Immune Cell Hacking: Challenges and Clinical Approaches to Create Smarter Generations of Chimeric Antigen Receptor T Cells

T cells equipped with chimeric antigen receptors (CAR T cells) have recently provided promising advances as a novel immunotherapeutic approach for cancer treatment. CAR T cell therapy has shown stunning results especially in B-cell malignancies; however, it has shown less success against solid tumors, which is more supposed to be related to the specific characteristics of the tumor microenvironment. In this review, we discuss the structure of the CAR, current clinical advantages from finished and ongoing trials, adverse effects, challenges and controversies, new engineering methods of CAR, and clinical considerations that are associated with CAR T cell therapy both in hematological malignancies and solid tumors. Also, we provide a comprehensive description of recently introduced modifications for designing smarter models of CAR T cells. Specific hurdles and problems that limit the optimal function of CAR T cells, especially on solid tumors, and possible solutions according to new modifications and generations of CAR T cells have been introduced here. We also provide information of the future directions on how to enhance engineering the next smarter generations of CAR T cells in order to decrease the adverse effects and increase the potency and efficacy of CAR T cells against cancer

Introducing the immunomodulatory effects of mesenchymal stem cells in an experimental model of Behçet’s disease

AbstractBehçet’s disease (BD) is a systemic vasculitis which is characterised by oral, aphthous ulcers, genital ulcers, skin lesions and ocular manifestations. Although the aetiopathogenesis of BD is still unknown, the critical role of Th1 immune responses, neutrophil hyperactivation alongside overproduction of pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, IL-8, tumour necrosis factor-alpha (TNFα) and particularly IL-17 have been demonstrated in the immunopathogenesis of the disease. Despite significant progress in understanding of the aetiology of the disease, its treatment remains intricate, and is still treated with immune-suppressive drugs and biological agents with probable systemic side effects. Accordingly, there is a necessity to establish the more efficient and less toxic therapeutic methods which may offer a long-time remission of BD.Mesenchymal stem cells (MSCs) are non-haematopoietic and multipotential stem cells with immunosuppressive capacities in innate and acquired immune systems. MSCs can migrate to damaged tissues and prevent secretion of proinflammatory cytokines and other immunomodulatory effectors, increasing the survival of damaged cells, although the exact underlying mechanisms are still unknown. For this purpose, numerous herpes simplex viruses are injected into C57BL/6 mice to produce Behçet’s mouse model and transferring a certain number of MSCs may have therapeutic value for control of Behçet’s animal model, so researchers could deliberate the function of MSCs and proinflammatory cytokines particularly IL-17A-F, TNF-α, interferon gamma (IFN-γ), IL-2, IL-6 and IL-8 in an experimental model.The aim of this hypothesis is to evaluate immunosuppressive and immunomodulatory properties of MSCs in syngeneic animal model for BD, in order to clarify the mechanisms of MSCs in BD management, as a broad and more confident treatment in clinical application

Repair of rat cranial bone defect by using amniotic fluid-derived mesenchymal stem cells in polycaprolactone fibrous scaffolds and platelet-rich plasma

Introduction: Tissue regenerative medicine strategies, as a promising alternative has become of major interest to the reconstruction of critical size bone defects. This study evaluated the effects of the simultaneous application of polycaprolactone (PCL), amniotic fluid mesenchymal stem cells (AF-MSCs) and platelet-rich plasma (PRP) on the repair of rat cranial bone defects. Methods: The AF-MSCs were isolated at the end of the second week of pregnancy in rats. PRP obtained from rat blood and the random PCL fibrous scaffolds were prepared using the electrospinning method. Circular full thickness (5 mm) bone defects were developed on both sides of the parietal bones (animal number=24) and the scaffolds containing AF-MSCs and PRP were implanted in the right lesions. Thereafter, after eight weeks the histological and immunohistochemistry studies were performed to evaluate the bone formation and collagen type I expression. Results: The spindle-shaped mesenchymal stem cells were isolated and the electron microscope images indicated the preparation of a random PCL scaffold. Immunohistochemical findings showed that collagen type I was expressed by AF-MSCs cultured on the scaffold. The results of hematoxylin and eosin (H & E) staining indicated the formation of blood vessels in the presence of PRP. Additionally, immunofluorescence findings suggested that PRP had a positive effect on collagen type I expression. Conclusion: The simultaneous application of fibrous scaffold + AF-MSCs + PRP has positive effects on bone regeneration. This study showed that PRP can affect the formation of new blood vessels in the scaffold transplanted in the bone defect

