Treatment Of Hematological Tumors Research Articles

Targeting metabolism to improve CAR-T cells therapeutic efficacy.

Chimeric antigen receptor T (CAR-T) cell therapy achieved advanced progress in the treatment of hematological tumors. However, the application of CAR-T cell therapy for solid tumors still faces many challenges. Competition with tumor cells for metabolic resources in an already nutrient-poor tumor microenvironment is a major contributing cause to CAR-T cell therapy's low effectiveness. Abnormal metabolic processes are now acknowledged to shape the tumor microenvironment, which is characterized by increased interstitial fluid pressure, low pH level, hypoxia, accumulation of immunosuppressive metabolites, and mitochondrial dysfunction. These factors are important contributors to restriction of T cell proliferation, cytokine release, and suppression of tumor cell-killing ability. This review provides an overview of how different metabolites regulate T cell activity, analyzes the current dilemmas, and proposes key strategies to reestablish the CAR-T cell therapy's effectiveness through targeting metabolism, with the aim of providing new strategies to surmount the obstacle in the way of solid tumor CAR-T cell treatment.

Cardiovascular Toxicity of Antineoplastic Treatments in Hematological Diseases: Focus on Molecular Mechanisms to Improve Therapeutic Management.

In recent years, advancements in the treatment of hematologic neoplasms have led to more effective and less toxic therapeutic schemes, resulting in prolonged patient life expectancy. However, the success of these treatments has also brought about an increased prevalence of cardiovascular adverse events, becoming a significant concern for the growing population of cancer survivors. Antineoplastic therapies, targeting both tumor and organ vessels, contribute to vascular toxicity, influenced by genetic factors and pre-existing vascular diseases. Chemotherapeutic agents and targeted treatments can induce cardiovascular toxicity by affecting endothelial cells and cardiomyocytes through various mechanisms, including hypoxia, vasculature abnormalities, and direct effects on cardiomyocytes. Cardiovascular adverse events encompass a wide range, from cardiac dysfunction to an elevated risk of arrhythmias. While early cardiac events are well-described in clinical trials, delayed toxicities are gaining relevance due to prolonged patient survival. The review focuses on the cardiac and vascular toxicity of antineoplastic drugs in hematological disorders, providing insights into the molecular physiopathology of cancer therapy-associated cardiotoxicity. Understanding how these drugs interact with the heart and blood vessels is essential for predicting, detecting, and managing chemotherapy-related heart issues.

Purinergic pathways and their clinical use in the treatment of acute myeloid leukemia.

Despite the use of various therapies such as hematopoietic stem cell transplantation and chimeric antigen receptor T cell therapy (CAR-T), the prognosis of patients with acute myeloid leukemia (AML) is still generally poor. However, immunotherapy is currently a hot topic in the treatment of hematological tumors. Extracellular adenosine triphosphate (ATP) can be converted to adenosine diphosphate (ADP) via CD39, and ADP can be converted to adenosine via CD73, which can bind to P1 and P2 receptors to exert immunomodulatory effects. Research on the mechanism of the purinergic signaling pathway can provide a new direction for the treatment of AML, and inhibitors of this signaling pathway have been discovered by several researchers and gradually applied in the clinic. In this paper, the mechanism of the purinergic signaling pathway and its clinical application are described, revealing a new target for the treatment of AML and subsequent improvement in patient prognosis.

When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms.

Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic syndrome and acute myeloid leukemia are unequivocal myeloid neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs are detected in approximately one-third of AA patients. In AA patients harboring MN-related genetic aberrations, a poor response to immunosuppressive therapy (IST) and an increased risk of transformation to MNs occurring either naturally or after IST are predicted. Approximately 10%-15% of patients with severe AA transform the disease phenotype to MNs following IST, and in some patients, leukemic transformation emerges during or shortly after IST. Phenotypic transformations between AHF and MNs can occur reciprocally. A fraction of advanced MN patients experience an aplastic crisis during which leukemic blasts are repressed. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammation. Both AHF and MNs have an immune-active bone marrow (BM) environment (BME). In AHF patients, an inflamed BME can be evoked by infiltrated immune cells targeting neoplastic molecules, which contributes to the BM-specific autoimmune impairment. Autoimmune responses in AHF may represent an antileukemic mechanism, and inflammatory stressors strengthen antileukemic immunity, at least in a significant proportion of patients who have MN-related genetic aberrations. During active inflammatory episodes, normal and leukemic hematopoieses are suppressed, which leads to the occurrence of aplastic cytopenia and leukemic cell regression. The successful treatment of underlying infections mitigates inflammatory stress-related antileukemic activities and promotes the penetration of leukemic hematopoiesis. The effect of IST is similar to that of treating underlying infections. Investigating inflammatory stress-powered antileukemic immunity is highly important in theoretical studies and clinical practice, especially given the wide application of immune-activating agents and immune checkpoint inhibitors in the treatment of hematological neoplasms.

Prediction of severe CRS and determination of biomarkers in B cell-acute lymphoblastic leukemia treated with CAR-T cells.

CAR-T cell therapy is a novel approach in the treatment of hematological tumors. However, it is associated with life-threatening side effects, such as the severe cytokine release syndrome (sCRS). Therefore, predicting the occurrence and development of sCRS is of great significance for clinical CAR-T therapy. The study of existing clinical data by artificial intelligence may bring useful information. By analyzing the heat map of clinical factors and comparing them between severe and non-severe CRS, we can identify significant differences among these factors and understand their interrelationships. Ultimately, a decision tree approach was employed to predict the timing of severe CRS in both children and adults, considering variables such as the same day, the day before, and initial values. We measured cytokines and clinical biomarkers in 202 patients who received CAR-T therapy. Peak levels of 25 clinical factors, including IFN-γ, IL6, IL10, ferritin, and D-dimer, were highly associated with severe CRS after CAR T cell infusion. Using the decision tree model, we were able to accurately predict which patients would develop severe CRS consisting of three clinical factors, classified as same-day, day-ahead, and initial value prediction. Changes in serum biomarkers, including C-reactive protein and ferritin, were associated with CRS, but did not alone predict the development of severe CRS. Our research will provide significant information for the timely prevention and treatment of sCRS, during CAR-T immunotherapy for tumors, which is essential to reduce the mortality rate of patients.

Delivery of Plasmid DNA by Ionizable Lipid Nanoparticles to Induce CAR Expression in T Cells.

Chimeric antigen receptor (CAR) cell therapy represents a hallmark in cancer immunotherapy, with significant clinical results in the treatment of hematological tumors. However, current approved methods to engineer T cells to express CAR use viral vectors, which are integrative and have been associated with severe adverse effects due to constitutive expression of CAR. In this context, non-viral vectors such as ionizable lipid nanoparticles (LNPs) arise as an alternative to engineer CAR T cells with transient expression of CAR. Here, we formulated a mini-library of LNPs to deliver pDNA to T cells by varying the molar ratios of excipient lipids in each formulation. LNPs were characterized and screened in vitro using a T cell line (Jurkat). The optimized formulation was used ex vivo to engineer T cells derived from human peripheral blood mononuclear cells (PBMCs) for the expression of an anti-CD19 CAR (CAR-CD19BBz). The effectiveness of these CAR T cells was assessed in vitro against Raji (CD19+) cells. LNPs formulated with different molar ratios of excipient lipids efficiently delivered pDNA to Jurkat cells with low cytotoxicity compared to conventional transfection methods, such as electroporation and lipofectamine. We show that CAR-CD19BBz expression in T cells was transient after transfection with LNPs. Jurkat cells transfected with our top-performing LNPs underwent activation when exposed to CD19+ target cells. Using our top-performing LNP-9-CAR, we were able to engineer human primary T cells to express CAR-CD19BBz, which elicited significant specific killing of CD19+ target cells in vitro. Collectively, our results show that LNP-mediated delivery of pDNA is a suitable method to engineer human T cells to express CAR, which holds promise for improving the production methods and broader application of this therapy in the future.

