenchymal stem cells, and other cell types associated with immune targets. We hope this Special Issue highlights the efficient cell-based therapy, attesting new cellular or molecular interventions, which promote novel cellular therapeutic strategies for hematologic malignancies.

Prof. Dr. Kazuhiko Ikeda
Guest Editor

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

  • hematopoietic stem cell
  • Chimeric Antigen Receptor (CAR)
  • mesenchymal stem cell
  • immune modulation
  • engineering
  • expansion
  • processing
  • anti-tumor effect
  • graft-versus-tumor effect
  • histocompatibility

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Published Papers (7 papers)

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Research

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12 pages, 3282 KiB  
Article
Graft-Specific Regulatory T Cells for Long-Lasting, Local Tolerance Induction
by Nadja Seltrecht, Matthias Hardtke-Wolenski, Konstantinos Iordanidis, Danny Jonigk, Melanie Galla, Axel Schambach, Laura Elisa Buitrago-Molina, Heiner Wedemeyer, Fatih Noyan and Elmar Jaeckel
Cells 2024, 13(14), 1216; https://doi.org/10.3390/cells13141216 - 19 Jul 2024
Viewed by 1049
Abstract
Background: Solid organ transplantation is hindered by immune-mediated chronic graft dysfunction and the side effects of immunosuppressive therapy. Regulatory T cells (Tregs) are crucial for modulating immune responses post-transplantation; however, the transfer of polyspecific Tregs alone is insufficient to induce allotolerance in rodent [...] Read more.
Background: Solid organ transplantation is hindered by immune-mediated chronic graft dysfunction and the side effects of immunosuppressive therapy. Regulatory T cells (Tregs) are crucial for modulating immune responses post-transplantation; however, the transfer of polyspecific Tregs alone is insufficient to induce allotolerance in rodent models. Methods: To enhance the efficacy of adoptive Treg therapy, we investigated different immune interventions in the recipients. By utilizing an immunogenic skin transplant model and existing transplantation medicine reagents, we facilitated the clinical translation of our findings. Specifically, antigen-specific Tregs were used. Results: Our study demonstrated that combining the available induction therapies with drug-induced T-cell proliferation due to lymphopenia effectively increased the Treg/T effector ratios. This results in significant Treg accumulation within the graft, leading to long-term tolerance after the transfer of antigen-specific Tregs. Importantly, all the animals achieved operational tolerance, which boosted the presence of adoptively transferred Tregs within the graft. Conclusions: This protocol offers a means to establish tolerance by utilizing antigen-specific Tregs. These results have promising implications for future trials involving adoptive Treg therapy in organ transplantation. Full article
(This article belongs to the Special Issue Advances in Allogeneic Cell Therapy)
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17 pages, 4336 KiB  
Article
Adjunct Therapy with T Regulatory Cells Decreases Inflammation and Preserves the Anti-Tumor Activity of CAR T Cells
by Ke Zeng, Meixian Huang, Mi-Ae Lyu, Joseph D. Khoury, Sairah Ahmed, Krina K. Patel, Boro Dropulić, Jane Reese-Koc, Paolo F. Caimi, Tara Sadeghi, Marcos de Lima, Christopher R. Flowers and Simrit Parmar
Cells 2023, 12(14), 1880; https://doi.org/10.3390/cells12141880 - 18 Jul 2023
Cited by 3 | Viewed by 2746
Abstract
With greater accessibility and an increased number of patients being treated with CAR T cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood-derived (UCB) regulatory T cells (Tregs) can [...] Read more.
