Th17 cell function in cancers: immunosuppressive agents or anti-tumor allies?

T helper (Th) 17 cells, a distinct subset of Th lymphocytes, are known for their prominent interleukin (IL)-17 production and other pro-inflammatory cytokines. These cells exhibit remarkable plasticity, allowing them to exhibit different phenotypes in the cancer microenvironment. This adaptability enables Th17 cells to promote tumor progression by immunosuppressive activities and angiogenesis, but also mediate anti-tumor immune responses through employing immune cells in tumor setting or even by directly converting toward Th1 phenotype and producing interferon-gamma (IFN-γ). This dual role of Th17 cells in cancer makes it a double-edged sword in encountering cancer. In this review, we aim to elucidate the complexities of Th17 cell function in cancer by summarizing recent studies and, ultimately, to design novel therapeutic strategies, especially targeting Th17 cells in the tumor milieu, which could pave the way for more effective cancer treatments.

Effect of genetic profiling on surgical decisions at hereditary colorectal cancer syndromes.

Hereditary colorectal cancer syndromes, such as Lynch syndrome and familial adenomatous polyposis (FAP), present significant clinical challenges due to the heightened cancer risks associated with these genetic conditions. This review explores genetic profiling impact on surgical decisions for hereditary colorectal cancer (HCRC), assessing options, timing, and outcomes. Genotypes of different HCRCs are discussed, revealing a connection between genetic profiles, disease severity, and outcomes. For Lynch syndrome, mutations in the MLH1, MSH2, MSH6, and PMS2 genes guide the choice of surgery. Subtotal colectomy is recommended for patients with mutations in MLH1 and MSH2, while segmental colectomy is preferred for those with MSH6 and PMS2 mutations. In cases of metachronous colon cancer after segmental colectomy, subtotal colectomy with ileorectal anastomosis is advised for all mutations. Surgical strategies for primary rectal cancer include anterior resection or abdominoperineal resection (APR), irrespective of the specific mutation. For rectal cancer occurring after a previous segmental colectomy, proctocolectomy with ileal pouch-anal anastomosis (IPAA) or APR with a permanent ileostomy is recommended. In FAP, surgical decisions are based on genotype-phenotype correlations. The risk of desmoid tumors post-surgery supports a single-stage approach, particularly for certain APC gene variants. Juvenile Polyposis Syndrome (JPS) surgical decisions involve genetic testing, polyp characteristics with attention to vascular lesions in SMAD4 mutation carriers. However, genetic profiling does not directly dictate the specific surgical approach for JPS. In conclusion this review highlights the critical role of personalized surgical plans based on genetic profiles to optimize patient outcomes and reduce cancer risk. Further research is needed to refine these strategies and enhance clinical guidelines.

Recent advances in non-small cell lung cancer targeted therapy; an update review.

Lung cancer continues to be the leading cause of cancer-related death worldwide. In the last decade, significant advancements in the diagnosis and treatment of lung cancer, particularly NSCLC, have been achieved with the help of molecular translational research. Among the hopeful breakthroughs in therapeutic approaches, advances in targeted therapy have brought the most successful outcomes in NSCLC treatment. In targeted therapy, antagonists target the specific genes, proteins, or the microenvironment of tumors supporting cancer growth and survival. Indeed, cancer can be managed by blocking the target genes related to tumor cell progression without causing noticeable damage to normal cells. Currently, efforts have been focused on improving the targeted therapy aspects regarding the encouraging outcomes in cancer treatment and the quality of life of patients. Treatment with targeted therapy for NSCLC is changing rapidly due to the pace of scientific research. Accordingly, this updated study aimed to discuss the tumor target antigens comprehensively and targeted therapy-related agents in NSCLC. The current study also summarized the available clinical trial studies for NSCLC patients.

CAR-NKT cell therapy: a new promising paradigm of cancer immunotherapy.

Today, cancer treatment is one of the fundamental problems facing clinicians and researchers worldwide. Efforts to find an excellent way to treat this illness continue, and new therapeutic strategies are developed quickly. Adoptive cell therapy (ACT) is a practical approach that has been emerged to improve clinical outcomes in cancer patients. In the ACT, one of the best ways to arm the immune cells against tumors is by employing chimeric antigen receptors (CARs) via genetic engineering. CAR equips cells to target specific antigens on tumor cells and selectively eradicate them. Researchers have achieved promising preclinical and clinical outcomes with different cells by using CARs. One of the potent immune cells that seems to be a good candidate for CAR-immune cell therapy is the Natural Killer-T (NKT) cell. NKT cells have multiple features that make them potent cells against tumors and would be a powerful replacement for T cells and natural killer (NK) cells. NKT cells are cytotoxic immune cells with various capabilities and no notable side effects on normal cells. The current study aimed to comprehensively provide the latest advances in CAR-NKT cell therapy for cancers.

