Facing challenges with hope:universal immune cells for hematologic malignancies

Many patients have achieved a favorable overall survival rate since allogenic hematopoietic stem cell transplantation(allo-HSCT)has been widely implemented to treat hematologic malignancies.However,graft-versus-host disease(GVHD)and complications of immunosuppressive drugs after allo-HSCT are the main causes of non-relapse mortality and a poor quality of life.In addition,GVHD and infusion-induced toxicity still occur with donor lymphocyte infusions(DLIs)and chimeric antigen receptor(CAR)T-cell therapy.Because of the special immune tolerance characteristics and anti-tumor ability of universal immune cells,universal immune cell therapy may strongly reduce GVHD,while simultaneously reducing tumor burden.Nevertheless,widespread application of universal immune cell therapy is mainly restricted by poor expansion and persistence efficacy.Many strategies have been applied to improve universal immune cell proliferation and persistence efficacy,including the use of universal cell lines,signaling regulation and CAR technology.In this review we have summarized current advances in universal immune cell therapy for hematologic malignancies with a discussion of future perspectives.

A universal ionic liquid solvent for non-halide lead sources in perovskite solar cells

Replacing lead iodide(PbI_(2))with suitable non-halides lead source has been found to be an effective method to control crystallization and fabricate high-performance perovskite solar cells(PSCs).However,the solubility of non-halide lead sources is highly limited by traditional solvents due to the chemical interaction limitation.Here,we report a series of non-halide lead sources(e.g.,lead acetate(PbAc_(2)),lead sulfate(PbSO_(4)),lead carbonate(PbCO_(3)),lead nitrate(Pb(NO_(3))_(2)),lead formate(Pb(HCOO)_(2))and lead oxalate(PbC_(2)O_(4)))can be well dissolved in an ionic liquid solvent methylammonium acetate(MAAc).We found that the universal strong coordination of C=O with lead ion(Pb^(2+))and the formation of hydrogen bonds were observed in perovskite precursor solution.This allows the dissolution of non-halide lead salts and is able to produce perovskite film with smooth,compact,and full coverage crystal grain.The power conversion efficiency(PCE)of 14.48%,19.21%,and 20.13%in PSCs based on PbSO_(4),PbAc_(2),and PbCO_(3) was achieved,respectively,in the absence of any additives and passivation agents.This study demonstrates the universality of ionic liquid for the preparation of PSCs based on nonhalides lead sources.

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.

Culturing adequate CAR-T cells from less peripheral blood to treat B-cell malignancies

Objective:Chimeric antigen receptor-modified T(CAR-T)cells have shown impressive results against relapsed/refractory B cell malignancies.However,the traditional manufacture of CAR-T cells requires leukapheresis to isolate large amounts of peripheral blood T cells,thus making some patients ineligible for the procedure.Methods:We developed a simple method for CAR-T cell preparation requiring small volumes of peripheral blood.First,CD3+T cells isolated from 50 mL peripheral blood from patients(B-cell malignancies)were stimulated with immobilized anti-CD3/RetroNectin in 6-well plates and then transduced with CAR-expressing lentiviral vector.After 4 d,the T cells were transferred to culture bags for large-scale CAR-T cell expansion.In vitro and animal experiments were performed to evaluate the activity of the manufactured CAR-T cells.Finally,29 patients with B-cell acute lymphoblastic leukemia(B-ALL)and 9 patients with B-cell lymphoma were treated with the CAR-T cells.Results:The CAR-T cells were expanded to 1–3×10^(8) cells in 8–10 d and successfully killed B cell-derived malignant tumor cells in vitro and in vivo.For patients with B-ALL,the complete remission rate was 93%1 month after CAR-T cell infusion;after 12 months,the overall survival(OS)and leukemia-free survival rates were 69%and 31%,respectively.For patients with lymphoma,the objective response rate(including complete and partial remission)was 78%2 months after CAR-T cell infusion,and after 12 months,the OS and progression-free survival rates were 71%and 43%,respectively.Cytokine-release syndrome(CRS)occurred in 65.51%and 55.56%of patients with B-ALL and B-cell lymphoma,respectively;severe CRS developed in 20.69%of patients with B-ALL and in no patients with lymphoma.Conclusions:Our novel method can generate sufficient numbers of CAR-T cells for clinical use from 50–100 mL peripheral blood,thus providing an alternative means of CAR-T cell generation for patients ineligible for leukapheresis.