With greater accessibility and an increased number of patients being treated with CAR T cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood-derived (UCB) regulatory T cells (Tregs) can resolve inflammation and treat acute and immune-mediated lung injuries. Allogeneic, cryopreserved UCB Tregs have shown a clinical benefit in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Treg cells include a lack of plasticity under inflammatory micro-environments, no requirement for HLA matching, a long shelf life of cryopreserved cells, and immediate product availability, which makes them attractive for treating acute inflammatory syndromes. Therefore, we hypothesized that adjunct therapy with UCB Tregs may resolve the undesirable inflammation responsible for CAR T cell therapy-associated toxicity. In in vitro analysis, no interference from the addition of UCB Tregs was observed on CD19 CAR T cells’ ability to kill CD19 Raji cells at different CAR T: Raji cell ratios of 8:1 (80.4% vs. 81.5%); 4:1 (62.0% vs. 66.2%); 2:1 (50.1% vs. 54.7%); and 1:1 (35.4% vs. 44.1%). In the xenogeneic B-cell lymphoma model, multiple injections of UCB Tregs were administered 3 days after CD19 CAR T cell injection, and no detrimental effect of add-on Tregs was noted on the circulating CD8+ T effector cells. The distribution of CAR T cells in multiple organs remained unaffected by the addition of the UCB Tregs. Specifically, no difference in the overall tumor burden was detected between the UCB Treg + CAR T vs. CAR T alone recipients. No tumor was detected in the liver or bone marrow in CAR T cells + UCB Tregs recipients, with a notable corresponding decrease in multiple circulating inflammatory cytokines when compared to CART alone recipients. Here we show the proof of concept for adjunct therapy with UCB Tregs to mitigate the hyper-inflammatory state induced by CAR T cells without any interference in their on-target anti-tumor activity. Administration of UCB Tregs after CAR T cells allows sufficient time for their synapse formation with tumor cells and exerts cytotoxicity, such that the UCB Tregs are diverted to interact with the antigen-presenting cells at the site of inflammation. Such a differential distribution of cells would allow for a two-pronged strategy of a UCB Treg “cooling blanket” effect and lay the groundwork for clinical study. Full article
(This article belongs to the Special Issue Advances in Allogeneic Cell Therapy)
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12 pages, 1317 KiB  
Article
Impact of the Recipient’s Pre-Treatment Blood Lymphocyte Count on Intended and Unintended Effects of Anti-T-Lymphocyte Globulin in Allogeneic Hematopoietic Stem Cell Transplantation
by Alexander Nikoloudis, Veronika Buxhofer-Ausch, Christoph Aichinger, Michaela Binder, Petra Hasengruber, Emine Kaynak, Dagmar Wipplinger, Robert Milanov, Irene Strassl, Olga Stiefel, Sigrid Machherndl-Spandl, Andreas Petzer, Ansgar Weltermann and Johannes Clausen
Cells 2023, 12(14), 1831; https://doi.org/10.3390/cells12141831 - 12 Jul 2023
Viewed by 1251
Abstract
Background: In allogeneic hematopoietic stem cell transplantation (HSCT), Anti-T-Lymphocyte Globulin (ATLG) may be used for the prevention of severe graft-versus-host disease (GVHD). ATLG targets both the recipient’s lymphocytes and those transferred with the graft. Assuming an inverse relation between the recipient’s absolute lymphocyte [...] Read more.
Background: In allogeneic hematopoietic stem cell transplantation (HSCT), Anti-T-Lymphocyte Globulin (ATLG) may be used for the prevention of severe graft-versus-host disease (GVHD). ATLG targets both the recipient’s lymphocytes and those transferred with the graft. Assuming an inverse relation between the recipient’s absolute lymphocyte count (ALC) and exposure of remaining ATLG to the graft, we aim to evaluate the impact of the recipient’s ALC before the first ATLG administration on the benefits (prevention of GVHD and GVHD-associated mortality) and potential risks (increased relapse incidence) associated with