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The aim of this research is to use bibliometric analysis to investigate the status and patterns of the 100 most frequently cited publications regarding the cytotoxic T-lymphocyte-associated protein (CTLA-4) research for cancer. The articles published on the topic were retrieved from the core collection database of Web of Science and PubMed using the Medical Subject Heading (MeSH) of "CTLA-4" from 1986 to December 6, 2020. The selected articles were examined and the bibliometric data compiled based on the number of citations, the author's name, journal, publication year, institution, country, and co-occurrence keywords. 4,874 eligible papers were returned from the Web of Science Core Collection Database and PubMed. The citation frequency ranged from 2372 to 205, with a median of 460, and the top cited paper had 2372 citations. The journals with the most papers were Cell (n = 8, 3541 citations, Impact Factor (IF) = 41.577) and Journal of Experimental Medicine (n = 7, 2716 citations, IF = 10.790). Most of the published papers were from the United States of America (USA) (41.8%). A total of 485 institutes and 29 countries were involved in these 100 articles. There were 1192 authors and the author with the highest number of papers was the Nobel Prize winner, Professor James P. Allison (17 papers; 8700 citations). CTLA-4 blockade was the most frequent keyword (42.1%), followed by metastatic melanoma (4.26%). This work presents an important bibliographic source and can be saved as a reference for future medical health research on the function of CTLA-4 in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) cells express certain tumour-associated antigens (TAAs) that could serve as targets for active-specific immunotherapy. The aim of the present study was to test the MM/dendritic cell (DC) fusion as a vaccination strategy. We fused MM cells with DC to generate fusion cells (FCs) and tested their antigen presenting cell (APC) function in mixed lymphocyte reactions and cytotoxicity assays. First, the HS Sultan and SK0-007 HAT sensitive human MM cell lines and DCs generated from peripheral blood of normal donors were fused in the presence of 50% polyethylene glycol to form FCs. Next, tumour cells freshly isolated from patients were similarly fused with autologous DCs to generate FCs. The FCs demonstrated a biphenotypic profile, confirmed both by flow-cytometry and dual immunofluorescence microscopy. These FCs induced MM-specific cytotoxicity. FCs, but not MM cells or DCs alone, were potent stimulators of autologous patient T cells. More importantly, FC-primed autologous peripheral blood mononuclear cells demonstrated major histocompatibility complex-restricted MM-specific cytolysis. These studies therefore demonstrated that MM/DC FC can trigger an autologous immune response to MM cells and formed the framework for a clinical trial currently underway. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent advancements in cancer research have proven immunotherapies to be a promising strategy for the treatment of hematological malignancies. The bispecific antibody (BsAb) format was developed to overcome the issues of monoclonal antibody-based therapies. T-cell engagers (TCEs) are BsAbs, which directly activate T-cells and their anti-tumor features, ultimately resulting in the lysis of the targeted tumor cells. In 2014, the FDA approved blinatumomab for treatment of acute lymphoblastic leukemia. As of November 2023, seven clinically approved TCE therapies are on the market. In this paper, we summarized the technical basis of the TCE technology, its application in hematology, and its current issues and prospects. Recent advancements in cancer immunotherapy have made directing the cellular immune response onto cancer cells a promising strategy for the treatment of hematological malignancies. The introduction of monoclonal antibody-based (mAbs) targeted therapy has significantly improved the prognosis for hematological patients. Facing the issues of mAb-based therapies, a novel bispecific antibody (BsAb) format was developed. T-cell engagers (TCEs) are BsAbs, which simultaneously target tumor-associated antigens on tumor cells and CD3 molecules present on T-cells. This mechanism allows for the direct activation of T-cells and their anti-tumor features, ultimately resulting in the lysis of tumor cells. In 2014, the FDA approved blinatumomab, a TCE directed to CD3 and CD19 for treatment of acute lymphoblastic leukemia. Since then, numerous TCEs have been developed, allowing for treating different hematological malignancies such as acute myeloid leukemia, multiple myeloma, and non-Hodgkin lymphoma and Hodgkin lymphoma. As of November 2023, seven clinically approved TCE therapies are on the market. TCE-based therapies still have their limitations; however, improving the properties of TCEs, as well as combining TCE-based therapies with other forms of treatment, give hope to find the cures for currently terminal diseases. In this paper, we summarized the technical basis of the TCE technology, its application in hematology, and its current issues and prospects. [ABSTRACT FROM AUTHOR]

Simple Summary: This review explores the emerging area of the therapeutic use of chimeric antigen receptor (CAR)-T cells in nervous tissue tumors. Through a detailed analysis of the existing literature, this paper highlights the most recent applications of CAR-T cells to the therapy of pediatric and adult nervous system neoplasia. Furthermore, it discusses the potential mechanisms underlying sensitivity or resistance to CAR-T cell-based therapies. Overall, this review underscores the importance of CAR-T cell therapies to the treatment of some nervous system tumors. Chimeric antigen receptor T cells (CAR-Ts) have shown a remarkable efficacy in hematological malignancies but limited responses in solid tumors. Among solid tumors, CAR-T cell therapy has been particularly explored in brain tumors. CAR-T cells have shown a limited clinical efficacy in various types of brain tumors due to several factors that have hampered their activity, including tumor antigen heterogeneity, the limited access of CAR-T cells to brain tumor cells, limited CAR-T cell trafficking and in vivo persistence and the presence of a highly immunosuppressive tumor microenvironment. Despite these considerations, some recent studies have shown promising antitumor activity of GD2-CAR-T cells on diffuse midline gliomas and neuroblastomas and of CARv3-TEAM-E cells in glioblastomas. However, strategies are required to improve the effect of CAR-T cells in brain tumors, including advanced CAR-T cell design with multiple antigenic targeting and incorporation of combination therapies. [ABSTRACT FROM AUTHOR]

Background: Tumor immunotherapy can not only eliminate the primary lesion, but also produce long-term immune memory, effectively inhibiting tumor metastasis and recurrence. However, immunotherapy also showed plenty of limitations in clinical practice. In recent years, the combination of nanomaterials and immunotherapy has brought new light for completely eliminating tumors with its fabulous anti-tumor effects and negligible side effects. Methods: The Core Collection of Web of Science (WOSCC) was used to retrieve and obtain relevant literatures on antitumor nano-immunotherapy since the establishment of the WOSCC. Bibliometrix, VOSviewer, CiteSpace, GraphPad Prism, and Excel were adopted to perform statistical analysis and visualization. The annual output, active institutions, core journals, main authors, keywords, major countries, key documents, and impact factor of the included journals were evaluated. Results: A total of 443 related studies were enrolled from 2004 to 2022, and the annual growth rate of articles reached an astonishing 16.85%. The leading countries in terms of number of publications were China and the United States. Journal of Controlled Release, Biomaterials, Acta Biomaterialia, Theranostics, Advanced Materials, and ACS Nano were core journals publishing high-quality literature on the latest advances in the field. Articles focused on dendritic cells and drug delivery accounted for a large percentage in this field. Key words such as regulatory T cells, tumor microenvironment, immune checkpoint blockade, drug delivery, photodynamic therapy, photothermal therapy, tumor-associated macrophages were among the hottest themes with high maturity. Dendritic cells, vaccine, and T cells tend to become the popular and emerging research topics in the future. Conclusions: The combined treatment of nanomaterials and antitumor immunotherapy, namely antitumor nano-immunotherapy has been paid increasing attention. Antitumor nano-immunotherapy is undergoing a transition from simple to complex, from phenotype to mechanism. [ABSTRACT FROM AUTHOR]

CAR-T cell therapy offers a promising way for prolonged cancer remission, specifically in the case of blood cancers. However, its application in the treatment of solid tumors still faces many limitations. This review paper provides a comprehensive overview of the challenges and strategies associated with CAR-T cell therapy for solid tumors, with a focus on gynecological cancer. This study discusses the limitations of CAR-T therapy for solid tumor treatment, such as T cell exhaustion, stromal barrier, and antigen shedding. Additionally, it addresses possible approaches to increase CAR-T efficacy in solid tumors, including combination therapies with checkpoint inhibitors and chemotherapy, as well as the novel approach of combining CAR-T with oncolytic virotherapy. Given the lack of comprehensive research on CAR-T combination therapies for treating gynecological cancers, this review aims to provide insights into the current landscape of combination therapies for solid tumors and highlight the potential of such an approach in gynecology. [ABSTRACT FROM AUTHOR]

