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ABSTRACTCAR-T cell therapy has emerged as a significant approach for the management of hematological malignancies. Over the past few years, the utilization of CAR-T cells in the investigation and treatment of solid tumors has gained momentum, thereby establishing itself as a prominent area of research. This descriptive study involved the retrieval of articles about CAR-T cell therapy for solid tumors from the Web of Science Core Collection (WoSCC) database. Subsequently, bibliometric analysis and knowledge map analysis were conducted on these articles. The field under consideration is currently experiencing a period of swift advancement, as evidenced by the escalating number of publications in this domain each year. The United States holds an indisputable position as the foremost leader in this particular field, with the University of Pennsylvania emerging as the most active institution. The authors with the highest citation frequency and co-citation frequency are Carl H. June and Shannon L. Maude, respectively. The research hotspots in this field mainly focus on five aspects. Additionally, 10 emerging themes were identified. This study undertakes a comprehensive, systematic, and objective analysis and exploration of the field of CAR-T cell treatment for solid tumors, utilizing bibliometric methods. The findings of this study are expected to serve as a valuable reference and enlightenment for future research endeavors in this particular domain.

Abstract Background Studies have found that c-Met plays a critical role in the progression of solid tumors. This study aimed to investigate the expression of c-Met in gastric cancer (GC) and its correlation with preoperative serum tumor markers and prognosis, in order to provide a more theoretical basis for targeting c-Met in the treatment of GC. Methods Ninety-seven patients who underwent curative gastrectomy in our hospital from December 2013 to September 2015 were included in this study. The tissue microarray was constructed by paraffin-embedded tumor tissue of enrolled patients, including 97 GC points and 83 paracancerous points. Then, it was used for c-Met immunohistochemical staining, followed by an immunological H-score. The clinical baseline data and 5-year survival of patients with low and high c-Met expression were compared. Besides, the correlation between the expression of c-Met in tumor tissues and preoperative serum tumor markers was investigated. Finally, multivariate Cox regression analysis was used to explore the survival risk factors of patients. Results c-Met has a high expression rate in GC tissues 64.95% (63/97). The expression of c-Met was significantly different in different clinicopathological stages (p < 0.05); the high expression group also had a higher M stage and clinicopathological stage of GC. The correlation test between the c-Met H-score and CA125 was statistically significant (p = 0.004), indicating a positive correlation. Furthermore, high c-Met expression correlated with poor overall survival (OS) for 5 years (p = 0.005). It was also found that the high expression of c-Met in stage I–II patients was correlative with poor OS for 5 years (p = 0.026), while stage III–IV patients had no statistical significance (p > 0.05). Multivariate Cox regression analysis showed that c-Met might be an independent risk factor for survival 5 years after surgery. Conclusion This study found that the high expression of c-Met in GC tissues was associated with poor 5-year OS in GC patients and was an independent risk factor for 5-year survival after curative gastrectomy. The expression of c-Met in GC tissues was also positively correlated with preoperative serum CA125.

Boron Neutron Capture Therapy (BNCT) is a new binary radiation therapy for tumor tissue, which kills tumor cells with neutron capture reaction. Boron neutron capture therapy has become a technical means for glioma, melanoma, and other diseases has been included in the clinical backup program. However, BNCT is faced with the key problem of developing and innovating more efficient boron delivery agents to solve the targeting and selectivity. We constructed a tyrosine kinase inhibitor-L-p-boronophenylalanine (TKI-BPA) molecule, aiming to improve the selectivity of boron delivery agents by conjugating targeted drugs while increasing the molecular solubility by adding hydrophilic groups. It shows excellent selectivity in differential uptake of cells, and its solubility is more than 6 times higher than BPA, leading to the saving of boron delivery agents. This modification method is effective for improving the efficiency of the boron delivery agent and is expected to become a potential alternative with high clinical application value.