CAR-modified immune cells as a rapidly evolving approach in the context of cancer immunotherapies.

Nowadays, one of the main challenges clinicians face is malignancies. Through the progression of technology in recent years, tumor nature and tumor microenvironment (TME) can be better understood. Because of immune system involvement in tumorigenesis and immune cell dysfunction in the tumor microenvironment, clinicians encounter significant challenges in patient treatment and normal function recovery. The tumor microenvironment can stop the development of tumor antigen-specific helper and cytotoxic T cells in the tumor invasion process. Tumors stimulate the production of proinflammatory and immunosuppressive factors and cells that inhibit immune responses. Despite the more successful outcomes, the current cancer therapeutic approaches, including surgery, chemotherapy, and radiotherapy, have not been effective enough for tumor eradication. Hence, developing new treatment strategies such as monoclonal antibodies, adaptive cell therapies, cancer vaccines, checkpoint inhibitors, and cytokines helps improve cancer treatment. Among adoptive cell therapies, the interaction between the immune system and malignancies and using molecular biology led to the development of chimeric antigen receptor (CAR) T cell therapy. CAR-modified immune cells are one of the modern cancer therapeutic methods with encouraging outcomes in most hematological and solid cancers. The current study aimed to discuss the structure, formation, subtypes, and application of CAR immune cells in hematologic malignancies and solid tumors.

Exosome engineering in cell therapy and drug delivery.

Cell-derived exosomes have opened new horizons in modern therapy for advanced drug delivery and therapeutic applications, due to their key features such as low immunogenicity, high physicochemical stability, capacity to penetrate into tissues, and the innate capacity to communicate with other cells over long distances. Exosome-based liquid biopsy has been potentially used for the diagnosis and prognosis of a range of disorders. Exosomes deliver therapeutic agents, including immunological modulators, therapeutic drugs, and antisense oligonucleotides to certain targets, and can be used as vaccines, though their clinical application is still far from reality. Producing exosomes on a large-scale is restricted to their low circulation lifetime, weak targeting capacity, and inappropriate controls, which need to be refined before being implemented in practice. Several bioengineering methods have been used for refining therapeutic applications of exosomes and promoting their effectiveness, on the one hand, and addressing the existing challenges, on the other. In the short run, new diagnostic platforms and emerging therapeutic strategies will further develop exosome engineering and therapeutic potential. This requires a thorough analysis of exosome engineering approaches along with their merits and drawbacks, as outlined in this paper. The present study is a comprehensive review of novel techniques for exosome development in terms of circulation time in the body, targeting capacity, and higher drug loading/delivery efficacies.

Mesenchymal stem cell-based therapy as a new therapeutic approach for acute inflammation.

Acute inflammatory diseases such as acute colitis, kidney injury, liver failure, lung injury, myocardial infarction, pancreatitis, septic shock, and spinal cord injury are significant causes of death worldwide. Despite advances in the understanding of its pathophysiology, there are many restrictions in the treatment of these diseases, and new therapeutic approaches are required. Mesenchymal stem cell-based therapy due to immunomodulatory and regenerative properties is a promising candidate for acute inflammatory disease management. Based on preclinical results, mesenchymal stem cells and their-derived secretome improved immunological and clinical parameters. Furthermore, many clinical trials of acute kidney, liver, lung, myocardial, and spinal cord injury have yielded promising results. In this review, we try to provide a comprehensive view of mesenchymal stem cell-based therapy in acute inflammatory diseases as a new treatment approach.

CAR-T cell combination therapy: the next revolution in cancer treatment.