Objective: Multiple myeloma (MM) is a bone marrow cancer that profoundly affects plasma cells involved in the immune response. Myeloma cells alter the average production of cells in the bone marrow. Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy allows genetic modifications of an individual's T-cells to increase the expression of CARs used to identify and attach BCMA proteins to the malignant cells. Our main objective is to perform a systematic review and meta-analysis to explore the efficacy and safety of anti-BCMA CAR T-cell therapy for MM. Material and Methods: We searched five databases, PubMed, CNKI, EMBASE, Cochrane, Web of Science, and CNKI, for studies published on anti-BCMA,CAR-T-cell treatment for MM. Inclusion criteria involved prospective single-arm studies either single or multi-center, in various MM phases and studies that reported anti-BCMA,CAR-T-cell treatment for MM. We excluded non-English publications and conference papers. All statistical analyses were performed in R software and Review Manager 5.4.1. Results: Thirteen articles were included in the analysis. We found that the overall response survival complete response increase was statistically significant. Similarly, the reduction in cytokine release syndrome grades 3 and 4 and neurotoxicity after follow-up was statistically significant. However, the reduction in minimal residual disease negativity (MRDN) was not statistically significant. Conclusion: Using anti-BCMA CAR T-cell therapy in MM was highly efficacious and safe in lowering the adverse outcomes and improving the survival outcomes, complete response, and overall response. [ABSTRACT FROM AUTHOR]

Efforts to treat cancer using chimeric antigen receptor (CAR)-T therapy have made astonishing progress and clinical trials against hematopoietic malignancies have demonstrated their use. However, there are still disadvantages which need to be addressed: high costs, and side effects such as Graft-versus-Host Disease (GvHD) and Cytokine Release Syndrome (CRS). Therefore, recent efforts have been made to harness the properties of certain immune cells to treat cancer—not just T cells, but also natural killer (NK) cells, macrophages (Mφ), dendritic cells (DC), etc. In this paper, we will introduce immune cell-based cellular therapies that use various immune cells and describe their characteristics and their clinical situation. The development of immune cell-based cancer therapy fully utilizing the unique advantages of each and every immune cell is expected to enhance the survival of tumor patients owing to their high efficiency and fewer side effects. [ABSTRACT FROM AUTHOR]

Cancer is a worldwide health problem. Nevertheless, new technologies in the immunotherapy field have emerged. Chimeric antigen receptor (CAR) technology is a novel biological form to treat cancer; CAR-T cell genetic engineering has positively revolutionized cancer immunotherapy. In this paper, we review the latest developments in CAR-T in cancer treatment. We present the structure of the different generations and variants of CAR-T cells including TRUCK (T cells redirected for universal cytokine killing. We explain the approaches of the CAR-T cells manufactured ex vivo and in vivo. Moreover, we describe the limitations and areas of opportunity for this immunotherapy and the current challenges of treating hematological and solid cancer using CAR-T technology as well as its constraints and engineering approaches. We summarize other immune cells that have been using CAR technology, such as natural killer (NK), macrophages (M), and dendritic cells (DC). We conclude that CAR-T cells have the potential to treat not only cancer but other chronic diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy targeting immune checkpoints and stromal cells in the tumor microenvironment is currently one of the most promising directions for tumor therapy. Ongoing studies suggest that CD73 plays an important role in the tumor immune process in certain tumors, however, the exact mechanism is unknown. We aim to fully reveal the prognostic value of CD73 in pan-cancer and its role in tumor immunity through large-scale single-cell and bulk sequencing analysis. We found that high CD73 expression was significantly associated with poor prognosis in many tumors. It is also strongly associated with immune scores, stromal cell infiltration, and immune-related pathways. CD73 can regulate the biological behavior of immune cells in the tumor microenvironment, especially macrophages and T cells. Immunotherapy targeting CD73 has obvious effects, and CD73 may shine as a new immune checkpoint in future tumor immunotherapy. CD73 is essential in promoting tumor growth by prohibiting anti-tumor immunity in many cancer types. While the mechanism remains largely unknown, our paper comprehensively confirmed the onco-immunological characteristics of CD73 in the tumor microenvironment (TME) of pan-cancer. This paper explored the expression pattern, mutational profile, prognostic value, tumor immune infiltration, and response to immunotherapy of CD73 in a continuous cohort of cancers through various computational tools. The co-expression of CD73 on cancer cells, immune cells, and stromal cells in the TME was also detected. Especially, we examined the correlation between CD73 and CD8+ (a marker of T cell), CD68+ (a marker of macrophage), and CD163+ (a marker of M2 macrophage) cells using multiplex immunofluorescence staining of tissue microarrays. CD73 expression is significantly associated with a patient's prognosis and could be a promising predictor of these cancers. High CD73 levels are strongly linked to immune infiltrations, neoantigens, and immune checkpoint expression in the TME. In particular, enrichment signaling pathway analysis demonstrated that CD73 was obviously related to activation pathways of immune cells, including T cells, macrophages, and cancer-associated fibroblasts (CAFs). Meanwhile, single-cell sequencing algorithms found that CD73 is predominantly co-expressed on cancer cells, CAFs, M2 macrophages, and T cells in several cancers. In addition, we explored the cellular communication among 14 cell types in glioblastoma (GBM) based on CD73 expression. Based on the expression of CD73 as well as macrophage and T cell markers, we predicted the methylation and enrichment pathways of these markers in pan-cancer. Furthermore, a lot of therapeutic molecules sensitive to these markers were predicted. Finally, potential anticancer inhibitors, immunotherapies, and gene therapy responses targeting CD73 were identified from a series of immunotherapy cohorts. CD73 is closely linked to clinical prognosis and immune infiltration in many cancers. Targeting CD73-dependent signaling pathways may be a promising therapeutic strategy for future tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Immunohistochemical staining is a common technique to study tissue morphology and in situ protein expression. With the rise of immunotherapy, more and more markers in the tumor microenvironment have been discovered. In this paper, the multiplex immunofluorescence staining method was used to stain paraffin sections of 35 cases of gastric adenocarcinoma tissue and 35 cases of colorectal adenocarcinoma tissue and its adjacent tissue. The infiltration of CD8+ T cells and CD103+CD8+ T cells in the slices was detected by using the slice scanner to form the map and CaseViewer2.0 software analysis. The experimental results in this paper showed that compared with adjacent tissues, the infiltration degree of CD8+ T cells in gastric adenocarcinoma tissue was significantly lower (Z = 2.244 , P = 0.025 , P < 0.05), and the infiltration degree of cells was significantly lower (Z = 2.785 , P = 0.005 , P < 0.05). In gastric adenocarcinoma tissue, the infiltration of CD8+ T cells was correlated with the tumor diameter of gastric adenocarcinoma (P = 0.002). There was a statistically significant difference. The degree of CD103+CD8+ T cell infiltration was related to the survival of patients with gastric adenocarcinoma (P = 0.002) and the degree of tumor differentiation (P = 0.004). The infiltration of CD103+CD8+ T cells in gastric cancer tissue and colorectal cancer tissue is related to the survival of patients. CD103+CD8+ T cells are thought to play a role in the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma. Experiments have shown that the more the CD103+CD8+ T cells, the better the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma, so the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma can be improved by increasing CD103+CD8+ T cells. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "glioblastomas," "immunotherapies," and "treatment." The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell infiltration, extracellular matrix (ECM) degradation, and vascular smooth muscle cell (SMC) dysfunction. The inflammatory cells involved in AAA mainly include immune cells including macrophages, neutrophils, T-lymphocytes and B lymphocytes and endothelial cells. As the blood vessel wall expands, more and more lymphocytes infiltrate into the outer membrane. It was found that more than 50% of lymphocytes in AAA tissues were CD3+ T cells, including CD4+, CD8+T cells, gd T cells and regulatory T cells (Tregs). Due to the important role of T cells in inflammatory response, an increasing number of researchers have paid attention to the role of T cells in AAA and dug into the relevant mechanism. Therefore, this paper focuses on reviewing the immunoregulatory role of T cells in AAA and their role in immunotherapy, seeking potential targets for immunotherapy and putting forward future research directions. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) plays an important role in the development of tumors. Immunoregulatory cells and cytokines facilitate cancer cells to avoid immune surveillance. Overexpression of immune checkpoint molecules such as CTLA-4 and PD-1/PD-L1 inhibits immune function and enables cancer cells to avoid clearance by the immune system. Thus, minimizing tumor immunosuppression could be an important strategy for cancer therapy. Currently, many immune checkpoint-targeted drugs, such as PD-1/PD-L1 inhibitors, have been approved for marketing and have shown unique advantages in the clinical treatment of cancers. The concept of "strengthening resistance to eliminate pathogenic factors" in traditional Chinese medicine (TCM) is consistent with the immunotherapy of cancer. According to previous studies, the role of TCM in tumor immunotherapy is mainly associated with the positive regulation of natural killer cells, CD8/CD4 T cells, dendritic cells, M2 macrophages, interleukin-2, tumor necrosis factor- α , and IFN- γ , as well as with the negative regulation of Tregs, myeloid-derived suppressor cells, cancer-associated fibroblasts, PD-1/PD-L1, transforming growth factor- β , and tumor necrosis factor- β. This paper summarizes the current research on the effect of TCM targeting the TME, and further introduces the research progress on studying the effects of TCM on immune checkpoints. Modern pharmacological studies have demonstrated that TCM can directly or indirectly affect the TME by inhibiting the overexpression of immune checkpoint molecules and enhancing the efficacy of tumor immunotherapy. TCM with immunomodulatory stimulation could be the key factor to achieve benefits from immunotherapy for patients with non-inflammatory, or "cold", tumors. [ABSTRACT FROM AUTHOR]

