Репозиторий Университета

© 2021, The Author(s). Background: CARs are simulated receptors containing an extracellular single-chain variable fragment (scFv), a transmembrane domain, as well as an intracellular region of immunoreceptor tyrosine-based activation motifs (ITAMs) in association with a co-stimulatory signal. Main body: Chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. The CAR T cells obtain supra-physiological properties and conduct as “living drugs” presenting both immediate and steady effects after expression in T cells surface. But, their efficacy in solid tumor treatment has not yet been supported. The pivotal challenges in the field of solid tumor CAR T cell therapy can be summarized in three major parts: recognition, trafficking, and surviving in the tumor. On the other hand, the immunosuppressive tumor microenvironment (TME) interferes with T cell activity in terms of differentiation and exhaustion, and as a result of the combined use of CARs and checkpoint blockade, as well as the suppression of other inhibitor factors in the microenvironment, very promising results were obtained from the reduction of T cell exhaustion. Conclusion: Nowadays, identifying and defeating the mechanisms associated with CAR T cell dysfunction is crucial to establish CAR T cells that can proliferate and lyse tumor cells severely. In this review, we discuss the CAR signaling and efficacy T in solid tumors and evaluate the most significant barriers in this process and describe the most novel therapeutic methods aiming to the acquirement of the promising therapeutic outcome in non-hematologic malignancies.

© 2021, The Author(s). Background: CARs are simulated receptors containing an extracellular single-chain variable fragment (scFv), a transmembrane domain, as well as an intracellular region of immunoreceptor tyrosine-based activation motifs (ITAMs) in association with a co-stimulatory signal. Main body: Chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. The CAR T cells obtain supra-physiological properties and conduct as “living drugs” presenting both immediate and steady effects after expression in T cells surface. But, their efficacy in solid tumor treatment has not yet been supported. The pivotal challenges in the field of solid tumor CAR T cell therapy can be summarized in three major parts: recognition, trafficking, and surviving in the tumor. On the other hand, the immunosuppressive tumor microenvironment (TME) interferes with T cell activity in terms of differentiation and exhaustion, and as a result of the combined use of CARs and checkpoint blockade, as well as the suppression of other inhibitor factors in the microenvironment, very promising results were obtained from the reduction of T cell exhaustion. Conclusion: Nowadays, identifying and defeating the mechanisms associated with CAR T cell dysfunction is crucial to establish CAR T cells that can proliferate and lyse tumor cells severely. In this review, we discuss the CAR signaling and efficacy T in solid tumors and evaluate the most significant barriers in this process and describe the most novel therapeutic methods aiming to the acquirement of the promising therapeutic outcome in non-hematologic malignancies.

Despite many recent advances on cancer novel therapies, researchers have yet a long way to cure cancer. They have to deal with tough challenges before they can reach success. Nonetheless, it seems that recently developed immunotherapy-based therapy approaches such as adoptive cell transfer (ACT) have emerged as a promising therapeutic strategy against various kinds of tumors even the cancers in the blood (liquid cancers). The hematological (liquid) cancers are hard to be targeted by usual cancer therapies, for they do not form localized solid tumors. Until recently, two types of ACTs have been developed and introduced; tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR)-T cells which the latter is the subject of our discussion. It is interesting about engineered CAR-T cells that they are genetically endowed with unique cancer-specific characteristics, so they can use the potency of the host immune system to fight against either solid or liquid cancers. Multiple myeloma (MM) or simply referred to as myeloma is a type of hematological malignancy that affects the plasma cells. The cancerous plasma cells produce immunoglobulins (antibodies) uncontrollably which consequently damage the tissues and organs and break the immune system function. Although the last few years have seen significant progressions in the treatment of MM, still a complete remission remains unconvincing. MM is a medically challenging and stubborn disease with a disappointingly low rate of survival rate. When comparing the three most occurring blood cancers (i.e., lymphoma, leukemia, and myeloma), myeloma has the lowest 5-year survival rate (around 40%). A low survival rate indicates a high mortality rate with difficulty in treatment. Therefore, novel CAR-T cell-based therapies or combination therapies along with CAT-T cells may bring new hope for multiple myeloma patients. CAR-T cell therapy has a high potential to improve the remission success rate in patients with MM. To date, many preclinical and clinical trial studies have been conducted to investigate the ability and capacity of CAR T cells in targeting the antigens on myeloma cells. Despite the problems and obstacles, CAR-T cell experiments in MM patients revealed a robust therapeutic potential. However, several factors might be considered during CAR-T cell therapy for better response and reduced side effects. Also, incorporating the CAT-T cell method into a combinational treatment schedule may be a promising approach. In this paper, with a greater emphasis on CAR-T cell application in the treatment of MM, we will discuss and introduce CAR-T cell’s history and functions, their limitations, and the solutions to defeat the limitations and different types of modifications on CAR-T cells.