Principle and Application of CAR-T Cell Therapy for Cancer

CAR-T therapy is a High-profile technology in cancer immunotherapy, which has developed rapidly and has made great achievements in the treatment of hematologic tumors. Its therapeutic principle makes CAR-T cell therapy a great advantage in the treatment of relapsed refractory chronic lymphocytic leukemia. However, CAR-T cell therapy still faces many problems, such as side effects, off-target effects, and the lack of specific antigen deficiency on the surface of solid tumors and so on. At present, it is an important research direction to reduce the impact of side effects on patients and its application in solid tumors. This paper focused on the principles and application of involved in CAR-T cell therapy, and the side effects brought by CAR-T therapy were sorted out. Finally, the further development of CAR-T therapy has prospected

DC vaccine enhances CAR-T cell antitumor activity by overcoming T cell exhaustion and promoting T cell infiltration in solid tumors.

Great success has been achieved in CAR-T cell immunotherapy in the treatment of hematological tumors. However, it is particularly difficult in solid tumors, because CAR-T is difficult to enter interior and exert long-term stable immune effects. Dendritic cells (DCs) can not only present tumor antigens but also promote the infiltration of T cells. Therefore, CAR-T cells with the help of DC vaccines are a reliable approach to treat solid tumors. To test whether DC vaccine could promote CAR-T cell therapy in solid tumors, DC vaccine was co-cultured with MSLN CAR-T cells. The in vitro effects of DC vaccine on CAR-T were assessed by measuring cell proliferation, cell differentiation, and cytokine secretion. Effects of DC vaccine on CAR-T were evaluated using mice with subcutaneous tumors in vivo. The infiltration of CAR-T was analyzed using immunofluorescence. The persistence of CAR-T in mouse blood was analyzed using real-time quantitative PCR. The results showed that DC vaccine significantly enhanced the proliferation potential of MSLN CAR-T cells in vitro. DC vaccines not only promoted the infiltration of CAR-T cells, but also significantly improved the persistence of CAR-T in solid tumors in vivo. In conclusion, this study has demonstrated that DC vaccine can promote CAR-T therapy in solid tumors, which provides the possibility of widespread clinical application of CAR-T cells in the future.

The Immuno-Oncology and Genomic Aspects of DNA-Hypomethylating Therapeutics in Acute Myeloid Leukemia.

Hypomethylating agents (HMAs) have been used for decades in the treatment of hematologic neoplasms, and now, have gathered attention again in terms of their combination with potent molecular-targeted agents such as a BCL-6 inhibitor venetoclax and an IDH1 inhibitor ivosidenib, as well as a novel immune-checkpoint inhibitor (anit-CD47 antibody) megrolimab. Several studies have shown that leukemic cells have a distinct immunological microenvironment, which is at least partially due to genetic alterations such as the TP53 mutation and epigenetic dysregulation. HMAs possibly improve intrinsic anti-leukemic immunity and sensitivity to immune therapies such as PD-1/PD-L1 inhibitors and anti-CD47 agents. This review describes the immuno-oncological backgrounds of the leukemic microenvironment and the therapeutic mechanisms of HMAs, as well as current clinical trials of HMAs and/or venetoclax-based combination therapies.

Research Status of CAR-T Cell Immunotherapy in Tumor Treatment

In recent years, chimeric antigen receptor T-cell (CAR-T) therapy has made breakthroughs in the treatment of hematological tumors. However, due to the different characteristics of solid tumors from hematological tumors, CAR-T has not achieved good efficacy in the treatment of solid tumors. The key factors limiting the efficacy of CAR-T mainly include the solid tumor cells themselves and their special tumor microenvironment (TME), which damage CAR-T function in multiple processes such as CAR-T infiltration to tumor tissue sites, CAR-T maintaining anti-tumor activity in TME, and target recognition and killing of tumor cells by CAR-T. To solve these problems, more and more preclinical studies have proposed potentially effective solutions, and corresponding clinical studies have been carried out one after another. In this article, the existing challenges and corresponding optimization strategies of CAR-T cell therapy for solid tumors will be reviewed, to provide a reference for the future exploration of CAR-T therapy.