In recent decades, the advent of immune-based therapies, most notably Chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer treatment. The promising results of numerous studies indicate that CAR-T cell therapy has had a remarkable ability and successful performance in treating blood cancers. However, the heterogeneity and immunosuppressive tumor microenvironment (TME) of solid tumors have challenged the effectiveness of these anti-tumor fighters by creating various barriers. Despite the promising results of this therapeutic approach, including tumor degradation and patient improvement, there are some concerns about the efficacy and safety of the widespread use of this treatment in the clinic. Complex and suppressing tumor microenvironment, tumor antigen heterogeneity, the difficulty of cell trafficking, CAR-T cell exhaustion, and reduced cytotoxicity in the tumor site limit the applicability of CAR-T cell therapy and highlights the requiring to improve the performance of this treatment. With this in mind, in the last decade, many efforts have been made to use other treatments for cancer in combination with tuberculosis to increase the effectiveness of CAR-T cell therapy, especially in solid tumors. The combination therapy results have promising consequences for tumor regression and better cancer control compared to single therapies. Therefore, this study aimed to comprehensively discuss different cancer treatment methods in combination with CAR-T cell therapy and their therapeutic outcomes, which can be a helpful perspective for improving cancer treatment in the near future.

Immunomodulatory role of Nanocurcumin in COVID-19 patients with dropped natural killer cells frequency and function.

The ongoing COVID-19 pandemic is still a challenging problem in the case of infection treatment. The immunomodulatory effect of Nanocurcumin was investigated in the present study in an attempt to counterbalance the immune response and improve the patients' clinical symptoms. 60 confirmed COVID-19 patients and 60 healthy controls enrolled in the study. COVID-19 patients were divided into Nanocurcumin and placebo received groups. Due to the importance of the role of NK cells in this disease, the frequency, cytotoxicity, receptor gene expression of NK cells, and serum secretion levels of inflammatory cytokines IL-1ß, IL-6, TNF-α, as well as circulating C5a as a chemotactic factor an inflammatory mediator was evaluated by flow cytometry, real-time PCR and enzyme-linked immunosorbent assay in both experimental groups before and after the intervention. Given the role of measured factors in the progression and pathogenesis of COVID-19 disease, the results can help find appropriate treatments. The results of this study indicated that the Nanocurcumin could significantly increase the frequency and function of NK cells compared to the placebo-treated group. As an immunomodulatory agent, Nanocurcumin may be a helpful choice to improve NK cell function in COVID-19 patients and improve the clinical outcome of patients.

Study of immunomodulatory effects of mesenchymal stem cell-derived exosomes in a mouse model of LPS induced systemic inflammation.

BACKGROUND: Sepsis is a debilitating systemic inflammation that resulted from infection or injury. Despite many advances in treatment, the resulting mortality rate has remained high due to increasing antibiotic resistance and aging communities. The present study investigated the effects of stem cell-derived exosomes in a mouse model of LPS-induced systemic inflammation. MATERIALS AND METHODS: To induce sepsis, the LPS model was used. Mice were divided into three groups: normal, patient group (LPS + PBS), and treatment group (LPS + exosome). The treatment group received an intravenous exosome 1 h after induction of the model. Patient and treatment groups were sacrificed at 4, 6, 24, and 48 h after induction of the model, and their tissues were isolated. Blood samples were taken from animal hearts to perform biochemical and immunological tests. The study results were analyzed using Graph Pad Prism software version 9. RESULTS: Mesenchymal stem cell-derived exosomes decreased serum levels of ALT and AST liver enzymes, decreased neutrophil to lymphocyte ratio (NLR), and improved kidney, liver, and lung tissue damage at 4, 6, and 24 h after model induction. At 24 h, the exosomes were able to reduce serum urea levels. This study revealed decreased levels of inflammatory cytokines such as IL-6, IL-1ß, and TNF-α after exosome injection. CONCLUSION: Our findings suggest that treating mice with stem cell-derived exosomes can ameliorate the destructive effects of inflammation caused by sepsis by reducing inflammatory factors and tissue damage.

Novel CAR T therapy is a ray of hope in the treatment of seriously ill AML patients.

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.

Risk factors for adverse outcomes of COVID-19 patients: Possible basis for diverse responses to the novel coronavirus SARS-CoV-2.

Severe coronavirus disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is characterized by an unpredictable disease course, with variable presentations of different organ systems. The clinical manifestations of COVID-19 are highly variable ranging from mild presentations to severe, life-threatening symptoms and the wide individual variability may be due to the broad heterogeneity in the underlying pathologies. There is no doubt that early management may have a major influence on the outcome. This led the scientists to search for ways to monitor disease progression or to predict outcomes in COVID-19. Although it is not yet possible to predict who will progress to the severe forms or in what time, numerous prospective and longitudinal studies represent the evidence for determining the potential immunological risk factors of COVID-19 critical disease and death. The kinetics and breadth of immune responses during COVID-19 appear to follow a trend which is consistent to the predominant pathological alterations. Recent publications have used these biomarkers to help identify patients who will develop the severe acute COVID-19. Of particular interest is the relationship between the kinetics of peripheral leukocytes and clinical progress of the disease in COVID-19. Although research is ongoing in this area, we present details about the current status of the evaluation. Understanding of the COVID-19 related alterations of the innate and adaptive immune responses may help to promote the vaccine development and immunological interventions.