Insights gained from single-cell analysis of chimeric antigen receptor T-cell immunotherapy in cancer

Advances in chimeric antigen receptor(CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies.However,progress is still hindered as clinical benefit is only available for a fraction of patients.A lack of understanding of CAR-T cell behaviors in vivo at the single-cell level impedes their more extensive application in clinical practice.Mounting evidence suggests that single-cell sequencing techniques can help perfect the receptor design,guide gene-based T cell modification,and optimize the CAR-T manufacturing conditions,and all of them are essential for long-term immunosurveillance and more favorable clinical outcomes.The information generated by employing these methods also potentially informs our understanding of the numerous complex factors that dictate therapeutic efficacy and toxicities.In this review,we discuss the reasons why CAR-T immunotherapy fails in clinical practice and what this field has learned since the milestone of single-cell sequencing technologies.We further outline recent advances in the application of single-cell analyses in CAR-T immunotherapy.Specifically,we provide an overview of single-cell studies focusing on target antigens,CAR-transgene integration,and preclinical research and clinical applications,and then discuss how it will affect the future of CAR-T cell therapy.

Nanotherapeutics approaches to improve the efficacy of CAR-T cells in solid tumors

Adoptive cell therapy and Immune Checkpoint Blockade Inhibitors have recently revolutionized the field of oncology.However,these types of immunotherapeutic approaches have limited success in treating solid tumors.In particular,chimeric antigen receptor(CAR)-T cells efficacy is hampered by immunosuppressive signals in the tumor microenvironment(TME)and by a limited infiltration of re-infused T cells to the tumor site.The field of nanobiotechnology applied to oncology is also rapidly expanding.Nanoparticles-based delivery systems can be employed to modulate the activity of immune cells present in the TME enhancing the efficacy of CAR-T cells.Interestingly,nano-backpacks can be attached to CAR-T cells prior to re-infusion to support their homing to the tumor site and to slowly release immunopotentiators directly in the TME.Furthermore,nanovaccines can also be employed to support the in vivo expansion of CAR-T cells with consequent enhancement of their therapeutic potential.In this viewpoint,recent advancement in the field of nanobiotechnology to support CAR-T cell therapy will be discussed.The development of novel therapeutic CAR-T cells protocols together with nanotherapies is warranted in order to take full advantage of the high therapeutic potential of CAR-T cell therapy.

Generating universal chimeric antigen receptor expressing cell products from induced pluripotent stem cells:beyond the autologous CAR-T cells

Adoptive therapeutic immune cells, such as chimeric antigen receptor (CAR)-T cells and natural killer cells, have established a new generation of precision medicine based on which dramatic breakthroughs have been achieved in intractable lymphoma treatments. Currently, well-explored approaches focus on autologous cells due to their low immunogenicity, but they are highly restricted by the high costs, time consumption of processing, and the insufficiency of primary cells in some patients. Induced pluripotent stem cells (iPSCs) are cell sources that can theoretically produce indefinite well-differentiated immune cells. Based on the above facts, it may be reasonable to combine the iPSC technology and the CAR design to produce a series of highly controllable and economical "live" drugs. Manufacturing hypoimmunogenic iPSCs by inactivation or over-expression at the genetic level and then arming the derived cells with CAR have emerged as a form of "off-the-shelf" strategy to eliminate tumor cells efficiently and safely in a broader range of patients. This review describes the reasonability, feasibility, superiority, and drawbacks of such approaches, summarizes the current practices and relevant research progress, and provides insights into the possible new paths for personalized cell-based therapies.

Tumor cell membrane remodeling with universal ligand for CAR-T cells to inhibit solid tumors

Heterogeneity is a major obstacle to the success of CAR-T therapy in treating solid tumors. The complex tumor micro-environment and varying phenotypes of tumor cells might result in antigen escape, drug resistance, and tumor recurrence. To address this issue, we proposed to use lipid-modified fluorescein isothiocyanate(Lip-FITC) as an artificial ligand to normalize the phenotypes of solid tumor cells. In murine cutaneous melanoma and colon adenocarcinoma that prefer to utilize exogenous long-chain fatty acids, we observed much more uptake of Lip-FITC and significantly increased FITC fluorescence on tumor cell membranes than normal cells. This specific exogenous labeling with FITC enhanced the recognition and selectivity of CART cells in solid tumors, bypassing the limitations derived from antigen expression differences in adoptive cell therapies. Lipid metabolism analysis and in vitro experiments demonstrated the sufficient uptake of long-chain fatty acid(LCFAs)-modified Lip-FITC by solid tumor cells, as well as satisfactory ligand assembly on cell membranes. In solid tumor model, the treatment induced the recognition and initiation of CART cells and successfully suppressed tumor progression through T-cell immunity.

