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Where Are We Now and Where Is Cell Therapy Headed?

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: 20 May 2025 | Viewed by 18534

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Special Issue Editors

Dr. Andrea Papait

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Guest Editor

Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Interests: immunomodulation; mesenchymal stromal cells; cancer biology; regenerative medicine; immunology; perinatal derivatives; secretoma; extracellular vesicles
Special Issues, Collections and Topics in MDPI journals

Dr. Paola Chiodelli

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Guest Editor

Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Interests: angiogenesis; cancer biology; spheroids; mesenchymal stromal cells; cancer associated fibroblasts; perinatal derivatives
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cell therapy has experienced both significant achievements and setbacks to date. Despite this, cell therapy continues to be a cutting-edge approach to the treatment of many illnesses for which there are no pharmaceutical alternatives at present. However, as with other areas of knowledge, the situation is continuously changing and follows the trend of technological advancements. What was once regarded as cell transplantation is now giving way to new horizons such as the use of the cell secretome, or constituents thereof, such as extracellular vesicles.

For this Special Issue, we invite renowned scientists to contribute their original research and review articles to advance the understanding of the applications of stem cells and mesenchymal stromal cells in health and disease, as well as how these could be exploited for therapeutic purposes.

Possible subjects include, but are not limited to:

Research on the therapeutic translation of mesenchymal stromal cells, stem cells, and their byproducts (e.g., secretome, extracellular vesicles);
Research on disease models that can explain how altered stem niches affect disease etiology;
Cell and gene therapy approaches for the treatment of diseases;
The use of CAR-T and CAR-NK cells for the treatment of leukemia and solid tumors;
The application of genetically modified MSC or of MSC to deliver drug cargoes for the treatment of cancer.

Dr. Andrea Papait
Dr. Paola Chiodelli
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. Pharmaceutics 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 2900 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

stem cells
mesenchymal stromal cells
cell therapy
CAR-T
CAR-NK
cancer
gene therapy
organoids and organ on a chip
extracellular vesicles
secretome

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Published Papers (8 papers)

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Research

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21 pages, 8290 KiB

Open AccessArticle

Synergistic Effect of Conditioned Medium from Amniotic Membrane Mesenchymal Stromal Cells Combined with Paclitaxel on Ovarian Cancer Cell Viability and Migration in 2D and 3D In Vitro Models

by Paola Chiodelli, Patrizia Bonassi Signoroni, Elisa Scalvini, Serafina Farigu, Elisabetta Giuzzi, Alice Paini, Andrea Papait, Francesca Romana Stefani, Antonietta Rosa Silini and Ornella Parolini

Pharmaceutics 2025, 17(4), 420; https://doi.org/10.3390/pharmaceutics17040420 - 26 Mar 2025

Viewed by 898

Abstract

Background: Ovarian cancer accounts for more deaths than any other cancer of the female reproductive system. Despite standard care, recurrence due to tumor spread and chemoresistance is common, highlighting the need for novel therapies. Mesenchymal stromal cells from the human amniotic membrane (hAMSC) and the intact amniotic membrane (hAM) are promising due to their secretion of tumor-modulating bioactive factors, accessibility from biological waste, and ethical favorability. Furthermore, unlike isolated cells, hAM provides an easier, clinically translatable product. We previously demonstrated that hAMSC can inhibit tumor cell proliferation, both in contact and transwell settings, suggesting that hAMSC secrete bioactive factors able to target tumor cells. This study evaluates the anti-tumor effects of bioactive factors from hAMSC and hAM conditioned medium (CM) on ovarian cancer cells in 2D and 3D models, alone or with paclitaxel. Methods: The impact of CM, alone or with paclitaxel, was tested on ovarian cancer cell proliferation, migration, invasion, and on angiogenesis. Results: hAMSC-CM and hAM-CM inhibited the proliferation and migration in 2D cultures and reduced spheroid growth and invasion in 3D models. Combining CM with paclitaxel enhanced anti-tumor effects in both settings. Conclusions: hAMSC-CM and hAM-CM show therapeutic potential against ovarian cancer, with synergistic benefits when combined with paclitaxel. Full article

(This article belongs to the Special Issue Where Are We Now and Where Is Cell Therapy Headed?)