ATLG. Methods: In recipients of HLA-matched, ATLG-based HSCT (n = 311), we assessed the incidence of acute GVHD, GVHD-related mortality and relapse, as well as other transplant-related outcomes, in relation to the respective ALC (divided into tertiles) before ATLG. Results: The top-tertile ALC group had a significantly increased risk of aGVHD (subhazard ratio (sHR) 1.81; [CI 95%; 1.14–2.88]; p = 0.01) and aGVHD-associated mortality (sHR 1.81; [CI 95%; 1.03–3.19]; p = 0.04). At the highest ATLG dose level (≥45 mg/kg), recipients with lowest-tertile ALC had a trend towards increased relapse incidence (sHR 4.19; [CI 95%; 0.99–17.7]; p = 0.05, n = 32). Conclusions: ATLG dosing based on the recipient’s ALC may be required for an optimal balance between GVHD suppression and relapse prevention. Full article
(This article belongs to the Special Issue Advances in Allogeneic Cell Therapy)
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14 pages, 1493 KiB  
Article
Early Visibility of Cellular Aggregates and Changes in Central Corneal Thickness as Predictors of Successful Corneal Endothelial Cell Injection Therapy
by Evan N. Wong, Valencia H. X. Foo, Gary S. L. Peh, Hla M. Htoon, Heng-Pei Ang, Belinda Y. L. Tan, Hon-Shing Ong and Jodhbir S. Mehta
Cells 2023, 12(8), 1167; https://doi.org/10.3390/cells12081167 - 15 Apr 2023
Viewed by 1930
Abstract
(1) Background: Cell injection therapy is an emerging treatment for bullous keratopathy (BK). Anterior segment optical coherence tomography (AS-OCT) imaging allows the high-resolution assessment of the anterior chamber. Our study aimed to investigate the predictive value of the visibility of cellular aggregates for [...] Read more.
(1) Background: Cell injection therapy is an emerging treatment for bullous keratopathy (BK). Anterior segment optical coherence tomography (AS-OCT) imaging allows the high-resolution assessment of the anterior chamber. Our study aimed to investigate the predictive value of the visibility of cellular aggregates for corneal deturgescence in an animal model of bullous keratopathy. (2) Methods: Cell injections of corneal endothelial cells were performed in 45 eyes in a rabbit model of BK. AS-OCT imaging and central corneal thickness (CCT) measurement were performed at baseline and on day 1, day 4, day 7 and day 14 following cell injection. A logistic regression was modelled to predict successful corneal deturgescence and its failure with cell aggregate visibility and CCT. Receiver-operating characteristic (ROC) curves were plotted, and areas under the curve (AUC) calculated for each time point in these models. (3) Results: Cellular aggregates were identified on days 1, 4, 7 and 14 in 86.7%, 39.5%, 20.0% and 4.4% of eyes, respectively. The positive predictive value of cellular aggregate visibility for successful corneal deturgescence was 71.8%, 64.7%, 66.7% and 100.0% at each time point, respectively. Using logistic regression modelling, the visibility of cellular aggregates on day 1 appeared to increase the likelihood of successful corneal deturgescence, but this did not reach statistical significance. An increase in pachymetry, however, resulted in a small but statistically significant decreased likelihood of success, with an odds ratio of 0.996 for days 1 (95% CI 0.993–1.000), 2 (95% CI 0.993–0.999) and 14 (95% CI 0.994–0.998) and an odds ratio of 0.994 (95% CI 0.991–0.998) for day 7. The ROC curves were plotted, and the AUC values were 0.72 (95% CI 0.55–0.89), 0.80 (95% CI 0. 62–0.98), 0.86 (95% CI 0.71–1.00) and 0.90 (95% CI 0.80–0.99) for days 1, 4, 7 and 14, respectively. (4) Conclusions: Logistic regression modelling of cell aggregate visibility and CCT was predictive of successful corneal endothelial cell injection therapy. Full article
(This article belongs to the Special Issue Advances in Allogeneic Cell Therapy)
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Review