Any closer to successful therapy of multiple myeloma? CAR-T cell is a good reason for optimism.

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.

COVID-19: Our Current Knowledge of Epidemiology, Pathology, Therapeutic Approaches, and Diagnostic Methods.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) firstly emerged in Wuhan, China at the end of 2019. After going through the experimental process, the virus was named the novel coronavirus (2019-nCoV) by the World Health Organization (WHO) in February 2020 which has created a global pandemic. The coronavirus disease 2019 (COVID-19) infection is challenging the people who are especially suffering from chronic health problems such as asthma, diabetes, and heart disease or immune system deteriorating disorders, including cancers, Alzheimer's, etc. Other predisposing/risk factors consist of smoking and age (elderly people are at higher risk). The 2019-nCoV attacks epithelial cells in all organs, particularly epithelial cells in the lungs, resulting in viral pneumonia. The 2019-nCoV starts its invasion with the attachment and entry into the respiratory tract epithelial cells via Angiotensin-Converting Enzyme 2 (ACE2) receptors on the epithelial cells. The critical problem with 2019-nCoV is its ability in human to human asymptomatic transmission which causes the rapid and hidden spread of the virus among the population. Also, there are several reports of highly variable and tightly case-dependent clinical manifestations caused by SARS-CoV2, which made the virus more enigmatic. The clinical symptoms are varied from common manifestations which occurred in flu and cold, such as cough, fever, body-ache, trembling, and runny nose to severe conditions, like the Acute Respiratory Distress Syndrome (ARDS) or even uncommon/unusual symptoms such as anosmia, skin color change, and stroke. In fact, besides serious injuries in the respiratory system, COVID-19 invades and damages various organs, including the kidney, liver, gastrointestinal, and nervous system. Accordingly, to cut the transmission chain of disease and control the infection spread. One of the major solutions seems to be early detection of the carriers, particularly the asymptomatic people, with sensitive and accurate diagnostic techniques. Moreover, developing novel and appropriate therapeutic approaches will contribute to the suitable management of the pandemic. Therefore, there is an urgent necessity to make comprehensive investigations and study reviews about COVID-19, offering the latest findings of novel therapies, drugs, epidemiology, and routes of virus transmission and pathogenesis. In this review, we discuss new therapeutic outcomes and cover and the most significant aspects of COVID-19, including the epidemiology, biological features, organs failure, and diagnostic techniques.

CAR T cells in solid tumors: challenges and opportunities.

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.

Immunomodulatory effects of nanocurcumin on Th17 cell responses in mild and severe COVID-19 patients.

In novel coronavirus disease 2019 (COVID-19), the increased frequency and overactivation of T helper (Th) 17 cells and subsequent production of large amounts of proinflammatory cytokines result in hyperinflammation and disease progression. The current study aimed to investigate the therapeutic effects of nanocurcumin on the frequency and responses of Th17 cells in mild and severe COVID-19 patients. In this study, 40 severe COVID-19 intensive care unit-admitted patients and 40 patients in mild condition were included. The frequency of Th17 cells, the messenger RNA expression of Th17 cell-related factors (RAR-related orphan receptor γt, interleukin [IL]-17, IL-21, IL-23, and granulocyte-macrophage colony-stimulating factor), and the serum levels of cytokines were measured in both nanocurcumin and placebo-treated groups before and after treatment. A significant decrease in the number of Th17 cells, downregulation of Th17 cell-related factors, and decreased levels of Th17 cell-related cytokines were found in mild and severe COVID-19 patients treated by nanocurcumin compared to the placebo group. Moreover, the abovementioned parameters were significantly decreased in the nanocurcumin-treated group after treatment versus before treatment. Curcumin could reduce the frequency of Th17 cells and their related inflammatory factors in both mild and severe COVID-19 patients. Hence, it could be considered as a potential modulatory compound in improving the patient's inflammatory condition.