Tumor immunotherapy, represented by immune checkpoint blocking and chimeric antigen receptor (CAR) T cell therapy, has achieved promising results in clinical applications. However, it faces challenges that hinder its further development, such as limited response rates and poor tumor permeability. The efficiency of tumor immunotherapy is also closely linked to the structure and function of the immune microenvironment where the tumor resides. Recently, nanoparticle‐based tumor immune microenvironment (TIME) modulation strategies have attracted a great deal of attention in cancer immunotherapy. This is primarily due to the distinctive physical characteristics of nanoparticles, which enable them to effectively infiltrate the TIME and selectively modulate its key constituents. This paper reviews recent advances in nanoparticle engineering to improve anti‐cancer immunotherapy. Emerging nanoparticle‐based approaches for modulating immune cells, tumor stroma, cytokines and immune checkpoints are discussed, aiming to overcome current challenges in the clinic. In addition, integrating immunotherapy with various treatment modalities such as chemotherapy and photodynamic therapy can be facilitated through the utilization of nanoparticles, thereby enhancing the efficacy of cancer treatment. The future challenges and opportunities of using nanomaterials to reeducate the suppressive immune microenvironment of tumors are also discussed, with the aim of anticipating further advancements in this growing field. [ABSTRACT FROM AUTHOR]

The recognition of smoking as an independent risk factor for lung cancer has become a widely accepted within the realm of respiratory medicine. The emergence of tumor immunotherapy has notably enhanced the prognosis for numerous late-stage cancer patients. Nevertheless, some studies have noted a tendency for lung cancer patients who smoke to derive greater benefit from immunotherapy. This observation has sparked increased interest in the interaction between smoking and the immune response to tumors in lung cancer. The concept of cancer immunoediting has shed light on the intricate and nuanced relationship between the immune system and tumors. Starting from the perspectives of immune surveillance, immune equilibrium, and immune evasion, this narrative review explores how smoking undermines the immune response against tumor cells and induces the generation of tumor neoantigens, and examines other behaviors that trigger tumor immune evasion. By elucidating these aspects, the review concludes that smoking is not conducive to tumor immunoediting. [ABSTRACT FROM AUTHOR]

Immunotherapy using immune checkpoint inhibitors (ICIs) has shown superior efficacy compared with conventional chemotherapy in certain cancer types, establishing immunotherapy as the fourth standard treatment alongside surgical intervention, chemotherapy, and radiotherapy. In cancer immunotherapy employing ICIs, CD8‐positive cytotoxic T lymphocytes are recognized as the primary effector cells. For effective clinical outcomes, it is essential that the targeted cancer cells express HLA class I molecules to present antigenic peptides derived from the tumor. However, cancer cells utilize various mechanisms to downregulate or lose HLA class I molecules from their surface, resulting in evasion from immune surveillance. Correlations between prognosis and the integrity of HLA class I molecules expressed by cancer cells have been consistently found across different types of cancer. This paper provides an overview of the regulatory mechanisms of HLA class I molecules and their role in cancer immunotherapy, with a particular emphasis on the significance of utilizing pathological tissues to evaluate HLA class I molecules expressed in cancer cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Cell therapy approaches, including adoptive cell therapy with engineered T cells remains challenging in the clinical setting of solid tumors. Clinical results have not been encouraging so far, with a general lack of significant therapeutic response and presence of on-target off-tumor toxicity. For this reason, novel cell therapy programs are currently exploring (i) advanced therapy medicinal products capable of increasing T cell affinity or avidity; and (ii) cell therapy in combination with other therapeutic agents. Our review will focus on the current clinical research in this setting, which will likely play a role in improving cancer treatment outcomes in the near future. In the past years cancer treatments have drastically changed, mainly due to the development of immune checkpoint inhibitors capable of immune modulation in vivo, thus providing major clinical benefit in a number of malignancies. Simultaneously, considerable technical refinements have opened new prospects for the development of immune cell-based medicinal products and unprecedented success with chimeric antigen receptor (CAR)-T cells targeting B-cell hematologic malignancies has been obtained. However, T cell therapies introduced and performed in the field of solid tumors have produced so far only limited responses in selected patient populations. This standstill is attributable to the difficulty in identifying target antigens which are homogeneously expressed by all tumor cells while absent from normal tissues, and the limited T cell persistence and proliferation in a hostile tumor microenvironment that favors immune escape. Replicating the results observed in hematology is a major scientific challenge in solid tumors, and ongoing translational and clinical research is focused on obtaining insight into the mechanisms of tumor recognition and evasion, and how to improve the efficacy of cellular therapies, also combining them with immune checkpoint inhibitors or other agents targeting either the cancer cell or the tumor environment. This paper provides an overview of current adaptive T cell therapy approaches in solid tumors, the research performed to increase their efficacy and safety, and results from ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most prevalent cerebral cancer in adults without proven therapy. Chimeric antigen receptor T cell treatment has demonstrated good clinical success in hematologic cancers. The application of chimeric antigen receptor T cell therapy to solid tumors, such as glioblastoma, is currently the subject of scientific investigation. The creation of chimeric antigen receptor T cells and its iterations are briefly described in this article. Specifically, this study addresses the obstacles and hurdles faced and glioblastoma targets studied in recent years. This review provides the reader with a comprehensive understanding of the current state of chimeric antigen receptor T cell therapy for glioblastoma and a clear understanding of each therapeutic target. Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis following conventional therapeutic interventions. Moreover, the blood–brain barrier (BBB) severely impedes the permeation of chemotherapy drugs, thereby reducing their efficacy. Consequently, it is essential to develop novel GBM treatment methods. A novel kind of pericyte immunotherapy known as chimeric antigen receptor T (CAR-T) cell treatment uses CAR-T cells to target and destroy tumor cells without the aid of the antigen with great specificity and in a manner that is not major histocompatibility complex (MHC)-restricted. It has emerged as one of the most promising therapy techniques with positive clinical outcomes in hematological cancers, particularly leukemia. Due to its efficacy in hematologic cancers, CAR-T cell therapy could potentially treat solid tumors, including GBM. On the other hand, CAR-T cell treatment has not been as therapeutically effective in treating GBM as it has in treating other hematologic malignancies. CAR-T cell treatments for GBM have several challenges. This paper reviewed the use of CAR-T cell therapy in hematologic tumors and the selection of targets, difficulties, and challenges in GBM. [ABSTRACT FROM AUTHOR]