Research Progress of Single-cell Transcriptome Sequencing Technology in Physiological Hematopoiesis--Review

Hematopoiesis starts from the embryo and runs through the entire life of a living body, which is a multi-stage and complex dynamic process that is regulated by multiple pathways, involving a variety of cells and hematopoietic anatomical locations. During the development of the mammalian hematopoietic system, the currently known hematopoietic anatomical locations mainly include yolk sac, aorta-gonad-mesonephros, fetal liver, bone marrow, and thymus. The first three are mainly responsible for hematopoiesis during the embryonic and fetal period, while bone marrow is the main place for postnatal hematopoiesis, and thymus is mainly responsible for the differentiation of T lymphocytes. Integrating flow cytometry, in vitro cell culture and in vivo animal transplantation models, early researchers conducted an in-depth analysis of the differentiation pathways of hematopoietic cells. However, due to technical limitations, it is difficult to track the single-cell hematopoietic activity of hematopoietic organs. Transcriptome sequencing at the single-cell level provides researchers with a unique perspective, making it possible to draw the most detailed cell fate transition maps of the hematopoietic development of living organisms, and providing new ideas for the diagnosis and treatment of hematological tumors. In this article, we reviewed the research progress in the use of large-scale single-cell transcriptome sequencing in the field of physiological hematopoiesis in recent years.

Construction of Dual- and Enhanced Dual-Antibodies Targeting CD19 in the Treatment of B-ALL and Investigation of the Relevant Mechanisms

Objective: Acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by the development of immature lymphocytes. Although many patients can achieve complete remission (CR) after chemotherapy, only minority can sustain long term remission without relapse. In the past decade, chimeric antigen receptor (CAR) T cells have achieved unprecedented clinical responses for B cells malignancies, however, it still encounters with substantial challenges, such as expensive cost and treatment failure. T cell-redirecting bispecific antibodies is able to build the connection between endogenous T cells and tumor cells in order to activate T cells function to eliminate cancer cells without the need for ex vivo genetic alteration or manipulation of the T cells. It can provide an off-the-shelf immune-oncology therapy, unlike the long-term preparation before CAR-T infusion. Here, we developed the novel dual-specific antibody (DuAb) and enhanced DuAb (EDuAb) with different stimulation signals to activate T cells and explored their impact on the treatment of hematologic tumors by altering the function of T cells. Methods: The expression plasmids of dual-specific antibody targeting CD19 and CD3 (DuAb) and the enhanced DuAb (EDuAb) containing CD80 molecule were constructed by cloning heavy chain and light chain variable fragments from previously established anti-human CD19 (HI19a) and CD3 (HIT3a) monoclonal antibodies, respectively. Both DuAb and EDuAb were produced through a eukaryotic expression system. The activation of human primary T cells was evaluated after stimulated by DuAb and EDuAb in vitro, by detecting T cells proliferation, cytokine secretion, apoptosis and inhibitor marker expression. The antitumor efficacy of human primary T cells mediated by DuAb and EDuAb was evaluated through co-culture killing assay. B-ALL xenograft NSG mouse model was established to investigate the in vivo therapeutic effect. Results: EDuAb promoted the optimal expansion of primary human T cells with low expression of inhibitor marker in vitro than DuAb did (fold change of proliferation on day 9: 61.39 vs 19.23, p<0.0001; proportion of annexin V+: 11.83% vs 45.13%, p<0.0001, Tim3+: 20.08% vs 35.37%, p=0.007, PD-1+: 11.6% vs 34.3%, p=0.001, Lag3+: 29.12% vs 51.42%, p=0.006). In addition, BCL-XL was upregulated and IL2 secretion increased in EDuAb group. DuAb and EDuAb showed a similar capability in inducing healthy donor T cells to specifically eliminate B-ALL cell lines in vitro. At the concentration of 0.01nM, E/T ratio (2/1), the lysis of Nalm6 cells exceeded 96% after co-cultured for 48 hours. The similar ability was also observed in the patient-derived T cells. Both DuAb and EDuAb markedly suppressed tumor burden to baseline level and extended survival of B-ALL xenograft NSG mice. The median survival of vehicle, DuAb and EDuAb treatment group were 27, 38 and 45 days, respectively, which illustrated that EDuAb had a better therapeutic effect in vivo than that of DuAb (p=0.0066). The phenotype of T cells and cytokine release in peripheral blood of B-ALL xenograft NSG mouse model on day 24 were analyzed as well. The results showed that the proportion of CD8+ T cells and the cytokine levels, including IL2, IFN-γ and TNF-α, were higher in the EDuAb group than that of DuAb (CD8+: 0.746% vs 0.064%, p=0.0079; IL2: 1.862pg/ml vs 0.654pg/ml，p=0.0014; IFN-γ: 432.27pg/ml vs 1.48pg/ml, p= 0.047; TNF-α: 4.57pg/ml vs 2.08pg/ml, p=0.018). Both DuAb and EDuAb could significantly decrease the residual Nalm6 cells in PB of B-ALL xenograft NSG mice, and the residual tumor cells on day 24 were 1.61%, 0.45% and 0.29% in Vehicle, DuAb and EDuAb groups, respectively (Vehicle vs DuAb, p=0.0134; Vehicle vs EDuAb, p=0.0034; DuAb vs EDuAb, p=0.0169). Conclusion: Both DuAb and EDuAb showed great potential for clinical application as a novel treatment method for B-ALL. Compared with DuAb, there is a significant advantage for EDuAb to promote the proliferation and survival of T cells. In addition, EDuAb showed better promising effect to eliminate tumor cells and extend survival in vivo, which provides a new insight for constructing new multi-specific antibodies.

