Immunotherapy in type 1 diabetes:Novel pathway to the future ahead

Since the discovery of insulin over 100 years ago,the focus of research in the management of type 1 diabetes(T1D)has centered around glycemic control and management of complications rather than the prevention of autoimmune destruc-tion of pancreaticβcells.Fortunately,in recent years,there has been significant advancement in immune-targeted pharmacotherapy to halt the natural progres-sion of T1D.The immune-targeted intervention aims to alter the underlying pa-thogenesis of T1D by targeting different aspects of the immune system.The im-munotherapy can either antagonize the immune mediators like T cells,B cells or cytokines(antibody-based therapy),or reinduce self-tolerance to pancreaticβcells(antigen-based therapy)or stem-cell treatment.Recently,the US Food and Drug Administration approved the first immunotherapy teplizumab to be used only in stage 2 of T1D.However,the window of opportunity to practically implement this approved molecule in the selected target population is limited.In this Edito-rial,we briefly discuss the various promising recent developments in the field of immunotherapy research in T1D.However,further studies of these newer thera-peutic agents are needed to explore their true potential for prevention or cure of T1D.

Preliminary Study of Local Immunotherapy with Autologous Cytokine-Induced Killer Cells for Glioma Patients

OBJECTIVE Cytokine-induced killer （CIK） cells are T-cells that display effective anti-tumor activity. In this stud, we investigated the anti-tumor activity of CIK cells in vitro, and conducted a preliminary investigation using autologous CIK cells to treat glioma patients through local administration. METHODS The CIK cells were derived from peripheral blood monocytes （PBMCs） of the glioma patients. The anti-tumor activity of the CIK cells against human T98-G glioma cell was tested in vitro. In addition, the autologous CIK cells were locally administrated into the tumor cavity in the malignant glioma patients through an Ommaya reservoir which was pre-inserted during tumor resection. The 4 x 108 CIK cells in a 5 ml suspension were injected once a week 2 times per cycle. Five hundreds KU of IL-2 was injected every other day. RESULTS （i） With incubation, the CIK cells showed dual staining of CD3^＋CD56^＋ with a positive rate of 3.45% on day 10 and 55.2% on day 30. In vitro anti-tumor activity （against T98-G cells） of the CIK cells reached the highest level after 18 days of incubation with different effector/target （E：T） ratios. （ii） Six patients received autologous CIK cell treatment （10 cycles）. Two patients showed no recurrence and are still alive （24 and 10 months）, while 4 cases had a recurrence 3 of which have died. The mean survival time from the first CIK cell treatment to the end of follow-up was 12.5 months. The main side-effects of the local CIK cell treatment was brain edema, which was controlled by mannitol in most of the cases. However for one patient injection of CIK cells and IL-2 had to be discontinued. CONCLUSION In vitro CIK cells are effective anti-glioma T-cells. Local therapy with CIK cells has potential anti-glioma efficacy and tolerable side-effects.

Experimental study on dendritic cells pulsed with brain tumor stem cells for immunotherapy of glioma

Objective To investigate the effect of dendritic cells pulsed with brain tumor stem cells which are used to treat on intracranial glioma. Methods We obtained murine brain tumor stem cells by grow ing C6 cells in epidermal grow th factor/basic fibroblast grow th factor w ithout serum.Dendritic cells isolated from rat bone marrow w ere pulsed w ith BTSCs. Rat brain

Engineered T cells and their therapeutic applications in autoimmune diseases

Chimeric antigen receptor T cells(CAR-T cells) are engineered recombinant T cells, which were initially used to treat hematopoietic malignancies and are now widely used in the treatment of various diseases. Considering their intrinsic targeting efficiency, CAR-T cells show considerable potential in the treatment of autoimmune diseases.Furthermore, regulatory T cells(Treg), a subset of CD4 T cells exhibiting immunosuppressive functions,have attracted increasing attention regarding CARTreg cell production. In this review, we report on recent developments in preclinical and clinical studies on CAR-T cells in autoimmune diseases and provide an outlook on opportunities and challenges of CAR-T application in such diseases.