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30 pages, 5226 KiB

Open AccessArticle

Banked Primary Progenitor Cells for Allogeneic Intervertebral Disc (IVD) Therapy: Preclinical Qualification and Functional Optimization within a Cell Spheroid Formulation Process

by Annick Jeannerat, Cédric Peneveyre, Sandra Jaccoud, Virginie Philippe, Corinne Scaletta, Nathalie Hirt-Burri, Philippe Abdel-Sayed, Robin Martin, Lee Ann Applegate, Dominique P. Pioletti and Alexis Laurent

Pharmaceutics 2024, 16(10), 1274; https://doi.org/10.3390/pharmaceutics16101274 - 29 Sep 2024

Viewed by 1476

Abstract

Background/Objectives: Biological products are emerging as therapeutic management options for intervertebral disc (IVD) degenerative affections and lower back pain. Autologous and allogeneic cell therapy protocols have been clinically implemented for IVD repair. Therein, several manufacturing process design considerations were shown to significantly influence clinical outcomes. The primary objective of this study was to preclinically qualify (chondrogenic potential, safety, resistance to hypoxic and inflammatory stimuli) cryopreserved primary progenitor cells (clinical grade FE002-Disc cells) as a potential cell source in IVD repair/regeneration. The secondary objective of this study was to assess the cell source’s delivery potential as cell spheroids (optimization of culture conditions, potential storage solutions). Methods/Results: Safety (soft agar transformation, β-galactosidase, telomerase activity) and functionality-related assays (hypoxic and inflammatory challenge) confirmed that the investigated cellular active substance was highly sustainable in defined cell banking workflows, despite possessing a finite in vitro lifespan. Functionality-related assays confirmed that the retained manufacturing process yielded strong collagen II and glycosaminoglycan (GAG) synthesis in the spheroids in 3-week chondrogenic induction. Then, the impacts of various process parameters (induction medium composition, hypoxic incubation, terminal spheroid lyophilization) were studied to gain insights on their criticality. Finally, an optimal set of technical specifications (use of 10 nM dexamethasone for chondrogenic induction, 2% O₂ incubation of spheroids) was set forth, based on specific fine tuning of finished product critical functional attributes. Conclusions: Generally, this study qualified the considered FE002-Disc progenitor cell source for further preclinical investigation based on safety, quality, and functionality datasets. The novelty and significance of this study resided in the establishment of defined processes for preparing fresh, off-the-freezer, or off-the-shelf IVD spheroids using a preclinically qualified allogeneic human cell source. Overall, this study underscored the importance of using robust product components and optimal manufacturing process variants for maximization of finished cell-based formulation quality attributes. Full article

(This article belongs to the Special Issue Where Are We Now and Where Is Cell Therapy Headed?)

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25 pages, 21282 KiB

Open AccessArticle

Cutaneous Cell Therapy Manufacturing Timeframe Rationalization: Allogeneic Off-the-Freezer Fibroblasts for Dermo-Epidermal Combined Preparations (DE-FE002-SK2) in Burn Care

by Xi Chen, Alexis Laurent, Zhifeng Liao, Sandra Jaccoud, Philippe Abdel-Sayed, Marjorie Flahaut, Corinne Scaletta, Wassim Raffoul, Lee Ann Applegate and Nathalie Hirt-Burri

Pharmaceutics 2023, 15(9), 2334; https://doi.org/10.3390/pharmaceutics15092334 - 16 Sep 2023

Cited by 4 | Viewed by 1767

Abstract

Autologous cell therapy manufacturing timeframes constitute bottlenecks in clinical management pathways of severe burn patients. While effective temporary wound coverings exist for high-TBSA burns, any means to shorten the time-to-treatment with cytotherapeutic skin grafts could provide substantial therapeutic benefits. This study aimed to establish proofs-of-concept for a novel combinational cytotherapeutic construct (autologous/allogeneic DE-FE002-SK2 full dermo-epidermal graft) designed for significant cutaneous cell therapy manufacturing timeframe rationalization. Process development was based on several decades (four for autologous protocols, three for allogeneic protocols) of in-house clinical experience in cutaneous cytotherapies. Clinical grade dermal progenitor fibroblasts (standardized FE002-SK2 cell source) were used as off-the-freezer substrates in novel autologous/allogeneic dermo-epidermal bilayer sheets. Under vitamin C stimulation, FE002-SK2 primary progenitor fibroblasts rapidly produced robust allogeneic dermal templates, allowing patient keratinocyte attachment in co-culture. Notably, FE002-SK2 primary progenitor fibroblasts significantly outperformed patient fibroblasts for collagen deposition. An ex vivo de-epidermalized dermis model was used to demonstrate the efficient DE-FE002-SK2 construct bio-adhesion properties. Importantly, the presented DE-FE002-SK2 manufacturing process decreased clinical lot production timeframes from 6–8 weeks (standard autologous combined cytotherapies) to 2–3 weeks. Overall, these findings bear the potential to significantly optimize burn patient clinical pathways (for rapid wound closure and enhanced tissue healing quality) by combining extensively clinically proven cutaneous cell-based technologies. Full article

(This article belongs to the Special Issue Where Are We Now and Where Is Cell Therapy Headed?)