Simple Summary: Every year, cervical cancer affects more than 500,000 women worldwide. The persistent infection caused by the human papillomavirus (HPV) is the main risk factor for the development of this type of cancer. Conventional treatments for cervical cancer are often associated with resistance and side effects. Therefore, it is necessary to find new targets for the development of more effective therapeutic approaches. In recent years, an increasing number of studies have been concerned with developing immunotherapeutic strategies for treating cancer. Thus, it is important to investigate new targets, such as the various molecules and cells that are involved in the cancer-immunity cycle (CIC). This process consists of the release of cancer antigens and their destruction by cytotoxic T-cells. Hence, in this review, we discuss the molecular changes that occur at each stage of the CIC for cervical cancer, including the impact of variables such as histological subtype and HPV infection. Moreover, we explore the latest immunotherapeutic approaches that have been adopted, together with their benefits and limitations. In this scenario, current studies are opening up new horizons in clinical practice for a personalized treatment of cervical cancer. Cervical cancer (CC) is the fourth most common cancer in women worldwide, with more than 500,000 new cases each year and a mortality rate of around 55%. Over 80% of these deaths occur in developing countries. The most important risk factor for CC is persistent infection by a sexually transmitted virus, the human papillomavirus (HPV). Conventional treatments to eradicate this type of cancer are accompanied by high rates of resistance and a large number of side effects. Hence, it is crucial to devise novel effective therapeutic strategies. In recent years, an increasing number of studies have aimed to develop immunotherapeutic methods for treating cancer. However, these strategies have not proven to be effective enough to combat CC. This means there is a need to investigate immune molecular targets. An adaptive immune response against cancer has been described in seven key stages or steps defined as the cancer-immunity cycle (CIC). The CIC begins with the release of antigens by tumor cells and ends with their destruction by cytotoxic T-cells. In this paper, we discuss several molecular alterations found in each stage of the CIC of CC. In addition, we analyze the evidence discovered, the molecular mechanisms and their relationship with variables such as histological subtype and HPV infection, as well as their potential impact for adopting novel immunotherapeutic approaches. [ABSTRACT FROM AUTHOR]

Oncolytic ability to direct target and lyse tumor cells makes oncolytic virus therapy (OVT) a promising approach to treating cancer. Despite its therapeutic potential to stimulate anti-tumor immune responses, it also has immunosuppressive effects. The efficacy of OVTs as monotherapies can be enhanced by appropriate adjuvant therapy such as anti-CTLA-4. In this paper, we propose a mathematical model to explore the interactions of combined therapy of oncolytic viruses and a checkpoint inhibitor, anti-CTLA-4. The model incorporates both the susceptible and infected tumor populations, natural killer cell population, virus population, tumor-specific immune populations, virus-specific immune populations, tumor suppressive cytokine IFN-g, and the effect of immune checkpoint inhibitor CTLA-4. In particular, we distinguish the tumor-specific immune abilities of CD8+ T, NK cells, and CD4+ T cells and describe the destructive ability of cytokine on tumor cells as well as the inhibitory capacity of CTLA-4 on various components. Our model is validated through the experimental results. We also investigate various dosing strategies to improve treatment outcomes. Our study reveals that tumor killing rate by cytokines, cytokine decay rate, and tumor growth rate play important roles on both the OVT monotherapy and the combination therapy. Moreover, parameters related to CD8+ T cell killing have a large impact on treatment outcomes with OVT alone, whereas parameters associated with IFN-g strongly influence treatment responses for the combined therapy. We also found that virus killing by NK cells may halt the desired spread of OVs and enhance the probability of tumor escape during the treatment. Our study reveals that it is the activation of host anti-tumor immune system responses rather than its direct destruction of the tumor cells plays a major biological function of the combined therapy. [ABSTRACT FROM AUTHOR]

Whether prostate brachytherapy (BT) results in opportunistic biological changes that can improve clinical outcomes is not well studied. We sought to investigate the impact of prostate BT on the immune system. A scoping review was performed using PubMed/Scopus for papers published between 2011-2021. Search terms were "brachytherapy" AND "immune" AND "prostate". A total of 81 records were identified and 6 were selected for further review. 2 low-dose-rate BT papers (n=68) evaluated changes in the peripheral blood following I-125 monotherapy. Both showed significant increases in peripheral CD3+ and CD4+ T cells post-BT. One also demonstrated significant increases in Treg subsets up to 150 days post-BT. 4 high-dose-rate (HDR) studies (n=37) were identified, and all were done in combination with EBRT. The largest study (n=24) showed a single 10 Gy fraction of HDR converted 80% of "cold" tumors into an "intermediate" or "hot" state, based on a tumor inflammation signature when comparing a pre-BT biopsy to one prior to a second HDR fraction. Prostate BT can invoke an immune activating phenotype; however, changes in immunosuppressive cells are also seen. Additional data is needed to understand how to promote synergy between BT and the immune system. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer in the head and neck region (HNSCC) is exponentially increasing due to human papillomavirus (HPV) infections. This paper helps us to understand the complexity of the inflammatory networks and the mechanisms of immune evasion in HPV+ HNSCC to open up new avenues and drive the discovery of useful tools to be translated clinically in the screening and treatment of these cases, especially to overcome resistance and improve patients' quality of life. Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignancies which have shown exponential incidence in the last two decades especially due to human papillomavirus (HPV) infection. The HPV family comprises more than 100 types of viruses with HPV16 and HPV18 being the most prevalent strains in HNSCC. Literature data reveal that the mutation profile as well as the response to chemotherapy and radiotherapy are distinct among HPV+ versus HPV-negative tumors. Furthermore, the presence of the virus induces activation of an immune response, in particular the recruitment of specific antiviral T lymphocytes to tumor sites. These T cells when activated produce soluble factors including cytokines and chemokines capable of modifying the local immune tumor microenvironment and impact on tumor response to the treatment. In this comprehensive review we investigated current knowledge on how the presence of an HPV can modify the inflammatory response systemically and within the tumor microenvironment's immunological responses, thereby impacting on disease prognosis and survival. We highlighted the research gaps and emerging approaches necessary to discover novel immunotherapeutic targets for HPV-associated HNSCC. [ABSTRACT FROM AUTHOR]

Objectives: This paper reviews current and emerging therapies for multiple myeloma (MM). Methods: Narrative review. Results: MM is a complex, heterogenous condition, and in recent years there has been an expansion in the number and range of treatments. Several new treatment approaches, including enhanced monoclonal antibodies, antibody‐drug conjugates, bispecific T‐cell engagers, and chimeric antigen‐T‐cell therapy are under development. Conclusions: The emergence of new treatments that aim to tackle MM‐associated immune dysfunction has led to improvements in overall survival. [ABSTRACT FROM AUTHOR]

Objective: This paper aimed to investigate the PI3K/Akt/mTOR signal-pathway regulator factor-related lncRNA signatures (PAM-SRFLncSigs), associated with regulators of the indicated signaling pathway in patients with lung adenocarcinoma (LUAD) undergoing immunotherapy. Materials and Methods: In this retrospective study, we employed univariate Cox, multivariate Cox, and least absolute shrinkage and selection operator (LASSO) regression analyses to identify prognostically relevant long non-coding RNAs (lncRNAs), construct prognostic models, and perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Subsequently, immunoassay and chemotherapy drug screening were conducted. Finally, the prognostic model was validated using the Imvigor210 cohort, and tumor stem cells were analyzed. Results: We identified seven prognosis-related lncRNAs (AC084757.3, AC010999.2, LINC02802, AC026979.2, AC024896.1, LINC00941 and LINC01312). We also developed prognostic models to predict survival in patients with LUAD. KEGG enrichment analysis confirmed association of LUAD with the PI3K/Akt/mTOR signaling pathway. In the analysis of immune function pathways, we discovered three good prognostic pathways (Cytolytic_activity, Inflammation-promoting, T_cell_co-inhibition) in LUAD. Additionally, we screened 73 oncology chemotherapy drugs using the "pRRophetic" algorithm. Conclusion: Identification of seven lncRNAs linked to regulators of the PI3K/Akt/mTOR signaling pathway provided valuable insights into predicting the prognosis of LUAD, understanding the immune microenvironment and optimizing immunotherapy strategies. [ABSTRACT FROM AUTHOR]