Deterministic and stochastic processes can simultaneously construct plant community assemblages. However, how they shape herbaceous plants’ phylogeny and functional structure in alpine meadows is unclear, hindering the understanding of species’ coexistence processes and diversity maintenance in herbaceous communities. We established a permanent research sample plot of 3.76 × 105 m2 in alpine meadows on the northeastern Qinghai-Tibet Plateau of China, investigated the flora, measured nine functional traits, analyzed inter- and intraspecific variation, and visualized phylogenetic signals. The results show that: (1) The phylogenetic structure based on DNA barcode sequences exhibits a range from competitive exclusion (NRI 0, NTI > 0) along an altitude gradient. (2) The interspecific functional structure varied with altitude, reflecting different survival strategies of plants. In contrast, intraspecific trait variation was associated with environmental screening processes. (3) Except for PH and LPC, none of the functional traits showed a phylogenetic signal (K 0.05), suggesting that they are more influenced by environmental heterogeneity; with increasing altitude, enhanced environmental filtering favors species with conservative strategies of selection. These results suggest that deterministic processes (interspecific competition, habitat filtering) may be the main mechanisms of species coexistence in alpine meadows. Low altitude drives niche differentiation of coexisting species through competitive exclusion to reduce competition for resources. In contrast, high altitude species lead to the coexistence of functionally similar species through habitat filtering.

Tumors pose a great threat to human health; as a subgroup of tumor cells, cancer stem cells (CSCs) contribute to the genesis, development, metastasis, and recurrence of tumors because of their enhanced proliferation and multidirectional differentiation. Thus, a critical step in tumor treatment is to inhibit CSCs. Researchers have proposed many methods to inhibit or reduce CSCs, including monoclonal antibodies targeting specific surface molecules of CSCs, signal pathway inhibitors, and energy metabolic enzyme inhibitors and inducing differentiation therapy. Additionally, immunotherapy with immune cells engineered with a chimeric antigen receptor (CAR) showed favorable results. However, there are few comprehensive reviews in this area. In this review, we summarize the recent CSC targets used for CSC inhibition and the different immune effector cells (T cells, natural killer (NK) cells, and macrophages) which are engineered with CAR used for CSC therapy. Finally, we list the main challenges and options in targeting CSC with CAR-based immunotherapy. The design targeting two tumor antigens (one CSC antigen and one mature common tumor antigen) should be more reasonable and practical; meanwhile, we highlight the potential of CAR-NK in tumor treatment.

ObjectivesAs emerging adoptive immunotherapy after CAR-T cell therapy, CAR-NK cell therapy has been developing rapidly in recent years. Presently, the research on CAR-NK cells has become a hotspot in the field of tumor immunotherapy.MethodsIn this descriptive study, CtieSpace and VOSviewer were used to perform the bibliometric and scientific knowledge-map analysis of articles and reviews related to CAR-NK cells.Results5371 authors from 715 institutions in 65 countries published 1028 papers about CAR-NK cells in 346 journals. The number of publications related to CAR-NK cells was increasing overall, especially from 2018 to 2021. The United States was in a leading position. The most active institution was Univ Texas, MD Anderson Cancer Center (USA). The journal with the most publications was Frontiers in immunology, and the most co-cited journal was Blood. The researcher with the most published papers was Winfried S. Wels, while the most co-cited researcher was Shannon L Maude. The research of CAR-NK cells in hematological malignancies and solid tumors (especially the selection of targets and the evaluation of efficacy and safety) was a research hotspot in this field. The emerging topics mainly included three aspects. First, further improve the proliferation and persistence of NK cells in vivo. Secondly, optimizing and improving the CAR structure for NK cells to improve the anti-tumor ability of CAR-NK cells. Thirdly, the related research of CRISPR/Cas9 gene-editing technology in constructing engineered immune cells.ConclusionIn this study, a bibliometric and scientific knowledge-map study provided a unique and objective perspective for the CAR-NK cell field. This information would provide a helpful reference for researchers interested in this field.