In vivo anti-tumor activity of murine hematopoietic stem cells expressing a p185HER2-specific chimeric T-cell receptor gene

We have confirmed efficient anti-tumor activities of the peripheral lymphocytes transduced with a p185HEH2-specific chimeric T-cell receptor gene both in murine and in human in our previous studies. To further test the feasibility of chimeric T-cell receptor in a bone marrow transplantation model, we first, made two routine tumor cell lines： MT901 and MCA-205, to express human p185HER2 by retroviral gene transduction. Murine bone marrow cells were retrovirally transduced to express the chimeric T-cell receptor and gene-modified bone marrow cells were transplanted into lethally irradiated mouse. Six months post transplantation, p185HER2-positive tumor ceils： MT-901/HER2 or MCA-205/ HER2 was subcutaneously or intravenously injected to make mouse models simulating primary breast cancer or pulmonary metastasis. The in vivo anti-tumor effects were monitored by the size of the subcutaneous tumor or counting the tumor nodules in the lungs after India ink staining. The size of the subcutaneous tumor was significantly inhibited and the number of pulmonary nodules were significantly decreased in mouse recipients transplanted with chimeric T-cell receptor modified bone marrow cells compared with the control group. Our results suggest the efficient in vivo anti-tumor activities of chimeric T-cell receptor gene modified bone marrow cells.

Advances in biological immunotherapy for gastric cancer:a mini-review

Gastric cancer immunotherapy refers to the use of biological technology to mobilize the immune function so that the body has a natural anti-cancer ability.It can be induced in vitro by collecting immune cells and cancer cells from patients with gastric cancer to form specific immune cell groups.Besides,a large number of these immune cell groups are cultured,separated,and then reinfused into patients,to achieve high efficiency,eliminate tumors and mobilize immune mechanisms in patients.In theory,this method can cure tumors because the principle of immunotherapy is to stimulate the body's autoimmune response.However,for some special populations,there may be more severe side effects.At present,the prediction,prevention,and treatment of this severe side effect are not complete.The immunotherapy of gastric cancer has not yet reached the full promotion,but it is a good treatment direction.It can be used clinically with chemotherapy and radiotherapy,surgery and traditional Chinese medicine cooperate,thereby achieving significant curative effects,and even curing gastric cancer.

Helicobacter pylori neutrophil-activating protein:From molecular pathogenesis to clinical applications

Helicobacter pylori (H. pylori) neutrophil-activating protein (HP-NAP) was originally identified as a virulence factor of H. pylori for its ability to activate neutrophils to generate respiratory burst by releasing reactive oxygen species. Later on, HP-NAP was also found to be involved in the protection of H. pylori from DNA damage, supporting the survival of H. pylori under oxidative stress. This protein is highly conserved and expressed by virtually all clinical isolates of H. pylori. The majority of patients infected with H. pylori produced antibodies specific for HP-NAP, suggesting its important role in immunity. In addition to acting as a pathogenic factor by activating the innate immunity through a wide range of human leukocytes, including neutrophils, monocytes, and mast cells, HP-NAP also mediates adaptive immunity through the induction of T helper cell type I responses. The pro-inflammatory and immunomodulatory properties of HP-NAP not only make it play an important role in disease pathogenesis but also make it a potential candidate for clinical use. Even though there is no convincing evidence to link HP-NAP to a disease outcome, recent findings supporting the pathogenic role of HP-NAP will be reviewed. In addition, the potential clinical applications of HP-NAP in vaccine development, clinical diagnosis, and drug development will be discussed.

Research progression of PD-1/PD-L1 in non-small cell lung cancer

Lung cancer is the leading cause of cancer-related mortality worldwide. Despite great progress in the development of target agents, most people who do not harbor a mutation do not benefit from these agents. Immunotherapy, which stimulates the body's immune system to improve the anti-tumor immunity effect, is a new therapeutic method for non-small cell lung cancer(NSCLC). Programmed cell death 1(PD-1) and its ligand(PD-L1) belong to the CD28/B7 immunoglobulin super-family and are co-stimulatory molecules that show negative regulation effects. Combined with its ligand, PD-1 can modulate the tumor microenvironment, enabling tumor cells to escape host immune surveillance and elimination and play a key role in the clinical significance of NSCLC. An increasing number of clinical trials have suggested that immune checkpoint inhibitors, including anti-PD-1 and anti-PD-L1 monoclonal antibodies, are beneficial and safe for NSCLC. Here, we review the brief history of PD-L1 as a biomarker, mechanism of action, and critical role of PD-1/PD-L1 in the treatment of NSCLC as well as the current research status and future directions.