Background: Based on molecular biomarkers, anti-angiogenic drugs in combination with programmed cell death protein 1 (PD-1) antibodies can screen the potentially beneficial populations with hepatocellular carcinoma (HCC) and predict the efficacy after treatment. Therefore, we aimed to study predictive molecular biomarkers to improve the effectiveness of immuno-targeted combination therapy for HCC. Patients and Methods: Baseline clinical data, blood samples, and imaging data of the first evaluation after two cycles of treatment were collected for 40 patients with advanced HCC who underwent combination therapy, and then these data were compared according to the efficacy. Since 15 patients had complete hematology samples, we additionally tested the T lymphocyte subpopulations of these 15 patients and also compared them according to the efficacy. In addition, we also selected five patients who benefited the most from the combination therapy and five patients with the worst curative effect for gene detection based on survival time and efficacy evaluation. Finally, the relationship between certain clinical characteristics, laboratory indicators, specific T lymphocyte subpopulations, gene mutations and the response of immuno-targeted combination therapy for HCC was evaluated. Results: The high levels of CD3+CD4+CD279+, CD3+CD8+CD45RO+CD62L+T lymphocytes and tumor mutational burden (TMB) were associated with good efficacy of the combination therapy (P=0.03, P<0.01 and P=0.03). The high levels of CD3+CD4+CD28+ T lymphocytes were associated with poor efficacy of the combination therapy (P=0.02). The high mutation frequency of TP53 and ARID1A appeared in the non-response cohort. In addition, amplification mutation of 11q13- CCND1, FGF3, FGF4, and FGF19 was found in a patient with hyperprogression (HP). Conclusions: The certain clinical characteristics, laboratory indicators, specific T lymphocyte subpopulations, and gene mutations established in this paper were potential predictive biomarkers for HCC patients treated with combination therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Primary liver cancer, also known as Hepatocellular carcinoma (HCC), is considered to be a major global health challenge. Due to delays in diagnosis at early asymptomatic stages, HCC reaches a severe aggressive stage, thereby having a significant negative impact on patient survival. In addition, HCC shows marked resistance to conventional cancer treatments such as chemo- and radiotherapy. A variety of new and advanced therapies are continuously being evaluated to acquire a breakthrough in HCC treatment to enhance overall and recurrence-free survival. Appropriate identification and selection of target genes and utilization of safe and effective therapeutic approaches, such as gene therapy or immunotherapy, are key strategies for the effective treatment for HCC. This review paper intends to provide a perspective on emerging approaches as avenues towards more effective and safer therapies for HCC. Hepatocellular carcinoma (HCC) arises from hepatocytes and accounts for 90% of primary liver cancer. According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, globally HCC is the sixth most common cancer and the third most common cause of cancer-related deaths. Reasons for HCC prognosis remaining dismal are that HCC is asymptomatic in its early stages, leading to late diagnosis, and it is markedly resistant to conventional chemo- and radiotherapy. Liver transplantation is the treatment of choice in early stages, while surgical resection, radiofrequency ablation (RFA) and trans arterial chemoembolization (TACE) are Food and Drug Administration (FDA)-approved treatments for advanced HCC. Additional first line therapy for advanced HCC includes broad-spectrum tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, as well as a combination of immunotherapy and anti-angiogenesis therapy, namely atezolizumab and bevacizumab. However, these strategies provide nominal extension in the survival curve, cause broad spectrum toxic side effects, and patients eventually develop therapy resistance. Some common mutations in HCC, such as in telomerase reverse transcriptase (TERT), catenin beta 1 (CTNNB1) and tumor protein p53 (TP53) genes, are still considered to be undruggable. In this context, identification of appropriate gene targets and specific gene delivery approaches create the potential of gene- and immune-based therapies for the safe and effective treatment of HCC. This review elaborates on the current status of HCC treatment by focusing on potential gene targets and advanced techniques, such as oncolytic viral vectors, nanoparticles, chimeric antigen receptor (CAR)-T cells, immunotherapy, and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), and describes future prospects in HCC treatment. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy is an effective treatment option against cancer. One of the approaches of cancer immunotherapy is the modification of T cell-based anti-tumor immune responses. T-cells, a type of adaptive immune response cells responsible for cell-mediated immunity, have long been recognized as key regulators of immune-mediated anti-tumor immunity. T-cell activities have been reported to be suppressed or enhanced by changes in cell metabolism. Moreover, metabolic reprogramming during activation of T cells is required for the development of distinct differentiation profiles of these cells, which may allow the development of long-term cell-mediated anti-tumor immunity. However, T cells have been shown to undergo metabolic exhaustion in tumor microenvironment (TME) as it poses several obstacles to their function. Applications of several mechanistic solutions to improve the efficacy of T cell-based therapies including chimeric antigen receptor (CAR) T cell therapy are yet to be determined. Modifying the metabolic properties of these cells and employing them in cancer immunotherapy is a potential strategy for improving their anti-tumor activity and therapeutic efficacy. To give an insight, in this review paper, we endeavoured to cover metabolic reprogramming in cancer and T cells, signalling mechanisms involved in immuno-metabolic regulation, the effects of the TME on T cell metabolic fitness, and targeting metabolic reprogramming of T cells for an enhanced anti-tumor response. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-expressing T-cells are without a doubt a breakthrough therapy for hematological malignancies. Despite their success, clinical experience has revealed several challenges, which include relapse after targeting single antigens such as CD19 in the case of B-cell acute lymphoblastic leukemia (B-ALL), and the occurrence of side effects that could be severe in some cases. Therefore, it became clear that improved safety approaches, and targeting multiple antigens, should be considered to further improve CAR T-cell therapy for B-ALL. In this paper, we address both issues by investigating the use of CD10 as a therapeutic target for B-ALL with our switchable UniCAR system. The UniCAR platform is a modular platform that depends on the presence of two elements to function. These include UniCAR T-cells and the target modules (TMs), which cross-link the T-cells to their respective targets on tumor cells. The TMs function as keys that control the switchability of UniCAR T-cells. Here, we demonstrate that UniCAR T-cells, armed with anti-CD10 TM, can efficiently kill B-ALL cell lines, as well as patient-derived B-ALL blasts, thereby highlighting the exciting possibility for using CD10 as an emerging therapeutic target for B-cell malignancies. [ABSTRACT FROM AUTHOR]

Background: Clinical studies have shown that the efficacy of programmed cell death receptor-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors on glioblastoma (GBM) is much lower than what is expected because of the low immunogenicity of GBM. Ferroptosis of cancer cells can induce the maturation of dendritic cells (DC cells) and increase the activity of T cell. The activated T cells release IFN-γ, which subsequently induces the ferroptosis of cancer cells. Thus, the aim of this paper is to set up a new GBM-targeted drug delivery system (Fe3O4-siPD-L1@M-BV2) to boost ferroptosis for immunotherapy of drug-resistant GBM. Results: Fe3O4-siPD-L1@M-BV2 significantly increased the accumulation of siPD-L1 and Fe2+ in orthotopic drug-resistant GBM tissue in mice. Fe3O4-siPD-L1@M-BV2 markedly decreased the protein expression of PD-L1 and increased the ratio between effector T cells and regulatory T cells in orthotopic drug-resistant GBM tissue. Moreover, Fe3O4-siPD-L1@M-BV2 induced ferroptosis of GBM cells and maturation of DC cell, and it also increased the ratio between M1-type microglia and M2-type microglia in orthotopic drug-resistant GBM tissue. Finally, the growth of orthotopic drug-resistant GBM in mice was significantly inhibited by Fe3O4-siPD-L1@M-BV2. Conclusion: The mutual cascade amplification effect between ferroptosis and immune reactivation induced by Fe3O4-siPD-L1@M-BV2 significantly inhibited the growth of orthotopic drug-resistant GBM and prolonged the survival time of orthotopic drug-resistant GBM mice. [ABSTRACT FROM AUTHOR]

Certain innovative technologies applied to medical product development require novel evaluation approaches and/or regulations. Horizon scanning for such technologies will help regulators prepare, allowing earlier access to the product for patients and an improved benefit/risk ratio. This study investigates whether citation network analysis and text mining of scientific papers could be a tool for horizon scanning in the field of immunology, which has developed over a long period, and attempts to grasp the latest research trends. As the result of the analysis, the academic landscape of the immunology field was identified by classifying 90,450 papers (obtained from PubMED) containing the keyword "immune* and t lymph*" into 38 clusters. The clustering was indicative of the research landscape of the immunology field. To confirm this, immune checkpoint inhibitors were used as a retrospective test topic of therapeutics with new mechanisms of action. Retrospective clustering around immune checkpoint inhibitors was found, supporting this approach. The analysis of the research trends over the last 3 to 5 years in this field revealed several candidate topics, including ARID1A gene mutation, CD300e, and tissue resident memory T cells, which shows notable progress and should be monitored for future possible product development. Our results have demonstrated the possibility that citation network analysis and text mining of scientific papers can be a useful objective tool for horizon scanning of life science fields such as immunology. [ABSTRACT FROM AUTHOR]