ObjectivesA bibliometric and knowledge-map analysis is used to explore hotspots’ evolution and development trends in the CAR-T cell field. By looking for research hotspots and new topics, we can provide new clues and ideas for researchers in this field.MethodsThe articles and reviews regarding CAR-T cells were retrieved and obtained from the Web of Science Core Collection (WOSCC) on October 28th, 2021. CtieSpace [version 5.8.R3 (64-bit)] and VOSviewer (version 1.6.17) were used to conduct the bibliometric and knowledge-map analysis.Results660 authors from 488 institutions in 104 countries/regions published 6,867 papers in 1,212 academic journals. The United States was absolutely in the leading position in this research field. The institution that contributed the most publications was the University of Pennsylvania. Carl H June published the most articles, while Shannon L Maude had the most co-citations. However, there was little cooperation between countries. After 2012, cooperation among various institutions was also small. The journals that published the most CAR-T cell-related papers were Frontiers in immunology and Cancers. Nevertheless, Blood and The New England Journal of Medicine were the most commonly co-cited journals. The most influential research hotspots were the research of CAR-T cells in hematological malignancies, the related research of cytokine release syndrome (CRS), CD19, and the anti-tumor activity and efficacy of CAR-T cells. The latest hotspots and topics included the study of CAR-T cells in solid tumors, universal CAR-T cells, CAR-NK cells, CD22, and anakinra (the IL-1 receptor antagonist). The research of CAR-T cells in solid tumors was a rapidly developing hot field. Emerging topics in this field mainly included the study of CAR-T cells in glioblastoma (related targets: IL13Rα2, EGFRvIII, and HER2), neuroblastoma (related target: GD2), sarcoma (related target: HER2), and pancreatic cancer (related target: mesothelin), especially glioblastoma.ConclusionAs an anti-tumor therapy with great potential and clinical application prospects, CAR-T cell therapy is still in a stage of rapid development. The related field of CAR-T cells will remain a research hotspot in the future.

Boron neutron capture therapy (BNCT) is a re-emerging therapy with the ability to selectively kill tumor cells. After the boron delivery agents enter the tumor tissue and enrich the tumor cells, the thermal neutrons trigger the fission of the boron atoms, leading to the release of boron atoms and then leading to the release of the α particles (4He) and recoil lithium particles (7Li), along with the production of large amounts of energy in the narrow region. With the advantages of targeted therapy and low toxicity, BNCT has become a unique method in the field of radiotherapy. Since the beginning of the last century, BNCT has been emerging worldwide and gradually developed into a technology for the treatment of glioblastoma multiforme, head and neck cancer, malignant melanoma, and other cancers. At present, how to develop and innovate more efficient boron delivery agents and establish a more accurate boron-dose measurement system have become the problem faced by the development of BNCT. We discuss the use of boron delivery agents over the past several decades and the corresponding clinical trials and preclinical outcomes. Furthermore, the discussion brings recommendations on the future of boron delivery agents and this therapy.

Chimeric antigen receptor (CAR) -T cell therapy has become one of the hot topics in tumor immunity research in recent years. Although CAR-T cell therapy is highly effective in treating hematological malignancies, there are numerous obstacles that prevent CAR-T cells from having anti-tumor effects. Traditional CARs, from the first to the fourth generation, are incapable of completely overcoming these challenges. Therefore, identifying ways to boost the efficacy of CAR-T cells by utilizing the limited tumor surface antigens has become an urgent area of research. Certain special CARs that have special structures, special systems, or are greatly improved on the basis of traditional CARs, such as tandem CAR, dual-signaling CARs, AND-gate CARs, inhibitory CAR, AND-NOT CARs, CARs with three scFvs, ON/OFF-switch CARs, and universal CARs have been introduced. This study aims to use these special CARs to improve the anti-tumor ability, accuracy, and safety of CAR-T cells. In addition to summarizing various special CARs of T cells, this paper also expounds some of our own conjectures, aiming to provide reference and inspiration for CARs researchers.