Universal chimeric Fcγreceptor T cells with appropriate affinity for IgG1 antibody exhibit optimal antitumor efficacy

Developing universal CARs with improved flexible targeting and controllable activities is urgently needed.While several studies have suggested the potential of CD16a in tandem with monoclonal antibodies to construct universal CAR-T cells,the weak affinity between them is one of the limiting factors for efficacy.Herein,we systematically investigated the impact of Fcγreceptor(FcγR)affinity on CAR-T cells properties by constructing universal CARs using Fcγreceptors with different affinities for IgG1 antibodies,namely CD16a,CD32a,and CD64.We demonstrated that the activities of these universal CAR-T cells on tumor cells could be redirected and regulated by IgG1 antibodies.In xenografted mice,64CAR chimeric Jurkat cells with the highest affinity showed significant antitumor effects in combination with herceptin in the HER2 low expression U251 MG model.However,in the CD20 high expression Raji model,64CAR caused excessive activation of CAR-T cells,which resulted in cytokine release syndrome(CRS)and the decline of antitumor activity,and 32CAR with a moderate affinity brought the best efficacy.Our work extended the knowledge about FcγR-based universal CAR-T cells and suggested that only the FcγRCAR with an appropriate affinity can offer the optimal antitumor advantages of CAR-T cells.

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.

Moderate expression of CD39 in GPC3-CAR-T cells shows high efficacy against hepatocellular carcinoma

CD39 serves as a crucial biomarker for neoantigen-specific CD8^(+)T cells and is associated with antitumor activity and exhaustion.However,the relationship between CD39 expression levels and the function of chimeric antigen receptor T(CAR-T)cells remains controversial.This study aimed to investigate the role of CD39 in the functional performance of CAR-T cells against hepatocellular carcinoma(HCC)and explore the therapeutic potential of CD39 modulators,such as mitochondrial division inhibitor-1(mdivi-1),or knockdown CD39 through short hairpin RNA.Our findings demonstrated that glypican-3-CAR-T cells with moderate CD39 expression exhibited a strong antitumor activity,while high and low levels of CD39 led to an impaired cellular function.Methods modulating the proportion of CD39 intermediate(CD39^(int))-phenotype CAR-T cells such as mdivi-1 and CD39 knockdown enhanced and impaired T cell function,respectively.The combination of mdivi-1 and CD39 knockdown in CAR-T cells yielded the highest proportion of infiltrated CD39^(int)CAR-T cells and demonstrated a robust antitumor activity in vivo.In conclusion,this study revealed the crucial role of CD39 in CAR-T cell function,demonstrated the potential therapeutic efficacy of combining mdivi-1 with CD39 knockdown in HCC,and provided a novel treatment strategy for HCC patients in the field of cellular immunotherapy.

Gastrointestinal cancer stem cells as targets for innovative immunotherapy

The role of cancer stem cells in gastrointestinal cancer-associated death has been widely recognized.Gastrointestinal cancer stem cells(GCSCs)are considered to be responsible for tumor initiation,growth,resistance to cytotoxic therapies,recurrence and metastasis due to their unique properties.These properties make the current therapeutic trials against GCSCs ineffective.Moreover,recent studies have shown that targeting stem cell surface markers or stemness associated pathways might have an additional off-target effect on the immune system.Recent advances in oncology and precision medicine have opened alternative therapeutic strategies in the form of cancer immunotherapy.This approach differs from classical anti-cancer therapy through its mechanism of action involving the activation and use of a functional immune system against tumor cells,instead of aiming physically destruction of cancer cells through radio-or chemotherapy.New immunological approaches for GCSCs targeting involve the use of different immune cells and various immune mechanisms like targeting specific surface antigens,using innate immune cells like the natural killer and T cells,T-cell chimeric antigen receptor technology,dendritic cell vaccine,or immune checkpoint inhibitors.In this respect,better understandings of immune regulatory mechanisms that govern anti-tumor response bring new hope in obtaining long-term remission for cancer therapy.