Acute myeloid leukemia (AML) is a serious, life-threatening, and hardly curable hematological malignancy that affects the myeloid cell progenies and challenges patients of all ages but mostly occurs in adults. Although several therapies are available including chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and receptor-antagonist drugs, the 5-year survival of patients is quietly disappointing, less than 30%. alloHSCT is the major curative approach for AML with promising results but the treatment has severe adverse effects such as graft-versus-host disease (GVHD). Therefore, as an alternative, more efficient and less harmful immunotherapy-based approaches such as the adoptive transferring T cell therapy are in development for the treatment of AML. As such, chimeric antigen receptor (CAR) T cells are engineered T cells which have been developed in recent years as a breakthrough in cancer therapy. Interestingly, CAR T cells are effective against both solid tumors and hematological cancers such as AML. Gradually, CAR T cell therapy found its way into cancer therapy and was widely used for the treatment of hematologic malignancies with successful results particularly with somewhat better results in hematological cancer in comparison to solid tumors. The AML is generally fatal, therapy-resistant, and sometimes refractory disease with a disappointing low survival rate and weak prognosis. The 5-year survival rate for AML is only about 30%. However, the survival rate seems to be age-dependent. Novel CAR T cell therapy is a light at the end of the tunnel. The CD19 is an important target antigen in AML and lymphoma and the CAR T cells are engineered to target the CD19. In addition, a lot of research goes on the discovery of novel target antigens with therapeutic efficacy and utilizable for generating CAR T cells against various types of cancers. In recent years, many pieces of research on screening and identification of novel AML antigen targets with the goal of generation of effective anti-cancer CAR T cells have led to new therapies with strong cytotoxicity against cancerous cells and impressive clinical outcomes. Also, more recently, an improved version of CAR T cells which were called modified or smartly reprogrammed CAR T cells has been designed with less unwelcome effects, less toxicity against normal cells, more safety, more specificity, longer persistence, and proliferation capability. The purpose of this review is to discuss and explain the most recent advances in CAR T cell-based therapies targeting AML antigens and review the results of preclinical and clinical trials. Moreover, we will criticize the clinical challenges, side effects, and the different strategies for CAR T cell therapy.

© Mary Ann Liebert, Inc., publishers 2019. The pathological processes developing after spinal cord injuries often lead to formation of cysts. Existing surgical and medical methods are insufficient for treatment of post-traumatic spinal cord cysts. One of the emerging tools is cell therapy. Olfactory ensheathing cells (OECs) are perspective cells for cell therapy. In this study, we demonstrated that human OEC transplantation is effective in experimental spinal cysts. For our experiments, we selected animals only at the intermediate stage of recovery with scores from 8 to 13 according to the Basso, Beattie, and Bresnahan (BBB) scale. Cells were transplanted in different quantities (0.75 and 1.5 million) into the fully formed cysts and in the areas of injury without cysts. Improvement of limb mobility after human OEC transplantation into post-traumatic cysts was shown. In the group of rats with cysts, time-dependent increase in the BBB score was observed in subgroups treated with 0.75 and 1.5 million OECs with no statistically significant time-dependent dynamics of BBB values in the control group. When all three subgroups (control and two OEC doses) were compared, the Kruskal-Wallis test showed the presence of differences between subgroups after 1, 3, and 4 weeks of treatment with evidence of divergence increase. There was no statistically significant difference between the two doses of OEC treatment. The human OECs in the experiments without cysts were not effective. It was also shown that PKH26-labeled human OECs survive throughout the experiment and migrate to nearby areas of the cyst. Therefore, it was found that it is effective to transplant human OECs into fully formed cysts. In the future, autologous OECs can be used to personalize the treatment of patients with spinal cysts.

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Olfactory ensheathing cells showed significant effects on the regeneration of the spinal cord in experimental models and in clinical trials. However, the use of these cells in the therapy of posttraumatic cysts of the spinal cord has not been studied. Cultures of human and rat olfactory mucosa were obtained according to the protocols developed by us. Passage 3-4 cultures are most enriched with olfactory ensheathing cells and are preferable for transplantation. We performed transplantation of 750,000 olfactory ensheathing cells into the region of modeled cysts. The therapeutic effect of human cells was more pronounced. The positive dynamics of recovery of motor activity in the hind limbs of rats can reflect regenerative processes in the spinal cord after transplantation of olfactory ensheathing cells into the region of posttraumatic cysts.