Hepatocellular carcinoma is one of the most common malignancies globally. It not only has a hidden onset but also progresses rapidly. Most HCC patients are already in the advanced stage of cancer when they are diagnosed, and have even lost the opportunity for surgical treatment. As an inflammation-related tumor, the immunosuppressive microenvironment of HCC can promote immune tolerance through a variety of mechanisms. Immunotherapy can activate tumor-specific immune responses, which brings a new hope for the treatment of HCC. At the present time, main immunotherapy strategies of HCC include immune checkpoint inhibitors, tumor vaccines, adoptive cell therapy, and so on. This article reviews the application and research progress of immune checkpoint inhibitors, tumor vaccines, and adoptive cell therapy in the treatment of HCC.

In recent years, chimeric antigen receptor T cells (CAR-T cells) have been faced with the problems of weak proliferation and poor persistence in the treatment of some malignancies. Researchers have been trying to perfect the function of CAR-T by genetically modifying its structure. In addition to the participation of T cell receptor (TCR) and costimulatory signals, immune cytokines also exert a decisive role in the activation and proliferation of T cells. Therefore, genetic engineering strategies were used to generate cytokines to enhance tumor killing function of CAR-T cells. When CAR-T cells are in contact with target tumor tissue, the proliferation ability and persistence of T cells can be improved by structurally or inductively releasing immunoregulatory molecules to the tumor region. There are a large number of CAR-T cells studies on gene-edited cytokines, and the most common cytokines involved are interleukins (IL-7, IL-12, IL-15, IL-18, IL-21, IL-23). Methods for the construction of gene-edited interleukin CAR-T cells include co-expression of single interleukin, two interleukin, interleukin combined with other cytokines, interleukin receptors, interleukin subunits, and fusion inverted cytokine receptors (ICR). Preclinical and clinical trials have yielded positive results, and many more are under way. By reading a large number of literatures, we summarized the functional characteristics of some members of the interleukin family related to tumor immunotherapy, and described the research status of gene-edited interleukin CAR-T cells in the treatment of malignant tumors. The objective is to explore the optimized strategy of gene edited interleukin-CAR-T cell function.

Chimeric antigen receptor (CAR) T-cell immunotherapy refers to an adoptive immunotherapy that has rapidly developed in recent years. It is a novel type of treatment that enables T cells to express specific CARs on their surface, then returns these T cells to tumor patients to kill the corresponding tumor cells. Significant strides in CAR-T cell immunotherapy against hematologic malignancies have elicited research interest among scholars in the treatment of solid tumors. Nonetheless, in contrast with the efficacy of CAR-T cell immunotherapy in the treatment of hematologic malignancies, its general efficacy against solid tumors is insignificant. This has been attributed to the complex biological characteristics of solid tumors. CAR-T cells play a better role in solid tumors, for instance by addressing obstacles including the lack of specific targets, inhibition of tumor microenvironment (TME), homing barriers of CAR-T cells, differentiation and depletion of CAR-T cells, inhibition of immune checkpoints, trogocytosis of CAR-T cells, tumor antigen heterogeneity, etc. This paper reviews the obstacles influencing the efficacy of CAR-T cell immunotherapy in solid tumors, their mechanism, and coping strategies, as well as economic restriction of CAR-T cell immunotherapy and its solutions. It aims to provide some references for researchers to better overcome the obstacles that affect the efficacy of CAR-T cells in solid tumors.

The application of chimeric antigen receptor (CAR) T-cell therapy as a tumor immunotherapy has received great interest in recent years. This therapeutic approach has been used to treat hematological malignancies solid tumors. However, it is associated with adverse reactions such as, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), off-target effects, anaphylaxis, infections associated with CAR-T-cell infusion (CTI), tumor lysis syndrome (TLS), B-cell dysplasia, hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) and coagulation disorders. These adverse reactions can be life-threatening, and thus they should be identified early and treated effectively. In this paper, we review the adverse reactions associated with CAR-T cells, the mechanisms driving such adverse reactions, and strategies to subvert them. This review will provide important reference data to guide clinical application of CAR-T cell therapy.