Metabolic plasticity of T cell fate decision

The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T cells.Upon antigen exposure,T cells undergo metabolic reprogramming,leading to the development of functional effectors or memory populations.However,within the tumor microenvironment(TME),metabolic stress impairs CD8+T cell anti-tumor immunity,resulting in exhausted differentiation.Recent studies suggested that targeting T cell metabolism could offer promising therapeutic opportunities to enhance T cell immunotherapy.In this review,we provide a comprehensive summary of the intrinsic and extrinsic factors necessary for metabolic reprogramming during the development of effector and memory T cells in response to acute and chronic inflammatory conditions.Furthermore,we delved into the different metabolic switches that occur during T cell exhaustion,exploring how prolonged metabolic stress within the TME triggers alterations in cellular metabolism and the epigenetic landscape that contribute to T cell exhaustion,ultimately leading to a persistently exhausted state.Understanding the intricate relationship between T cell metabolism and cancer immunotherapy can lead to the development of novel approaches to improve the efficacy of T cell-based treatments against cancer.

Establishing guidelines for CAR-T cells： challenges and considerations

T cells, genetically modified by chimeric antigen receptors(CAR-T), are endowed with specificity to a desired antigen and are cytotoxic to cells expressing the targeted antigen. CAR-T-based cancer immunotherapy is a promising therapy for curing hematological malignancy, such as acute lymphoid leukemia, and is promising for extending their efficacy to defeat solid tumors. To date, dozens of different CAR-T cells have been evaluated in clinical trials to treat tumors; this necessitates the establishment of guidelines for the production and application of CAR-T cells. However, it is challenging to standardize CAR-T cancer therapy because it involves a combination of gene therapy and cell therapy. In this review, we compare the existing guidelines for CAR-T cells and discuss the challenges and considerations for establishing guidance for CAR-T-based cancer immunotherapy.

Click CAR-T cell engineering for robustly boosting cell immunotherapy in blood and subcutaneous xenograft tumor

The adoptive transfer of chimeric antigen receptor-T(CAR-T)cells has shown remarkable clinical responses in hematologic malignancies.However,unsatisfactory curative results and side effects for tumor treatment are still unsolved problems.Herein we develop a click CAR-T cell engineering strategy via cell glycometabolic labeling for robustly boosting their antitumor effects and safety in vivo.Briefly,paired chemical groups(N3/BCN)are separately incorporated into CAR-T cell and tumor via nondestructive intrinsic glycometabolism of exogenous Ac4GalNAz and Ac4ManNBCN,serving as an artificial ligand-receptor.Functional groups anchored on cell surface strengthen the interaction of CAR-T cell and tumor via bioorthogonal click chemistry,further enhancing specific recognition,migration and selective antitumor effects of CAR-T cells.In vivo,click CAR-T cell completely removes lymphoma cells and minimizes off-target toxicity via selective and efficient bioorthogonal targeting in blood cancer.Surprisingly,compared to unlabeled cells,artificial bioorthogonal targeting significantly promotes the accumulation,deep penetration and homing of CAR-T cells into tumor tissues,ultimately improving its curative effect for solid tumor.Click CAR-T cell engineering robustly boosts selective recognition and antitumor capabilities of CAR T cells in vitro and in vivo,thereby holding a great potential for effective clinical cell immunotherapy with avoiding adverse events in patients.

Application of synthetic biology in bladder cancer

Bladder cancer(BC)is the most common malignant tumor of the genitourinary system.The age of individuals diagnosed with BC tends to decrease in recent years.A variety of standard therapeutic options are available for the clinical management of BC,but limitations exist.It is difficult to surgically eliminate small lesions,while radiation and chemotherapy damage normal tissues,leading to severe side effects.Therefore,new approaches are required to improve the efficacy and specificity of BC treatment.Synthetic biology is a field emerging in the last decade that refers to biological elements,devices,and materials that are artificially synthesized according to users’needs.In this review,we discuss how to utilize genetic elements to regulate BC-related gene expression periodically and quantitatively to inhibit the initiation and progression of BC.In addition,the design and construction of gene circuits to distinguish cancer cells from normal cells to kill the former but spare the latter are elaborated.Then,we introduce the development of genetically modified T cells for targeted attacks on BC.Finally,synthetic nanomaterials specializing in detecting and killing BC cells are detailed.This review aims to describe the innovative details of the clinical diagnosis and treatment of BC from the perspective of synthetic biology.

上期临床病案讨论结果

上期临床病案讨论结果术前诊断左上腹巨大包块：①腹膜后包块（嗜铬细胞瘤？）；②左肝肿瘤？手术情况于１９９４年５月７日在静脉复合麻醉下取双侧肋缘下人字形切口行剖腹探查术。术中见肝脏正常，未扣及结节或肿块，但在左肝下缘与胃小弯之间发现一凸出的巨大肿块。切开...