As an emerging technology, low-temperature plasma (LTP) is widely used in medical fields such as sterilization, wound healing, stomatology, and cancer treatment. Great achievements have been made in tumor therapy. In vitro and in vivo studies have shown that LTP has anti-tumor effects, and LTP is selective to tumor cells. Studies in recent years have found that LTP can activate dendritic cells (DC), macrophages, T cells, and other immune cells to achieve anti-tumor effects. This paper reviews the current status of tumor immunotherapy, the application of LTP in antitumor therapy, the activation of antitumor immunity by LTP, the possible mechanism of LTP in antitumor immunity, and meanwhile analyses the prospect of applying LTP in tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Programmed death protein 1 (PD1) is a common immunosuppressive member on the surface of T cells and plays an imperative part in downregulating the immune system and advancing self-tolerance. Its ligand programmed cell death ligand 1 (PDL1) is overexpressed on the surface of malignant tumor cells, where it binds to PD1, inhibits the proliferation of PD1-positive cells, and participates in the immune evasion of tumors leading to treatment failure. The PD1/PDL1-based pathway is of great value in immunotherapy of cancer and has become an important immune checkpoint in recent years, so understanding the mechanism of PD1/PDL1 action is of great significance for combined immunotherapy and patient prognosis. The inhibitors of PD1/PDL1 have shown clinical efficacy in many tumors, for example, blockade of PD1 or PDL1 with specific antibodies enhances T cell responses and mediates antitumor activity. However, some patients are prone to develop drug resistance, resulting in poor treatment outcomes, which is rooted in the insensitivity of patients to targeted inhibitors. In this paper, we reviewed the mechanism and application of PD1/PDL1 checkpoint inhibitors in tumor immunotherapy. We hope that in the future, promising combination therapy regimens can be developed to allow immunotherapeutic tools to play an important role in tumor treatment. We also discuss the safety issues of immunotherapy and further reflect on the effectiveness of the treatment and the side effects it brings. [ABSTRACT FROM AUTHOR]

Purpose: To identify CD8+ T cell-related factors and the co-expression network in melanoma and illustrate the interactions among CD8+ T cell-related genes in the melanoma tumor microenvironment. Method: We obtained melanoma and paracancerous tissue mRNA matrices from TCGA-SKCM and GSE65904. The CIBERSORT algorithm was used to assess CD8+ T cell proportions, and the "estimate" package was used to assess melanoma tumor microenvironment purity. Weighted gene co-expression network analysis was used to identify the most related co-expression modules in TCGA-SKCM and GSE65904. Subsequently, a co-expression network was built based on the joint results in the two cohorts. Subsequently, we identified the core genes of the two most relevant modules of CD8+T lymphocytes according to the module correlation, and constructed the signature using ssGSEA. Later, we compared the signature with the existing classical pathways and gene sets, and confirmed the important prognostic significance of the signature in this paper. Results: Nine co-expressed genes were identified as CD8+ T cell-related genes enriched in the cellular response to interferon−gamma process and antigen processing and presentation of peptide antigen. In the low expression level group, inflammation and immune responses were weaker. Single-cell sequencing and immunohistochemistry indicated that these nine genes were highly expressed in CD8+ T cells group. Conclusion: We identified nine-gene signature, and the signature is considered as the biomarker for T lymphocyte response and clinical response to immune checkpoint inhibitors for melanoma [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade (ICB) therapies are revolutionary cancer treatments; however, they only benefit about a third of patients. Therefore, extensive research is underway to find methods to improve their therapeutic efficacy. One avenue of study that has recently emerged is to consider the role the gut microbiome plays in therapeutic success. Several high‐impact studies have repeatedly shown that the presence, composition and level of diversity of the gut flora directly impact cancer treatment outcome in both mice and patients. These studies have also highlighted the danger of using antibiotics shortly before or during cancer treatments. However, there are still several questions that need to be answered, including which bacteria promote the greatest benefit, the mechanisms by which they act and how we can use this information to influence treatment outcome. In this review, we explain how the gut microbiome was realized to be of such importance and propose hypotheses for why gut flora have such a critical impact on ICB therapeutic success. We also describe a hypothetical mechanism involving bacterial translocation out of the gut and into the tumor, whereby the bacteria act in an adjuvant capacity to facilitate an antitumor response. By highlighting key papers in the field, we hope to hasten research on the subject so as to find a means to improve the therapeutic efficacy of these ground‐breaking cancer treatments. [ABSTRACT FROM AUTHOR]

In recent years, chimeric antigen receptor (CAR) T cell therapy has emerged as a cancer treatment. After initial therapeutic success for hematologic malignancies, this approach has been extended for the treatment of solid tumors including melanoma. T cells need to be reprogramed to recognize specific antigens expressed only in tumor cells, a difficult problem since cancer cells are simply transformed normal cells. Tumor antigens, namely, CSPG4, CD70, and GD2 have been targeted by CAR-T cells for melanoma. Moreover, different co-stimulatory signaling domains need to be selected to direct T cell fate. In this review, various approaches for the treatment of melanoma and their effectiveness are comprehensively reviewed and the current status, challenges, and future perspective of CAR-T cell therapy for melanoma are discussed. Literature search was accomplished in three databases (PubMed, Google scholar, and Clinicaltrials.gov). Published papers and clinical trials were screened and relevant documents were included by checking pre-defined eligibility criteria. Despite obstacles and the risk of adverse events, CAR T cell therapy could be used for patients with treatment-resistant cancer. Clinical trials are underway to determine the efficacy of this approach for the treatment of melanoma. [ABSTRACT FROM AUTHOR]

Immunotherapy is considered as an effective method for cancer treatment owing to the induction of specific and long-lasting anti-cancer effects. Immunotherapeutic strategies have shown significant success in human malignancies, particularly in prostate cancer (PCa), a major global health issue regarding its high metastatic rates. In fact, the first cancer vaccine approved by FDA was Provenge, which has been successfully used for treatment of PCa. Despite the remarkable success of cancer immunotherapy in PCa, many of the developed immunotherapy methods show poor therapeutic outcomes. Immunosuppression in tumor microenvironment (TME) induced by non-functional T cells (CD4+ and CD8+), tolerogenic dendritic cells (DCs), and regulatory T cells, has been reported to be the main obstacle to the effectiveness of anti-tumor immune responses induced by an immunotherapy method. The present review particularly focuses on the latest findings of the immune checkpoints (ICPs), including CTLA-4, PD-1, PD-L1, LAG-3, OX40, B7-H3, 4-1BB, VISTA, TIM-3, and ICOS; these checkpoints are able to have immune modulatory effects on the TME of PCa. This paper further discusses different approaches in ICPs targeting therapy and summarizes the latest advances in the clinical application of ICP-targeted therapy as monotherapy or in combination with other cancer therapy modalities in PCa. [ABSTRACT FROM AUTHOR]

A wide range of cancer immunotherapy approaches has been developed including non-specific immune-stimulants such as cytokines, cancer vaccines, immune checkpoint inhibitors (ICIs), and adoptive T cell therapy. Among them, ICIs are the most commonly used and intensively studied. Since 2011, these drugs have received marketing authorisation for melanoma, lung, bladder, renal, and head and neck cancers, with remarkable and long-lasting treatment response in some patients. The novel mechanism of action of ICIs, with immune and T cell activation, leads to unusual patterns of response on imaging, with the advent of so-called pseudoprogression being more pronounced and frequently observed when compared to other anticancer therapies. Pseudoprogression, described in about 2–10% of patients treated with ICIs, corresponds to an increase of tumour burden and/or the appearance of new lesions due to infiltration by activated T cells before the disease responds to therapy. To overcome the limitation of response evaluation criteria in solid tumors (RECIST) to assess these specific changes, new imaging criteria—so-called immune-related response criteria and then immune-related RECIST (irRECIST)—were proposed. The major modification involved the inclusion of the measurements of new target lesions into disease assessments and the need for a 4-week re-assessment to confirm or not confirm progression. The RECIST working group introduced the new concept of "unconfirmed progression", into the irRECIST. This paper reviews current immunotherapeutic approaches and summarises radiologic criteria to evaluate new patterns of response to immunotherapy. Furthermore, imaging features of immunotherapy-related adverse events and available predictive biomarkers of response are presented. [ABSTRACT FROM AUTHOR]