Research Progress of Oral BCL-2 Inhibitor Venetoclax in the Treatment of Non-Hodgkin's Lymphoma --Review

Abnormal cell apoptosis is closely related to the occurrence of hematologic tumors, B-cell lymphoma-2 (BCL-2), as a key anti-apoptotic protein in intrinsic programmed cell death, has become a hot spot in the treatment of hematologic tumors in recent years. Venetoclax is an oral small-molecule selective BCL-2 inhibitor approved by the Food and Drug Administration (FDA） for the treatment of chronic lymphocytic leukemia (CLL) patients or small lymphocytic lymphoma (SLL) patients and for the treatment of elderly acute myeloid leukemia (AML) patients that is not suitable for aggressive chemotherapy. In addition, it also showed a promising clinical application in treatment of non-Hodgkin's lymphoma (NHL) patients, which is a new expansion of the clinical indications for venetoclax. In this review, the role of BCL-2 protein family played in the regulation of NHL cell apoptosis, the development of BCL-2 inhibitors and the recent research progress of venetoclax in the treatment of NHL are reviewed.

CAR-T Cells in the Treatment of Urologic Neoplasms: Present and Future.

In recent years, with the breakthrough of CAR-T cells in the treatment of hematological tumors, they are increasingly being used to treat solid tumors, including urologic neoplasms. There are many relatively specific targets for urologic neoplasms, especially prostate cancer. Besides, urologic neoplasms tend to progress more slowly than tumors in other organs of the body, providing ample time for CAR-T cell application. Therefore, CAR-T cells technology has inherent advantages in urologic neoplasms. CAR-T cells in the treatment of urologic neoplasms have been extensively studied and preliminary achievements have been made. However, no breakthrough has been made due to the problems of targeting extra-tumor cytotoxicity and poor anti-tumor activity. we systematacially summarized the research actuality of CAR-T cells in urologic neoplasms, discussed the potential value and difficulties of the research. The application of CAR-T cells in the treatment of urologic neoplasms requires improvement of function through screening for better targets, modification of CAR structures, or in combination with other antitumor approaches.

Harnessing Unconventional T Cells and Innate Lymphoid Cells to Prevent and Treat Hematological Malignancies: Prospects for New Immunotherapy.