Changes in Th17 cells frequency and function after ozone therapy used to treat multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) is a neurodegenerative autoimmune disease with chronic inflammation. In the course of the disease, the increased levels of Th17 cell, and its relevant inflammatory factors, may cause disease inflammation and progression. Ozone therapy with anti-oxidant and anti-inflammatory functions is known as a beneficial therapeutic approach. The current non-controlled study aimed to evaluate the therapeutic implications of ozone autohemotherapy on Th17 responses in MS patients. METHODS: 20 MS patients as the experimental group received ozone therapy (100 ml of O2/O3 compound (25 ugs/ml concentration) with 100 ml of autologous blood) twice per week for 6 months. The frequency of Th17 cells, gene expression of the relevant factors (RORÉ£t, IL-17, IL-23, miR-141, miR-155, and miR-200), as well as the secretion levels of IL-17 and IL-23 cytokines, were compared between the patient and control groups, as well as the group of patients before and after ozone therapy using the flow cytometry, Real-time PCR, and ELISA techniques, respectively. RESULTS: Findings indicated the significant decrease in the frequency of Th17 cells (P = 0.0002), the expression levels of RORÉ£t and IL-17 (P = 0.0001 and P = 0.0004, respectively), as well as miR-141 and miR-155 (P<0.0001 and P<0.0001, respectively) in post-treatment condition with Ozone compared to pre-treatment condition. Also, the significant reduction in the secretion level of IL-17 (P = 0.043) was detected in treated patients. DISCUSSION: Since increased levels and responses of Th17 cells may have critical roles in MS pathogenesis and inflammation, our findings revealed that ozone autohemotherapy could lower the Th17 responses in peripheral blood of MS patients and can be a beneficial approach in MS treatment.

Chimeric antigen receptor -T cell therapy: Applications and challenges in treatment of allergy and asthma.

Despite the current advancements, cancer treatment approaches have limitations restricting their cure rate. Immunotherapy techniques are among novel and promising cancer therapeutic approaches. Therapeutic antibodies and adoptive cell therapy (ACT) are the main branches of immunotherapy. T lymphocytes and genetically engineered cells are among important cells which can be used in ACT. This review has focused on recent advances in engineered cell-based immunotherapy based on T lymphocytes with chimeric antigen receptors (CARs). CARs are recombinant receptors expressing T cell signaling domains with or without co-stimulatory molecules. CAR-T cells are expanded ex vivo and re-infused to patients in order to improve their therapeutic efficacy. Nowadays, the beneficial function of CAR-T cell therapy has been indicated in various diseases including hematological malignancies, solid tumors, autoimmune diseases, and allergic diseases such as asthma. Furthermore, antigen-specific T regulatory cells (Tregs) and gene-edited T cells seem to be beneficial in controlling inflammation in allergic asthma. In fact, dysregulated function of Tregs is responsible for dominance of T helper 2 immune response and progression of allergic asthma. CAR-Treg cells can also be designed and reproduced using iTreg population to manage asthma. In addition, universal CAR-T cells can be modified to selectively target multiple antigens. The fourth generation CAR-T cells (i.e. TRUCK cells) represent novel strategies to cure asthma and allergic diseases as well. Despite the advantages of CAR-T cells, their applications can be associated with some unwanted reactions such as cytokine storm, anaphylaxis, neurotoxicity, etc. For clinical application, there is a need to prevent and manage these complications by optimizing ACT protocols.

Solid Tumors Challenges and New Insights of CAR T Cell Engineering.

Adoptive cell therapy using CAR T cells has emerged as a novel treatment strategy with promising results against B cell malignancies; however, CAR T cells have not shown much success against solid malignancies. There are several obstacles which diminish the efficacy of CAR T cells, but the immunosuppressive tumor microenvironment (TME) of the tumor stands out as the most important factor. TME includes Tumor-Associated Stroma, Immunosuppressive cells and cytokines, tumor hypoxia and metabolism, and Immune Inhibitory Checkpoints which affect the CAR T cell efficacy and activity in solid tumors. A precise understanding of the TME could pave the way to engineer novel modifications of CAR T cells which can overcome the immunosuppressive TME. In this review, we will describe different sections of the TME and introduce novel approaches to improve the CAR T cells potential against solid tumors based on recent clinical and preclinical data. Also, we will provide new suggestions on how to modify CARs to augment of CAR T cells efficacy. Since there are also some challenges beyond the TME that are important for CAR function, we will also discuss and provide data about the improvement of CAR T cells trafficking and delivery to the tumor site and how to solve the problem of tumor antigen heterogeneity.