Mesenchymal Stromal/Stem Cells: A New Era in the Cell-Based Targeted Gene Therapy of Cancer

In recent years, in light of the promising potentials of mesenchymal stromal/stem cells (MSCs) for carrying therapeutic anticancer genes, a complete revisitation on old chemotherapy-based paradigms has been established. This review attempted to bring forward and introduce the novel therapeutic opportunities of using genetically engineered MSCs. The simplicities and advantages of MSCs for medical applications make them a unique and promising option in the case of cancer therapy. Some of the superiorities of using MSCs as therapeutic gene micro-carriers are the easy cell-extraction procedures and their abundant proliferation capacity in vitro without losing their main biological properties. Targeted therapy by using MSCs as the delivery vehicles of therapeutic genes is a new approach in the treatment of various types of cancers. Some of the distinct properties of MSCs, such as tumor-tropism, non-immunogenicity, stimulatory effect on the anti-inflammatory molecules, inhibitory effect on inflammatory responses, non-toxicity against the normal tissues, and easy processes for the clinical use, have formed the basis of attention to MSCs. They can be easily used for the treatment of damaged or injured tissues, regenerative medicine, and immune disorders. This review focused on the drugability of MSCs and their potential for the delivery of candidate anticancer genes. It also briefly reviewed the vectors and methods used for MSC-mediated gene therapy of malignancies. Also, the challenges, limitations, and considerations in using MSCs for gene therapy of cancer and the new methods developed for resolution of these problems are reviewed

Overexpression of MDA-7/IL-24 as an anticancer cytokine in gene therapy of thyroid carcinoma

AbstractThe annual incidence of thyroid cancer worldwide is alarming. Despite current various treatments such as surgical resection, radioiodine therapy and chemotherapy/radiotherapy, thyroid carcinoma remains a lethal cancer. Assuredly, the operative and new treatment strategies are necessary to control this malignancy. Gene therapy is regarded as one of the most reliable novel therapeutic methods for hopeless cases of thyroid cancer and those who do not respond to the prevalent treatments. Accumulated evidence suggests that interleukin-24 (IL-24), also known as melanoma differentiation-associated gene-7, has very important roles in regulation of cell differentiation, cell growth and apoptosis, and it is also a promising anticancer agent. Here, we propose that it could be advantageous to evaluate the anti-tumoural effect of IL-24 in a mouse xenograft model of thyroid cancer

Differentiation of conjunctiva mesenchymal stem cells into secreting islet beta cells on plasma treated electrospun nanofibrous scaffold

<p>Transplantation of stem cells using biocompatible nanofibrous scaffolds is a promising therapeutic method for treating Diabetic Mellitus. The aim of this study was to derive insulin-producing cells (IPCs) from conjunctiva-derived mesenchymal stem cell (CJMSCs) and to compare the functionality of differentiated IPCs in a three-dimensional (3D) culture with 2D. Furthermore, the effects of hydrophobicity of scaffold on IPCs differentiation were examined. Scanning electron microscopy (SEM), quantitative real times PCR (qPCR), Immunostaining and flow cytometry were used to analyze fabricated scaffold and the presence of IPCs. Functional maturity of differentiated cells was determined by measuring insulin release and the creation of IPCs was confirmed via gene and protein expression. In this study, the induced CJMSCs were morphologically similar to pancreatic islet-like cells. The expression of the islet-associated genes (glucagon, insulin and Pdx-1) and the insulin release (2.5-fold) in 3D-cultured cells was significantly higher than the 2D. The expression of IPCs genes was significantly higher in CJMSCs differentiated on plasma-treated nanofibers compared to those on untreated scaffolds. In conclusion, the results show that CJMSCs might be a new source for Diabetic Mellitus therapy and the nanofibrous scaffold could be used as a potential cell carrier for islet tissue engineering.</p