Challenges and interventions of chimeric antigen receptor-T cell therapy in solid tumors

Adoptive cellular therapy is rapidly improving immunotherapy in hematologic malignancies and several solid tumors.Remarkable clinical success has been achieved in chimeric antigen receptor(CAR)-T cell therapy which represents a paradigm-shifting strategy for the treatment of hematological malignancies.However,many challenges such as resistance,antigen heterogeneity,poor immune cell infiltration,immunosuppressive microenvironment,metabolic obstructive microenvironment,and T cell exhaustion remain as barriers to broader application especially in solid tumors.Encouragingly,the development of new approaches such as multidimensional omics and biomaterials technologies was aided to overcome these barriers.Here,in this perspective,we focus on the most recent clinical advancements,challenges,and strategies of immune cellular therapy in solid tumor treatment represented by CAR-T cell therapy,to provide new ideas to further overcome the bottleneck of immune cell therapy and anticipate future clinical advances.

Some Antioxidant Enzymes among Children with Sickle Cell Disease Attending Usmanu Danfodiyo University Teaching Hospital Sokoto, North Western Nigeria

Sickle Cell Disease (SCD) is one of the most common genetic diseases in the world. It is associated with oxidative stress which occurs as a result of HbS unstable character causing a rise in the formation of free radicals. The aim of this study was to determine some antioxidant enzymes activities among patients with SCD. We investigated the superoxide dismutase (SOD), and glutathione peroxidases (GPx) levels among 60 children aged 1 - 14 years with SCD. Twenty-two age-matched non-SCD children served as control. The study subjects were divided into two groups;steady state A (n = 30) and vaso- occlusive crisis (VOC) B (n = 30). The SOD, and GPx levels were significantly lower among the SCD subjects compared to controls (p = 0.000). There were no statistically significant differences in the SOD and GPX levels between sickle cell disease patient in steady state (A) and those in crisis (B) (p = 0.998 and 0.555) respectively. There was a statistically significant difference between the SOD and GPX levels between sickle cell disease patient in steady state (A) and non-sickle cell controls (p = 0.005 and 0.000) respectively as well as between sickle cell disease patient in VOC (B) and non-sickle cell controls (p = 0.000). There were no statistically significant differences in the SOD and GPX levels of sickle disease subjects based on age, gender, maternal level of educational attainment, occupational group and income (p = 0.629 and 0.476;p = 0.382 and 0.417;p = 0.450 and 0.314 and p = 0.397 and 0.762 and p = 0.553 and 0.929) respectively. There were no statistically significant differences in the SOD and GPX levels of sickle disease subjects of Hausa/Fulani extraction versus Yoruba (p = 0.714 and 0.856), between Hausa/Fulani extraction versus Igbo (0.917 and 0.486) and between Yoruba extraction versus Igbo (p = 0.740 and 0.965) respectively. This study confirms that SCD children have lower values of antioxidant enzymes compared to controls. SOD and GPX levels in sickle cell disease patient in steady state and vaso-occlusive crisis are significantly lower compared that of non-sickle cell controls. Patients with SCD may benefit from substances with antioxidant properties which can potentially reduce the complications associated with the disease.

Cell mobile media in the innovation of the carriers of the ideological and political education in colleges and universities

Along with the development of the information technologies and the increasing diversity of the ways of human communications, cell mobile media have widely come into colleges and universities, affecting college students＇ ideas and living habits. Colleges and universities should look at this historical opportunity with the vision of development, grasp the development trend of the new media technology, and continue to play the advantages of the cell phone media in the ideological and political education in colleges and universities. In addition, we should also make full use of the special educational carrier of the mobile phone media to carry out the ideological and political education, and constantly improve the ideological and moral qualities and comprehensive strengths of the college students.

CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors

In the past decade,chimeric antigen receptor(CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers,demonstrating remarkable efficacy in relapsed/refractory hematological malignancies in both pediatric and adult patients.CAR-natural killer(CAR-NK)cell complements CAR-T cell therapy by offering several distinct advantages.CAR-NK cells do not require HLA compatibility and exhibit low safety concerns.Moreover,CAR-NK cells are conducive to“off-the-shelf”therapeutics,providing significant logistic advantages over CAR-T cells.Both CAR-T and CAR-NK cells have shown consistent and promising results in hematological malignancies.However,their efficacy against solid tumors remains limited due to various obstacles including limited tumor trafficking and infiltration,as well as an immuno-suppressive tumor microenvironment.In this review,we discuss the recent advances and current challenges of CAR-T and CAR-NK cell immunotherapies,with a specific focus on the obstacles to their application in solid tumors.We also analyze in depth the advantages and drawbacks of CAR-NK cells compared to CAR-T cells and highlight CAR-NK CAR optimization.Finally,we explore future perspectives of these adoptive immunotherapies,highlighting the increasing contribution of cutting-edge biotechnological tools in shaping the next generation of cellular immunotherapy.