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17 pages, 1639 KiB  
Review
Prospects and Potential for Chimerism Analysis after Allogeneic Hematopoietic Stem Cell Transplantation
by Saori Miura, Koki Ueda, Keiji Minakawa, Kenneth E. Nollet and Kazuhiko Ikeda
Cells 2024, 13(11), 993; https://doi.org/10.3390/cells13110993 - 6 Jun 2024
Viewed by 1782
Abstract
Chimerism analysis after allogeneic hematopoietic stem cell transplantation serves to confirm engraftment, indicate relapse of hematologic malignancy, and attribute graft failure to either immune rejection or poor graft function. Short tandem repeat PCR (STR-PCR) is the prevailing method, followed by quantitative real-time PCR [...] Read more.
Chimerism analysis after allogeneic hematopoietic stem cell transplantation serves to confirm engraftment, indicate relapse of hematologic malignancy, and attribute graft failure to either immune rejection or poor graft function. Short tandem repeat PCR (STR-PCR) is the prevailing method, followed by quantitative real-time PCR (qPCR), with detection limits of 1–5% and 0.1%, respectively. Chimerism assays using digital PCR or next-generation sequencing, both of which are more sensitive than STR-PCR, are increasingly used. Stable mixed chimerism is usually not associated with poor outcomes in non-malignant diseases, but recipient chimerism may foretell relapse of hematologic malignancies, so higher detection sensitivity may be beneficial in such cases. Thus, the need for and the type of intervention, e.g., immunosuppression regimen, donor lymphocyte infusion, and/or salvage second transplantation, should be guided by donor chimerism in the context of the feature and/or residual malignant cells of the disease to be treated. Full article
(This article belongs to the Special Issue Advances in Allogeneic Cell Therapy)
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25 pages, 994 KiB  
Review
Allogeneic CAR-T Therapy Technologies: Has the Promise Been Met?
by Caroline Lonez and Eytan Breman
Cells 2024, 13(2), 146; https://doi.org/10.3390/cells13020146 - 12 Jan 2024
Cited by 4 | Viewed by 7425
Abstract
This last decade, chimeric antigen receptor (CAR) T-cell therapy has become a real treatment option for patients with B-cell malignancies, while multiple efforts are being made to extend this therapy to other malignancies and broader patient populations. However, several limitations remain, including those [...] Read more.
This last decade, chimeric antigen receptor (CAR) T-cell therapy has become a real treatment option for patients with B-cell malignancies, while multiple efforts are being made to extend this therapy to other malignancies and broader patient populations. However, several limitations remain, including those associated with the time-consuming and highly personalized manufacturing of autologous CAR-Ts. Technologies to establish “off-the-shelf” allogeneic CAR-Ts with low alloreactivity are currently being developed, with a strong focus on gene-editing technologies. Although these technologies have many advantages, they have also strong limitations, including double-strand breaks in the DNA with multiple associated safety risks as well as the lack of modulation. As an alternative, non-gene-editing technologies provide an interesting approach to support the development of allogeneic CAR-Ts in the future, with possibilities of fine-tuning gene expression and easy development. Here, we will review the different ways allogeneic CAR-Ts can be manufactured and discuss which technologies are currently used. The biggest hurdles for successful therapy of allogeneic CAR-Ts will be summarized, and finally, an overview of the current clinical evidence for allogeneic CAR-Ts in comparison to its autologous counterpart will be given. Full article
(This article belongs to the Special Issue Advances in Allogeneic Cell Therapy)
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13 pages, 1154 KiB  
Review
Advancements in Cell-Based Therapies for HIV Cure
by Yusuke Matsui and Yasuo Miura
Cells 2024, 13(1), 64; https://doi.org/10.3390/cells13010064 - 28 Dec 2023
Cited by 2 | Viewed by 4435
Abstract
The treatment of human immunodeficiency virus (HIV-1) has evolved since the establishment of combination antiretroviral therapy (ART) in the 1990s, providing HIV-infected individuals with approaches that suppress viral replication, prevent acquired immunodeficiency syndrome (AIDS) throughout their lifetime with continuous therapy, and halt HIV [...] Read more.
The treatment of human immunodeficiency virus (HIV-1) has evolved since the establishment of combination antiretroviral therapy (ART) in the 1990s, providing HIV-infected individuals with approaches that suppress viral replication, prevent acquired immunodeficiency syndrome (AIDS) throughout their lifetime with continuous therapy, and halt HIV transmission. However, despite the success of these regimens, the global HIV epidemic persists, prompting a comprehensive exploration of potential strategies for an HIV cure. Here, we offer a consolidated overview of cell-based therapies for HIV-1, focusing on CAR-T cell approaches, gene editing, and immune modulation. Persistent challenges, including CAR-T cell susceptibility to HIV infection, stability, and viral reservoir control, underscore the need for continued research. This review synthesizes current knowledge, highlighting the potential of cellular therapies to address persistent challenges in the pursuit of an HIV cure. Full article
(This article belongs to the Special Issue Advances in Allogeneic Cell Therapy)
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