© 2018 The American Society of Gene and Cell Therapy Treatment of myocardial infarction (MI) with bone marrow cells (BMCs) improves post-MI cardiac function in rodents. However, clinical trials of BMC therapy have been less effective. While most rodent experiments use young healthy donors, patients undergoing autologous cell therapy are older and post-MI. We previously demonstrated that BMCs from aged and post-MI donor mice are therapeutically impaired, and that donor MI induces inflammatory changes in BMC composition including reduced levels of B lymphocytes. Here, we hypothesized that B cell alterations in bone marrow account for the reduced therapeutic potential of post-MI and aged donor BMCs. Injection of BMCs from increasingly aged donor mice resulted in progressively poorer cardiac function and larger infarct size. Flow cytometry revealed fewer B cells in aged donor bone marrow. Therapeutic efficacy of young healthy donor BMCs was reduced by depletion of B cells. Implantation of intact or lysed B cells improved cardiac function, whereas intact or lysed T cells provided only minor benefit. We conclude that B cells play an important paracrine role in effective BMC therapy for MI. Reduction of bone marrow B cells because of age or MI may partially explain why clinical autologous cell therapy has not matched the success of rodent experiments. Implantation of bone marrow cells into mouse hearts after myocardial infarction is therapeutic, but if the cells are from donors that are older or post-MI (mimicking autologous cell therapy), they are less effective. This report presents evidence that a decrease in B lymphocytes is responsible for the reduced therapeutic response.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. We evaluated the efficacy of rat olfactory ensheathing cells in the therapy of experimental cysts of the spinal cord. Improvement of the motor function of the hind limbs after transplantation of the olfactory ensheathing cells into the posttraumatic spinal cord cysts rats was found. We also determined the required number of cells for transplantation and demonstrated a neuroprotective effect of this dosage. For further clinical studies, autologous tissue-specific cell preparation of olfactory ensheathing cells has to be created. Cell therapy in combination surgical and pharmacological treatment will substantially improve the quality of life of patients with posttraumatic spinal cord cysts.

© 2018 International Society for Cellular Therapy Background: Menstrual blood is only recently and still poorly studied, but it is an abundant and noninvasive source of highly proliferative mesenchymal stromal cells (MSCs). However, no appropriate isolation method has been reported due to its high viscosity and high content of clots and desquamated epithelium. Methods: We studied three different isolation approaches and their combinations: ammonium-containing lysing buffer, distilled water and gradient-density centrifugation. We tested the proliferative capacity, morphology, surface markers and pluripotency of the resulting cells. Results: Our isolation method yields up to four million nucleated cells per milliliter of initial blood, of which about 0.2–0.3% are colony-forming cells expressing standard mesenchymal markers CD90, CD105 and CD73, but not expressing CD45, CD34, CD117, CD133 or HLA-G. The cells have high proliferative potential (doubling in 26 h) and the ability to differentiate into adipocytes and osteocytes. Early endometrial MSCs (eMSCs) express epithelial marker cytokeratin 7 (CK7). CK7 is easily induced in later passages in a prohepatic environment. We show for the first time that a satisfactory and stable yield of eMSCs is observed throughout the whole menstrual period (5 consecutive days) of a healthy woman. Discussion: The new cost/yield adequate method allows isolation from menstrual blood a relatively homogenous pool of highly proliferative MSCs, which seem to be the best candidates for internal organ therapy due to their proepithelial background (early expression of CK7 and its easy induction in later passages) and for mass cryobanking due to their high yield and availability.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. We developed an optimal protocol for preparing and culturing of olfactory ensheathing cells from human olfactory mucosa. Using this protocol, we obtained a culture enriched with human olfactory ensheathing cells. Immunofluorescence analysis by simultaneous expression of GFAP and p75NTR markers showed that the content of ensheathing cells was maximum in passage 3 and 4 cultures (94 and 89.5%, respectively). The developed protocol can be recommended for obtaining autologous preparations of human ensheathing cells for cell therapy of spinal cord injuries.

© 2018 Human Stem Cell Institute. All rights reserved. Cell therapy is one of the most promising directions in the treatment of critical limb ischemia (CLI). In spite of certain advances achieved in this field in the last decades, which are related to application of bone marrow stem cells (BMSC), a large number of problems still remain unsolved. In this review, we discuss the BMSC biology, mechanisms of their therapeutic effect in the CLI treatment and results of the most notable BMSC-based clinical studies in detail.

© 2018 Bentham Science Publishers. Ischemic Heart Disease (IHD) has been recognized as the main cause of mortality in the modern world. Application of cell therapy technologies for the IHD treatment has been actively studied from the beginning of 2000s. The review is dedicated to the use of mesenchymal stem cells (MSC) in the therapy of IHD. The strategies of the MSC modification in vitro for improvement of their regenerative potential are extensively discussed, including preconditioning to enhance the cell survival, boosting their paracrine effect and manipulating their car-diomyogenic differentiation. The optimization of the MSC delivery and opportunities related to the use of biomaterials as cell carriers are also discussed. The results of the most important clinical studies on the MSC-based IHD therapy are presented, including those completed and published in the literature and the ongoing clinical trials registered at clinicaltrials.gov by June 2018.