Unlocking T cell exhaustion:Insights and implications for CAR-T cell therapy

Chimeric antigen receptor T(CAR-T)cell therapy as a form of adoptive cell therapy(ACT)has shown significant promise in cancer treatment,demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell maturation antigen(BCMA)for hematological malignancies,albeit with moderate outcomes in solid tumors.However,despite these advancements,the efficacy of CAR-T therapy is often compromised by T cell exhaustion,a phenomenon that impedes the persistence and effector function of CAR-T cells,leading to a relapse rate of up to 75%in patients treated with CD19 or CD22 CAR-T cells for hematological malignancies.Strategies to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing technologies.In this review,we provide a comprehensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell therapy.These insights,combined with lessons learned from benchmarking CAR-T based products in recent clinical trials,aim to address the challenges posed by T cell exhaustion,potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.

Dawn of CAR-T cell therapy in autoimmune diseases

Chimeric antigen receptor(CAR)-T cell therapy has achieved remarkable success in the treatment of hematological malignancies.Based on the immunomodulatory capability of CAR-T cells,efforts have turned toward exploring their potential in treating autoimmune diseases.Bibliometric analysis of 210 records from 128 academic journals published by 372 institutions in 40 countries/regions indicates a growing number of publications on CAR-T therapy for autoimmune diseases,covering a range of subtypes such as systemic lupus erythematosus,multiple sclerosis,among others.CAR-T therapy holds promise in mitigating several shortcomings,including the indiscriminate suppression of the immune system by traditional immunosuppressants,and non-sustaining therapeutic levels of monoclonal antibodies due to inherent pharmacokinetic constraints.By persisting and proliferating in vivo,CAR-T cells can offer a tailored and precise therapeutics.This paper reviewed preclinical experiments and clinical trials involving CAR-T and CAR-related therapies in various autoimmune diseases,incorporating innovations well-studied in the field of hematological tumors,aiming to explore a safe and effective therapeutic option for relapsed/refractory autoimmune diseases.

通用型CAR-NK细胞治疗系统性红斑狼疮的应用与展望

系统性红斑狼疮(SLE)的特点是B细胞异常活化产生大量自身抗体,这些自身抗体与自身抗原形成免疫复合物诱发系统性炎症,导致全身多系统多器官受累。现有靶向B细胞治疗策略(如贝利尤单抗、泰它西普及利妥昔单抗等)的临床疗效仍然有限,近年来靶向CD19的嵌合抗原受体(CAR)-T细胞治疗SLE展现出卓越的疗效。但自体CAR-T细胞治疗存在细胞因子释放综合征、T细胞肿瘤、感染等潜在风险,且价格昂贵。CAR-自然杀伤(NK)细胞治疗是现货型细胞疗法,其安全性高,无神经毒性及肿瘤化风险,且治疗费用低。目前,CAR-NK细胞在治疗血液系统肿瘤中取得了显著的研究成果,且CAR-NK细胞治疗SLE的初步临床研究展现出良好的治疗效果、优异的安全性及可预期的持久性。本文将重点阐述新一代通用型CAR-NK细胞的特点及其用于治疗复发难治性SLE的最新临床研究结果,展望其治疗SLE及B细胞相关自身免疫病的广阔前景。

CAR-T cells for cancer immunotherapy

Adoptive immunotherapy expressing synthetic chimeric antigen receptors(CAR)on T cells through in vitro modifications represents a new and innovative strategy in cancer treatment.This new approach enables T cells to recognize and bind tumor antigens via a single-chain variable fragment recognition domain,circumventing the restriction of major histocompatibility complex.This review summarized the structure/design of CAR-T cells and the evolution process this technology went through,displaying the theoretical foundation for CAR-T therapy,the marketed products and the latest preclinical and clinical research progress.Finally,we provided perspectives on this technology’s development and potential future applications,especially for treating hematological malignant and solid tumors.