Unconventional T cells and innate lymphoid cells (ILCs) make up a heterogeneous set of cells that characteristically show prompt responses toward specific antigens. Unconventional T cells recognize non-peptide antigens, which are bound and presented by diverse non-polymorphic antigen-presenting molecules and comprise γδ T cells, MR1-restricted mucosal-associated invariant T cells (MAITs), and natural killer T cells (NKTs). On the other hand, ILCs lack antigen-specific receptors and act as the innate counterpart to the T lymphocytes found in the adaptive immune response. The alteration of unconventional T cells and ILCs in frequency and functionality is correlated with the onset of several autoimmune diseases, allergy, inflammation, and tumor. However, depending on the physio-pathological framework, unconventional T cells may exhibit either protective or pathogenic activity in a range of neoplastic diseases. Nonetheless, experimental models and clinical studies have displayed that some unconventional T cells are potential therapeutic targets, as well as prognostic and diagnostic markers. In fact, cell-mediated immune response in tumors has become the focus in immunotherapy against neoplastic disease. This review concentrates on the present knowledge concerning the function of unconventional T cell sets in the antitumor immune response in hematological malignancies, such as acute and chronic leukemia, multiple myeloma, and lymphoproliferative disorders. Moreover, we discuss the possibility that modulating the activity of unconventional T cells could be useful in the treatment of hematological neoplasms, in the prevention of specific conditions (such as graft versus host disease), and in the formulation of an effective anticancer vaccine therapy. The exact knowledge of the role of these cells could represent the prerequisite for the creation of a new form of immunotherapy for hematological neoplasms.

Prospect of Prostate Cancer Treatment: Armed CAR-T or Combination Therapy.

Simple SummaryThere is still no effective treatment for advanced prostate cancer. CAR-T therapy is a promising approach; however, many obstacles remain for the treatment of solid tumors due to the complex physical barriers and inhibitory microenvironment in solid tumors. Single CAR-T therapy has a low response rate and a high recurrence rate. With the enhancement of CAR-T itself and the gradual improvement of the immune microenvironment, the number of CAR-T weapons against tumors is increasing. This article discusses the current status and future of CAR-T therapy for prostate cancer. We believe that the enhancement and modification of CAR-T or CAR-T combined with other therapies are expected to be a breakthrough in the treatment of prostate cancer.The incidence rate of prostate cancer is higher in male cancers. With a hidden initiation of disease and long duration, prostate cancer seriously affects men’s physical and mental health. Prostate cancer is initially androgen-dependent, and endocrine therapy can achieve good results. However, after 18–24 months of endocrine therapy, most patients eventually develop castration-resistant prostate cancer (CRPC), which becomes metastatic castration resistant prostate cancer (mCRPC) that is difficult to treat. Chimeric Antigen Receptor T cell (CAR-T) therapy is an emerging immune cell therapy that brings hope to cancer patients. CAR-T has shown considerable advantages in the treatment of hematologic tumors. However, there are still obstacles to CAR-T treatment of solid tumors because the physical barrier and the tumor microenvironment inhibit the function of CAR-T cells. In this article, we review the progress of CAR-T therapy in the treatment of prostate cancer and discuss the prospects and challenges of armed CAR-T and combined treatment strategies. At present, there are still many obstacles in the treatment of prostate cancer with CAR-T, but when these obstacles are solved, CAR-T cells can become a favorable weapon for the treatment of prostate cancer.

Intelligent Internet of Things Medical Technology in Implantable Intravenous Infusion Port in Children with Malignant Tumors.

Due to the recent technological revolution that is centered around information technology, the Internet of Medical Things (IoMT) has become an important research domain. IoMT is a combination of Internet of Things (IoT), big data, cloud computing, ubiquitous network, and three-dimensional holographic technology, which is used to build a smart medical diagnosis and treatment system. Additionally, this system should automate various activities, such as the patient's health record and health monitoring, which is an important issue in the development of modern and smart healthcare system. In this paper, we have thoroughly examined the role of a smart healthcare system architecture and other key supporting technologies in improving the health status of both indoor and outdoor patients. The proposed system has the capacity to investigate and predict (if feasible) the clinical application and nursing effects of totally implantable intravenous port (TIVAP) in pediatric hematological tumors. For this purpose, seventy children with hematologic tumors were treated with TIVAP, and IoMT-enabled care was provided to them, where the occurrence of adverse events, specifically after the treatment, was observed. The experimental results collected after the 70 children were treated and cared for by TIVAP show that there were five cases of adverse events, whereas the incidence rate of the adverse events was 7.14%. Moreover, TIVAP has significant efficacy in the treatment of hematologic tumors in children, and it equally reduces the vascular injury caused by chemotherapy in younger patients. Likewise, targeted care reduces the incidence of adverse events in children with expected ratio.