Purpose: The human peroxiredoxin-5 (hPRDX5) is a member of the family of antioxidant enzymes, which could resist immunosuppression by promoting immune organs development, lymphocyte proliferation and up-regulation of the levels of serum cytokines. However, being a recombinant protein, the hPRDX5 exhibits some problems including the high production cost and bad tissue penetration. Compared to macromolecular therapeutic agents, synthetic peptides have several advantages as drug candidates, such as lower manufacturing costs, reduced immunogenicity, and better organ or tumor penetration. The purpose of this research was to design the novel peptides come from hPRDX5 that can block the interaction of PD-1 and PD-L1.Methods: Herein in this work, we firstly confirmed the inhibitory activity of hPRDX5 on the binding of PD-L1 to PD-1 based on the previous observation, subsequently, in silico proteolysis and rational design (such as alanine scanning mutagenesis and truncation) were used to automate the design of new peptides derived from hPRDX5 with anti-tumour activity.Results: We found that the most potent peptide could block the PD-1/PD-L1 interaction effectively with an IC50 of 0.646 μM, and could restore the function of Jurkat T cells which had been suppressed by stimulated HCT116 cells. Moreover, experiments with tumor-bearing mice models showed that the peptide IMB-P6-10 could effectively inhibit tumor growth and showed extraordinary low acute toxicity in vivo.Conclusions: The peptides described in this paper may provide novel low-molecular-weight drug candidates for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Immunotherapy is often perceived as a relatively recent advance. In reality, however, one should be looking for the beginnings of cancer immunotherapy under different names as far as in the Antiquity. The first scientific attempts to modulate patients' immune systems to cure cancer can be attributed to two German physicians, Fehleisen and Busch, who independently noticed significant tumor regression after erysipelas infection. The next significant advances came from William Bradley Coley who is known today as the Father of Immunotherapy. It was Coley who first attempted to harness the immune system for treating bone cancer in 1891. His achievements were largely unnoticed for over fifty years, and several seminal discoveries in the field of Immunology, such as the existence of T cells and their crucial role in immunity in 1967, stepped up the research toward cancer immunotherapy known today. The following paper tracks cancer immunotherapy from its known beginnings up until recent events, including the 2018 Nobel Prize award to James Allison and Tasuku Honjo for their meticulous work on checkpoint molecules as potential therapeutic targets. That work has led to the successful development of new checkpoint inhibitors, CAR T-cells and oncolytic viruses and the pace of such advances brings the highest hope for the future of cancer treatment. [ABSTRACT FROM AUTHOR]

In the first of two papers we described the development in the field of allergy mechanisms as described by Clinical and Experimental Allergy in 2015. Experimental models of allergic disease, basic mechanisms, clinical mechanisms and allergens are all covered. A second paper will cover clinical aspects. [ABSTRACT FROM AUTHOR]

The occurrence and development of tumors are closely associated with abnormalities in the immune system's structure and function, with tumor immunotherapy being intricately linked to the tumor microenvironment (TME). Early studies on lymphocytes within the TME primarily concentrated on T cells. However, as research has advanced, the multifaceted roles of tumor-infiltrating B cells (TIL-Bs) in tumor immunity, encompassing both anti-tumor and pro-tumor effects, have garnered increasing attention. This paper explored the composition of the TME and the biological characteristics of TIL-Bs, investigating the dual roles within the TME to offer new insights and strategies for tumor immunotherapy. [Display omitted] • Dual roles of tumor-infiltrating B cells in tumor microenvironment: anti-tumor and pro-tumor effects. • Tumor-infiltrating B cells boost anti-tumor immunity via antigen presentation, antibody production, cytokine secretion, etc. • Regulatory B cells aid tumor immune evasion by releasing suppressive cytokines, specific antibodies, and metabolites. • Insights into Tumor-infiltrating B cells may offer potential new targets for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Tumor-infiltrating lymphocytes (TILs) are significantly implicated in regulating the tumor immune microenvironment (TIME) and immunotherapeutic response. However, little is known about the impact of the resident and exhausted status of TILs in hepatocellular carcinoma (HCC). Methods: Single-cell RNA sequencing data was applied to discover resident and exhausted signatures of TILs. Survival outcomes, biological function, immune infiltration, genomic variation, immunotherapeutic efficacy, and sorafenib response were further explored the clinical significance and molecular association of TILs in HCC. Moreover, a candidate gene with predictive capability for the dismal subtype was identified through univariate Cox regression analysis, survival analysis, and the BEST website. Results: Single-cell analysis revealed that CD8 + T, CD4 + T, and NK cells were strongly associated with resident and exhausted patterns. Specific resident and exhausted signatures for each subpopulation were extracted in HCC. Further multivariate Cox analysis revealed that the ratio of resident to exhausted CD4 + T cells in TIME was an independent prognostic factor. After incorporating tumor purity with the ratio of resident to exhausted CD4 + T cells, we stratified HCC patients into three subtypes and found that (i) CD4 residencyhighexhaustionlow subtype was endowed with favorable prognosis, immune activation, and sensitivity to immunotherapy; (ii) CD4 exhaustionhighresidencylow subtype was characterized by genome instability and sensitivity to sorafenib; (iii) Immune-desert subtype was associated with malignant-related pathways and poor prognosis. Furthermore, spindle assembly abnormal protein 6 homolog (SASS6) was identified as a key gene, which accurately predicted the immune-desert subtype. Prognostic analysis as well as in vitro and in vivo experiments further demonstrated that SASS6 was closely associated with tumor prognosis, proliferation, and migration. Conclusions: The ratio of resident to exhausted CD4 + T cells shows promise as a potential biomarker for HCC prognosis and immunotherapy response and SASS6 may serve as a biomarker and therapeutic target for prognostic assessment of HCC. [ABSTRACT FROM AUTHOR]

Invariant natural killer T (iNKT) cells are a subset of lipid-reactive, unconventional T cells that have anti-tumor properties that make them a promising target for cancer immunotherapy. Recent studies have deciphered the developmental pathway of human MAIT and Vγ9Vδ2 γδ-T cells as well as murine iNKT cells, yet our understanding of human NKT cell development is limited. Here, we provide an update in our understanding of how NKT cells develop in the human body and how knowledge regarding their development could enhance human treatments by targeting these cells. [ABSTRACT FROM AUTHOR]

Great progress has been made in utilizing immune checkpoint blockade (ICB) for the treatment of non-small-cell lung cancer (NSCLC). Therapies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1, expressed on tumor cells, have demonstrated potential in improving patient survival rates. An unresolved issue involves immune suppression induced by exosomal PD-L1 within the tumor microenvironment (TME), particularly regarding CD8+ T cells. Our study unveiled the crucial involvement of LAMTOR1 in suppressing the exosomes of PD-L1 and promoting CD8+ T cell infiltration in NSCLC. Through its interaction with HRS, LAMTOR1 facilitates PD-L1 lysosomal degradation, thereby reducing exosomal PD-L1 release. Notably, the ability of LAMTOR1 to promote PD-L1 lysosomal degradation relies on a specific ubiquitination site and an HRS binding sequence. The findings suggest that employing LAMTOR1 to construct peptides could serve as a promising strategy for bolstering the efficacy of immunotherapy in NSCLC. The discovery and comprehension of how LAMTOR1 inhibits the release of exosomal PD-L1 offer insights into potential therapeutic strategies for improving immunotherapy. It is imperative to conduct further research and clinical trials to investigate the feasibility and efficacy of targeting LAMTOR1 in NSCLC treatment. [ABSTRACT FROM AUTHOR]

