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Mesenchymal Stem/Stromal Cells as a Vehicle for Cytokine Delivery: An Emerging Approach for Tumor Immunotherapy.

ABSTRACT: Pro-inflammatory cytokines can effectively be used for tumor immunotherapy, affecting every step of the tumor immunity cycle. Thereby, they can restore antigen priming, improve the effector immune cell frequencies in the tumor microenvironment (TME), and eventually strengthen their cytolytic function. A renewed interest in the anticancer competencies of cytokines has resulted in a substantial promotion in the number of trials to address the safety and efficacy of cytokine-based therapeutic options. However, low response rate along with the high toxicity associated with high-dose cytokine for reaching desired therapeutic outcomes negatively affect their clinical utility. Recently, mesenchymal stem/stromal cells (MSCs) due to their pronounced tropism to tumors and also lower immunogenicity have become a promising vehicle for cytokine delivery for human malignancies. MSC-based delivery of the cytokine can lead to the more effective immune cell-induced antitumor response and provide sustained release of target cytokines, as widely evidenced in a myriad of xenograft models. In the current review, we offer a summary of the novel trends in cytokine immunotherapy using MSCs as a potent and encouraging carrier for antitumor cytokines, focusing on the last two decades' animal reports.

SUBMITTER: Razeghian E

PROVIDER: S-EPMC8430327 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Mesenchymal Stem/Stromal Cells as a Vehicle for Cytokine Delivery: An Emerging Approach for Tumor Immunotherapy.

Razeghian Ehsan E Margiana Ria R Margiana Ria R Chupradit Supat S Bokov Dmitry O DO Abdelbasset Walid Kamal WK Marofi Faroogh F Shariatzadeh Siavash S Tosan Foad F Jarahian Mostafa M

Frontiers in medicine 20210827

Pro-inflammatory cytokines can effectively be used for tumor immunotherapy, affecting every step of the tumor immunity cycle. Thereby, they can restore antigen priming, improve the effector immune cell frequencies in the tumor microenvironment (TME), and eventually strengthen their cytolytic function. A renewed interest in the anticancer competencies of cytokines has resulted in a substantial promotion in the number of trials to address the safety and efficacy of cytokine-based therapeutic optio ...[more]

PMID: 34513882

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Project description:Study designMeta-analysis.ObjectivesWe aim to analyze and compare the efficacy and safety of vehicle-based delivery of Mesenchymal Stromal Cells (MSCs) in the management of osteoarthritis of the knee from Randomized Controlled Trials (RCTs) available in the literature.Materials and methodsWe conducted independent and duplicate electronic database searches including PubMed, Embase, Web of Science, and Cochrane Library till August 2021 for RCTs analyzing the efficacy and safety of vehicle-based delivery of MSCs in the management of knee osteoarthritis. Visual Analog Score (VAS) for Pain, Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score, and adverse events were the outcomes analyzed. Analysis was performed in R-platform using OpenMeta [Analyst] software.Results21 studies involving 936 patients were included for analysis. None of the studies made a direct comparison of the direct and vehicle-based delivery of MSCs, hence we pooled the results of all the included studies of both groups and made a comparative analysis of their outcomes. Although at 6 months, both direct and vehicle-based delivery of MSCs showed significantly better VAS improvement (p = 0.002, p = 0.010), it was not consistent at 1 year for the vehicle delivery (p = 0.973). During 6 months and 12 months, direct delivery of MSCs (p < 0.001, p < 0.001) outperformed vehicle delivery (p = 0.969, p = 0.922) compared to their control based on WOMAC scores respectively. Both direct (p = 0.713) and vehicle-based delivery (p = 0.123) of MSCs did not produce significant adverse events compared to their controls.ConclusionOur analysis of literature showed that current clinically employed methods of vehicle-based delivery of MSCs such as platelet-rich plasma, hyaluronic acid did not demonstrate superior results compared to direct delivery, concerning the efficacy of treatment measured by improvement in pain, functional outcomes, and safety. Hence, we urge future clinical trials to be conducted to validate the effectiveness of advanced delivery vehicles such as composite bioscaffolds to establish their practical utility in cartilage regeneration with respect to its encouraging in-vitro evidence.

Project description:Three-dimensional (3D) multicellular aggregates, in comparison to two-dimensional monolayer culture, can provide tissue culture models that better recapitulate the abundant cell-cell and cell-matrix interactions found in vivo. In addition, aggregates are potentially useful building blocks for tissue engineering. However, control over the interior aggregate microenvironment is challenging due to inherent barriers for diffusion of biological mediators (e.g. growth factors) throughout the multicellular aggregates. Previous studies have shown that incorporation of biomaterials into multicellular aggregates can support cell survival and control differentiation of stem cell aggregates by delivering morphogens from within the 3D construct. In this study, we developed a highly efficient microparticle-based gene delivery approach to uniformly transfect human mesenchymal stromal cells (hMSC) within multicellular aggregates and cell sheets. We hypothesized that release of plasmid DNA (pDNA) lipoplexes from mineral-coated microparticles (MCMs) within 3D hMSC constructs would improve transfection in comparison to standard free pDNA lipoplex delivery in the media. Our approach increased transfection efficiency 5-fold over delivery of free pDNA lipoplexes in the media and resulted in homogenous distribution of transfected cells throughout the 3D constructs. Additionally, we found that MCMs improved hMSC transfection by specifically increasing macropinocytosis-mediated uptake of pDNA. Finally, we showed up to a three-fold increase of bone morphogenetic protein-2 (BMP-2) expression and enhanced calcium deposition within 3D hMSC constructs following MCM-mediated delivery of a BMP-2 encoding plasmid and culture in osteogenic medium. The technology described here provides a valuable tool for achieving efficient and homogenous transfection of 3D cell constructs and is therefore of particular value in tissue engineering and regenerative medicine applications. STATEMENT OF SIGNIFICANCE: This original research describes a materials-based approach, whereby use of mineral-coated microparticles improves the efficiency of non-viral gene delivery in three-dimensional human mesenchymal stromal cell constructs. Specifically, it demonstrates the use of mineral-coated microparticles to enable highly efficient transfection of human mesenchymal stromal cells in large, 3D culture formats. The manuscript also identifies specific endocytosis pathways that interact with the mineral coating to afford the improved transfection efficiency, as well as demonstrates the utility of this approach toward improving differentiation of large cell constructs. We feel that this manuscript will impact the current understanding and near-term development of materials for non-viral gene delivery in broad tissue engineering and biofabrication applications, and therefore be of interest to a diverse biomaterials audience.

Dataset Information

Mesenchymal Stem/Stromal Cells as a Vehicle for Cytokine Delivery: An Emerging Approach for Tumor Immunotherapy.

Publications

Mesenchymal Stem/Stromal Cells as a Vehicle for Cytokine Delivery: An Emerging Approach for Tumor Immunotherapy.

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