Research advances in chimeric antigen receptor-modified T-cell therapy (Review).

Chimeric antigen receptor (CAR)-modified T-cells are T-cells that have been genetically engineered to express CAR molecules to target specific surface antigens on tumor cells. CAR T-cell therapy, a novel cancer immunotherapy, has been attracting increasing attention, since it exhibited notable efficacy in the treatment of hematological tumors in clinical trials. However, for this type of therapy, challenges must be overcome in the treatment of solid tumors. Furthermore, certain side effects associated with CAR T-cell therapy, including cytokine release syndrome, immune effector cell-related neurotoxicity syndrome, tumor lysis syndrome and on-target off-tumor toxicity, must be taken into consideration. The present study provides a systematic review of the principle, clinical application, current challenges, possible solutions and future perspectives for CAR T-cell therapy.

Preclinical Chimeric Antibody Chimeric Antigen Receptor T Cell Progress in Digestive System Cancers.

Digestive system cancers, including hepatocellular carcinoma, colorectal and gastric tumors, are characterized by high rates of incidence and mortality. Digestive cancers are difficult to diagnose during the early stages, and the side effects of chemotherapy are often severe and may outweigh the therapeutic benefits. Chimeric antibody chimeric antigen receptor T cell (CAR-T) therapy, a novel immunotherapy, has achieved excellent results for the treatment of hematological tumors. However, CAR-T treatment of solid tumors has struggled due to a lack of target specificity, a difficult tumor microenvironment, and T cell homing. Despite the challenges, CAR-T treatment of digestive cancers is progressing. Combining CAR-T with other targets and/or modifying the CAR may represent the most promising approaches for future treatment of digestive cancers.

Fn14-targeted BiTE and CAR-T cells demonstrate potent preclinical activity against glioblastoma

ABSTRACT T cell-engaging therapies involving bispecific T cell engager (BiTE) and chimeric antigen receptor T (CAR-T) cells have achieved great success in the treatment of hematological tumors. However, the paucity of ideal cell surface molecules that can be targeted on glioblastoma (GBM) partially reduces the immunotherapeutic efficacy. Recently, high expression of Fn14 has been reported in several solid tumors, so the strategy of exploiting this specific antigen for GBM immunotherapy is worth studying. Consequently, we constructed Fn14× CD3 BiTE and Fn14-specific CAR-T cells and investigated their cytotoxic activity against GBM in vitro and in vivo. First, expression of Fn14 was confirmed in glioma tissues and GBM cells. Then, we designed Fn14-specific BiTE and CAR-T cells and tested their cytotoxicity in GBM cell cultures and mouse models of GBM. Fn14 was highly expressed in GBM tissues and cell lines, while it was undetectable in normal brain samples. Fn14× CD3 BiTE, Fn14 CAR-T cells and Fn14 CAR-T/IL-15 cells were antigen-specific and highly cytotoxic, showing good antitumor activity in vitro and causing significant regression of established solid tumors in xenograft models. However, the xenografts treated with Fn14 CAR-T cells regrew, whereas xenografts treated with Fn14 CAR-T/IL-15 cells did not. IL-15 engineering augmented the antitumor activity of Fn14 CAR-T cells and resulted in significant antitumor effects similar to those of Fn14× CD3 BiTE. Our results suggest that Fn14 is an appropriate target for GBM. Anti-Fn14 BiTE and Fn14-specific CAR-T/IL-15 cells may be exciting immunotherapeutic options for malignant brain cancer.