This mini-review reports a brief description of the first experiments conducted by Canti's group on the role of photodynamic therapy in generating immunity against cancer. It highlights for the first time the effective role of PDT in the induction of anti-tumor T lymphocytes and shows that this effect is tumor-specific. It has also been reported how this adoptive immunity can improve the efficacy of chemotherapy. These studies have helped to open an important new field of scientific research on the role of PDT-generated immunity and to stimulate today's important new pre-clinical approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) are cancer immunotherapeutics that reinvigorate immune cells' ability to attack tumor cells. Despite remarkable results in some patients, ICIs do not demonstrate the same efficacy across all individuals. In this study, we present the first side-by-side comparison of an agent-based model (ABM) with an ordinary differential equation (ODE) model for ICIs targeting the PD-1/PD-L1 immune checkpoint. We consider tumor cells of high and low antigenicity and two distinct immune-cell kill mechanisms. Using key parameters calibrated from mouse bladder cancer studies, we simulate virtual tumors using both models. Our research identifies crucial tumor-immune characteristics that influence the efficacy of ICIs. By exploring the unique spatial insights provided by the ABM, we underscore the importance of considering the spatial complexity of the tumor microenvironment in mathematical models of ICIs, potentially paving the way for more effective cancer treatments. Since the introduction of the first immune checkpoint inhibitor (ICI), immunotherapy has changed the landscape of molecular therapeutics for cancers. However, ICIs do not work equally well on all cancers and for all patients. There has been a growing interest in using mathematical and computational models to optimize clinical responses. Ordinary differential equations (ODEs) have been widely used for mechanistic modeling in immuno-oncology and immunotherapy. They allow rapid simulations of temporal changes in the cellular and molecular populations involved. Nonetheless, ODEs cannot describe the spatial structure in the tumor microenvironment or quantify the influence of spatially-dependent characteristics of tumor-immune dynamics. For these reasons, agent-based models (ABMs) have gained popularity because they can model more detailed phenotypic and spatial heterogeneity that better reflect the complexity seen in vivo. In the context of anti-PD-1 ICIs, we compare treatment outcomes simulated from an ODE model and an ABM to show the importance of including spatial components in computational models of cancer immunotherapy. We consider tumor cells of high and low antigenicity and two distinct cytotoxic T lymphocyte (CTL) killing mechanisms. The preferred mechanism differs based on the antigenicity of tumor cells. Our ABM reveals varied phenotypic shifts within the tumor and spatial organization of tumor and CTLs despite similarities in key immune parameters, initial simulation conditions, and early temporal trajectories of the cell populations. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii (T. gondii)‐associated polymorphic effector proteins are crucial in parasite development and regulating host anti‐T. gondii immune responses. However, the mechanism remains obscure. Here, it is shown that Toxoplasma effector dense granules 4 (GRA4) restricts host IFN‐I activation. Infection with Δgra4 mutant T. gondii strain induces stronger IFN‐I responses and poses a severe threat to host health. Mechanistically, GRA4 binds to phosphorylated TBK1 to promote TRIM27‐catalyzed K48‐ubiquitination at Lys251/Lys372 residues, which enhances its recognition by autophagy receptor p62, ultimately leading to TBK1 autophagic degradation. Furthermore, an avirulent Δgra4 strain (ME49Δompdc/gra4) is constructed for tumor immunotherapy due to its ability to enhance IFN‐I production. Earlier vaccination with ME49Δompdc/gra4 confers complete host resistance to the tumor compared with the classical ME49Δompdc treatment. Notably, ME49Δompdc/gra4 vaccination induces a specific CD64+MAR‐1+CD11b+ dendritic cell subset, thereby enhancing T cell anti‐tumor responses. Overall, these findings identify the negative role of T. gondii GRA4 in modulating host IFN‐I signaling and suggest that GRA4 can be a potential target for the development of T. gondii vaccines and tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose: CXCR3 is expressed on activated T cells and plays a crucial role in T-cell recruitment to the tumor microenvironment (TME) during cell-based and immune checkpoint inhibitor (ICI) immunotherapy. This study utilized a 64Cu-labeled NOTA-α-CXCR3 antibody to assess CXCR3 expression in the TME and validate it as a potential T cell activation biomarker in vivo. Procedures: CXCR3+ cells infiltrating MC38 tumors (B57BL/6 mice, untreated and treated with αPD-1/αCTLA-4 ICI) were quantified using fluorescence microscopy and flow cytometry. A commercial anti-mouse CXCR3 antibody (α-CXCR3) was site-specifically conjugated with 2,2,2-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA) and radiolabeled with 64Cu. Saturation binding of [64Cu]Cu-NOTA-α-CXCR3 was investigated using CHO cells stably transfected with murine CXCR3. Biodistribution and PET imaging studies both at baseline and after 1 to 3 cycles of ICI, respectively, were carried out using different molar activities (10 GBq/µmol to 300 GBq/µmol) of [64Cu]Cu-NOTA-α-CXCR3. Results: Flow cytometry analysis at baseline confirmed the presence of CXCR3 + T-cells in MC38 tumors, which was significantly increased at day five after ICI (treated 33.8 ± 17.4 vs. control 8.8 ± 6.2 CD3+CXCR3+ cells/mg). These results were qualitatively and quantitatively confirmed by immunofluorescence of tumor cryoslices. In vivo PET imaging of MC38 tumor bearing mice before, during and after ICI using [64Cu]Cu-NOTA-α-CXCR3 (Kd = 3.3 nM) revealed a strong dependence of CXCR3-specificity of tracer accumulation in secondary lymphoid organs on molar activity. At 300 GBq/µmol (1.5 µg of antibody/mouse), a specific signal was observed in lymph nodes (6.33 ± 1.25 control vs. 3.95 ± 1.23%IA/g blocking) and the spleen (6.04 ± 1.02 control vs. 3.84 ± 0.79%IA/g blocking) at 48 h p.i. Spleen-to-liver ratios indicated a time dependent systemic immune response showing a steady increase from 1.08 ± 0.19 (untreated control) to 1.54 ± 0.14 (three ICI cycles). Conclusions: This study demonstrates the feasibility of in vivo imaging of CXCR3 upregulation under immunotherapy using antibodies. However, high molar activities and low antibody doses are essential for sensitive detection in lymph nodes and spleen. Detecting therapy-induced changes in CXCR3+ T cell numbers in tumors was challenging due to secondary antibody-related effects. Nonetheless, CXCR3 remains a promising target for imaging T cell activation, with anticipated improvements in sensitivity using alternative tracers with high affinities and favorable pharmacokinetics. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroblastoma (NBL) is the most common extracranial cancer in children. High-risk NBL is characterized by bone marrow metastasis and MYCN oncogene amplification and is associated with a dismal five-year overall survival of approximately 50%, despite an intensive multimodal treatment regimen including chemotherapy, surgery, high-dose chemotherapy with autologous stem cell rescue, and radiation. Herein, we systemically reviewed contemporary therapy schemes and their challenges as well as recent advancement in effective treatments for NBL. Due to its relative rarity, we hope this review can serve as a useful guidebook and potentially provide new insights to researchers and clinicians interested in this field. Neuroblastoma (NBL) cells highly express disialoganglioside GD2, which is restricted and weakly expressed in selected healthy cells, making it a desirable target of immunotherapy. Over the past two decades, application of dinutuximab, an anti-GD2 monoclonal antibody (mAb), has been one of the few new therapies to substantially improve outcomes to current levels. Given the persistent challenge of relapse and therapeutic resistance, there is an urgent need for new effective and tolerable treatment options for high-risk NBL. Recent breakthroughs in immune checkpoint inhibitor (ICI) therapeutics have not translated into high-risk NBL, like many other major pediatric solid tumors. Given the suppressed tumor microenvironment (TME), single ICIs like anti-CTLA4 and anti-PD1 have not demonstrated significant antitumor response rates. Meanwhile, emerging studies are reporting novel advancements in GD2-based therapies, targeted therapies, nanomedicines, and other immunotherapies such as adoptive transfer of natural killer (NK) cells and chimeric antigen receptors (CARs), and these hold interesting promise for the future of high-risk NBL patient care. Herein, we summarize the current state of the art in NBL therapeutic options and highlight the unique challenges posed by NBL that have limited the successful adoption of immune-modifying therapies. Through this review, we aim to direct the field's attention to opportunities that may benefit from a combination immunotherapy strategy. [ABSTRACT FROM AUTHOR]