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33 pages, 20827 KiB

Open AccessArticle

Autologous and Allogeneic Cytotherapies for Large Knee (Osteo)Chondral Defects: Manufacturing Process Benchmarking and Parallel Functional Qualification

by Virginie Philippe, Annick Jeannerat, Cédric Peneveyre, Sandra Jaccoud, Corinne Scaletta, Nathalie Hirt-Burri, Philippe Abdel-Sayed, Wassim Raffoul, Salim Darwiche, Lee Ann Applegate, Robin Martin and Alexis Laurent

Pharmaceutics 2023, 15(9), 2333; https://doi.org/10.3390/pharmaceutics15092333 - 16 Sep 2023

Cited by 4 | Viewed by 2013

Abstract

Cytotherapies are often necessary for the management of symptomatic large knee (osteo)-chondral defects. While autologous chondrocyte implantation (ACI) has been clinically used for 30 years, allogeneic cells (clinical-grade FE002 primary chondroprogenitors) have been investigated in translational settings (Swiss progenitor cell transplantation program). The aim of this study was to comparatively assess autologous and allogeneic approaches (quality, safety, functional attributes) to cell-based knee chondrotherapies developed for clinical use. Protocol benchmarking from a manufacturing process and control viewpoint enabled us to highlight the respective advantages and risks. Safety data (telomerase and soft agarose colony formation assays, high passage cell senescence) and risk analyses were reported for the allogeneic FE002 cellular active substance in preparation for an autologous to allogeneic clinical protocol transposition. Validation results on autologous bioengineered grafts (autologous chondrocyte-bearing Chondro-Gide scaffolds) confirmed significant chondrogenic induction (COL2 and ACAN upregulation, extracellular matrix synthesis) after 2 weeks of co-culture. Allogeneic grafts (bearing FE002 primary chondroprogenitors) displayed comparable endpoint quality and functionality attributes. Parameters of translational relevance (transport medium, finished product suturability) were validated for the allogeneic protocol. Notably, the process-based benchmarking of both approaches highlighted the key advantages of allogeneic FE002 cell-bearing grafts (reduced cellular variability, enhanced process standardization, rationalized logistical and clinical pathways). Overall, this study built on our robust knowledge and local experience with ACI (long-term safety and efficacy), setting an appropriate standard for further clinical investigations into allogeneic progenitor cell-based orthopedic protocols. Full article

(This article belongs to the Special Issue Where Are We Now and Where Is Cell Therapy Headed?)

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39 pages, 11341 KiB

Open AccessArticle

Bio-Enhanced Neoligaments Graft Bearing FE002 Primary Progenitor Tenocytes: Allogeneic Tissue Engineering & Surgical Proofs-of-Concept for Hand Ligament Regenerative Medicine

by Annick Jeannerat, Joachim Meuli, Cédric Peneveyre, Sandra Jaccoud, Michèle Chemali, Axelle Thomas, Zhifeng Liao, Philippe Abdel-Sayed, Corinne Scaletta, Nathalie Hirt-Burri, Lee Ann Applegate, Wassim Raffoul and Alexis Laurent

Pharmaceutics 2023, 15(7), 1873; https://doi.org/10.3390/pharmaceutics15071873 - 3 Jul 2023

Cited by 2 | Viewed by 1976

Abstract

Hand tendon/ligament structural ruptures (tears, lacerations) often require surgical reconstruction and grafting, for the restauration of finger mechanical functions. Clinical-grade human primary progenitor tenocytes (FE002 cryopreserved progenitor cell source) have been previously proposed for diversified therapeutic uses within allogeneic tissue engineering and regenerative medicine applications. The aim of this study was to establish bioengineering and surgical proofs-of-concept for an artificial graft (Neoligaments Infinity-Lock 3 device) bearing cultured and viable FE002 primary progenitor tenocytes. Technical optimization and in vitro validation work showed that the combined preparations could be rapidly obtained (dynamic cell seeding of 10⁵ cells/cm of scaffold, 7 days of co-culture). The studied standardized transplants presented homogeneous cellular colonization in vitro (cellular alignment/coating along the scaffold fibers) and other critical functional attributes (tendon extracellular matrix component such as collagen I and aggrecan synthesis/deposition along the scaffold fibers). Notably, major safety- and functionality-related parameters/attributes of the FE002 cells/finished combination products were compiled and set forth (telomerase activity, adhesion and biological coating potentials). A two-part human cadaveric study enabled to establish clinical protocols for hand ligament cell-assisted surgery (ligamento-suspension plasty after trapeziectomy, thumb metacarpo-phalangeal ulnar collateral ligamentoplasty). Importantly, the aggregated experimental results clearly confirmed that functional and clinically usable allogeneic cell-scaffold combination products could be rapidly and robustly prepared for bio-enhanced hand ligament reconstruction. Major advantages of the considered bioengineered graft were discussed in light of existing clinical protocols based on autologous tenocyte transplantation. Overall, this study established proofs-of-concept for the translational development of a functional tissue engineering protocol in allogeneic musculoskeletal regenerative medicine, in view of a pilot clinical trial. Full article

(This article belongs to the Special Issue Where Are We Now and Where Is Cell Therapy Headed?)

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Review

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30 pages, 2236 KiB

Open AccessReview

Cell Therapy for Retinal Degenerative Diseases: Progress and Prospects

by Kevin Y. Wu, Jaskarn K. Dhaliwal, Akash Sasitharan and Ananda Kalevar

Pharmaceutics 2024, 16(10), 1299; https://doi.org/10.3390/pharmaceutics16101299 - 5 Oct 2024

Cited by 3 | Viewed by 3035

Abstract

Background/Objectives: Age-related macular degeneration (AMD) and retinitis pigmentosa (RP) are leading causes of vision loss, with AMD affecting older populations and RP being a rarer, genetically inherited condition. Both diseases result in progressive retinal degeneration, for which current treatments remain inadequate in advanced stages. This review aims to provide an overview of the retina’s anatomy and physiology, elucidate the pathophysiology of AMD and RP, and evaluate emerging cell-based therapies for these conditions. Methods: A comprehensive review of the literature was conducted, focusing on cell therapy approaches, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and retinal progenitor cells. Preclinical and clinical studies were analyzed to assess therapeutic potential, with attention to mechanisms such as cell replacement, neuroprotection, and paracrine effects. Relevant challenges, including ethical concerns and clinical translation, were also explored. Results: Cell-based therapies demonstrate potential for restoring retinal function and slowing disease progression through mechanisms like neuroprotection and cell replacement. Preclinical trials show promising outcomes, but clinical studies face significant hurdles, including challenges in cell delivery and long-term efficacy. Combination therapies integrating gene editing and biomaterials offer potential future advancements. Conclusions: While cell-based therapies for AMD and RP have made significant progress, substantial barriers to clinical application remain. Further research is essential to overcome these obstacles, improve delivery methods, and ensure the safe and effective translation of these therapies into clinical practice. Full article

(This article belongs to the Special Issue Where Are We Now and Where Is Cell Therapy Headed?)

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28 pages, 1133 KiB

Open AccessReview

Immunotherapies Targeting Tumor-Associated Macrophages (TAMs) in Cancer

by Mei-Ye Li, Wei Ye and Ke-Wang Luo

Pharmaceutics 2024, 16(7), 865; https://doi.org/10.3390/pharmaceutics16070865 - 27 Jun 2024

Cited by 4 | Viewed by 3641

Abstract

Tumor-associated macrophages (TAMs) are one of the most plentiful immune compositions in the tumor microenvironment, which are further divided into anti-tumor M1 subtype and pro-tumor M2 subtype. Recent findings found that TAMs play a vital function in the regulation and progression of tumorigenesis. Moreover, TAMs promote tumor vascularization, and support the survival of tumor cells, causing an impact on tumor growth and patient prognosis. Numerous studies show that reducing the density of TAMs, or modulating the polarization of TAMs, can inhibit tumor growth, indicating that TAMs are a promising target for tumor immunotherapy. Recently, clinical trials have found that treatments targeting TAMs have achieved encouraging results, and the U.S. Food and Drug Administration has approved a number of drugs for use in cancer treatment. In this review, we summarize the origin, polarization, and function of TAMs, and emphasize the therapeutic strategies targeting TAMs in cancer treatment in clinical studies and scientific research, which demonstrate a broad prospect of TAMs-targeted therapies in tumor immunotherapy. Full article

(This article belongs to the Special Issue Where Are We Now and Where Is Cell Therapy Headed?)

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22 pages, 1578 KiB

Open AccessReview

Therapies Targeting Immune Cells in Tumor Microenvironment for Non-Small Cell Lung Cancer

by Wei Ye, Meiye Li and Kewang Luo

Pharmaceutics 2023, 15(7), 1788; https://doi.org/10.3390/pharmaceutics15071788 - 21 Jun 2023

Cited by 6 | Viewed by 2458

Abstract

The tumor microenvironment (TME) plays critical roles in immune modulation and tumor malignancies in the process of cancer development. Immune cells constitute a significant component of the TME and influence the migration and metastasis of tumor cells. Recently, a number of therapeutic approaches targeting immune cells have proven promising and have already been used to treat different types of cancer. In particular, PD-1 and PD-L1 inhibitors have been used in the first-line setting in non-small cell lung cancer (NSCLC) with PD-L1 expression ≥1%, as approved by the FDA. In this review, we provide an introduction to the immune cells in the TME and their efficacies, and then we discuss current immunotherapies in NSCLC and scientific research progress in this field. Full article

(This article belongs to the Special Issue Where Are We Now and Where Is Cell Therapy Headed?)

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