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Background: The discovery and development of immune checkpoint inhibitors (ICIs) have resulted in their application as a novel therapeutic strategy for patients with small-cell lung cancer (SCLC). However, a comprehensive analysis of the potential adverse effects of ICIs in patients with SCLC remains to be conducted. Methods: Adverse event (ADE) reports relating to SCLC patients, submitted to the FDA Adverse Event Reporting System (FAERS) from the first quarter of 2013 to the second quarter of 2022, were extracted for analysis. The extracted data were subsequently screened and analyzed using the reporting odds ratio (ROR) method to assess the AE reports. Results: A total of 4,522 ADE reports were obtained from patients with SCLC who had received either chemotherapy alone or a combination of ICIs with chemotherapy. The ROR analysis identified a total of 91 immune-related adverse events in SCLC patients associated with the ICIs (SCLC-irAEs). Conclusion: This study revealed that the adverse effects resulting from irAEs in SCLC patients predominantly affected the hematologic and gastrointestinal systems, with the most severe cases potentially leading to fatality. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for non-small cell lung cancer (NSCLC). The variability in patient responses necessitates a blood-based, multi-cohort gene signature to predict ICI response in NSCLC. Methods: We performed transcriptomic profiling of peripheral blood mononuclear cell (PBMC) and buffy coat (BC) samples from three independent cohorts of NSCLC patients treated with ICIs: a retrospective cohort (PMBCR, n = 59), a retrospective validation cohort (BC, n = 44), and a prospective validation cohort (PBMCP, n = 42). We identified a 5-gene signature (UQCRB, NDUFA3, CDKN2D, FMNL1-DT, and APOL3) predictive of ICI response and validated its clinical utility in the prospective PBMCP cohort. Response was evaluated using RECIST criteria, and patients were followed up for progression-free survival (PFS) and overall survival (OS). Results: In the prospective PBMCP cohort, the 5-gene signature demonstrated high accuracy in stratifying patients into responders and non-responders (AUC = 0.89, 95% CI: 0.80–0.99). Predicted responders exhibited significantly longer PFS compared to predicted non-responders (median: 13.8 months vs. 4.2 months, HR = 0.21, 95% CI: 0.07–0.58, p = 0.005). Conclusion: Our study confirms a 5-gene signature as a key biomarker for ICI response in NSCLC, enhancing treatment precision. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) therapies for tumors of different systems have attained significant achievements and have changed the current situation of tumor treatment due to their therapeutic characteristics of high specificity and low side effects. The immune checkpoint Programmed death 1/Programmed cell death‐Ligand 1 (PD‐1/PD‐L1) axis exerts a vital role in the immune escape of tumor cells. As a result, it has become a key target for tumor immunotherapy. Therefore, to perfect research into potential regulatory factors for the PD‐1/PD‐L1 axis, in order to understand and illustrate tumor ICI therapy mechanisms, is a significant goal. Moreover, ncRNA has been verified to regulate the PD‐1/PD‐L1 axis in the tumor immune microenvironment to regulate tumor genesis and development. ncRNAs can improve or decrease the efficacy of ICI therapy by modulating PD‐L1 expression. This review aimed to investigate the mechanisms of action of ncRNA in regulating the PD‐1/PD‐L1 axis in ICI therapy, to provide more efficient immunotherapy for tumors of different systems. [ABSTRACT FROM AUTHOR]

Esophageal cancer (EC), a common type of malignant tumor, ranks as the sixth highest contributor to cancer-related mortality worldwide. Due to the condition that most patients with EC are diagnosed at advanced or metastatic status, the efficacy of conventional treatments including surgery, chemotherapy and radiotherapy is limited, resulting in a dismal 5-year overall survival rate. In recent years, the application of immune checkpoint inhibitors (ICIs) has presented a novel therapeutic avenue for EC patients. Both ICIs monotherapy and immunotherapy combined with chemotherapy or chemoradiotherapy (CRT) have demonstrated marked benefits for patients with advanced EC. Adjuvant or neoadjuvant therapy incorporating immunotherapy has also demonstrated promising prospects in the context of perioperative treatment. Nonetheless, due to the variable response observed among patients undergoing immunotherapy, it is of vital importance to identify predictive biomarkers for patient stratification, to facilitate identification of subgroups who may derive greater benefits from immunotherapy. In this review, we summarize validated or potential biomarkers for immunotherapy in EC in three dimensions: tumor-cellassociated biomarkers, tumor-immune microenvironment (TIME)-associated factors, and host-associated biomarkers, so as to provide a theoretical foundation to inform tailored therapy for individuals diagnosed with EC. [ABSTRACT FROM AUTHOR]

Abstract Background Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for non-small cell lung cancer (NSCLC). The variability in patient responses necessitates a blood-based, multi-cohort gene signature to predict ICI response in NSCLC. Methods We performed transcriptomic profiling of peripheral blood mononuclear cell (PBMC) and buffy coat (BC) samples from three independent cohorts of NSCLC patients treated with ICIs: a retrospective cohort (PMBCR, n = 59), a retrospective validation cohort (BC, n = 44), and a prospective validation cohort (PBMCP, n = 42). We identified a 5-gene signature (UQCRB, NDUFA3, CDKN2D, FMNL1-DT, and APOL3) predictive of ICI response and validated its clinical utility in the prospective PBMCP cohort. Response was evaluated using RECIST criteria, and patients were followed up for progression-free survival (PFS) and overall survival (OS). Results In the prospective PBMCP cohort, the 5-gene signature demonstrated high accuracy in stratifying patients into responders and non-responders (AUC = 0.89, 95% CI: 0.80–0.99). Predicted responders exhibited significantly longer PFS compared to predicted non-responders (median: 13.8 months vs. 4.2 months, HR = 0.21, 95% CI: 0.07–0.58, p = 0.005). Conclusion Our study confirms a 5-gene signature as a key biomarker for ICI response in NSCLC, enhancing treatment precision.

The escalating incidence of breast cancer (BC) in women underscores its grave health threat. Current molecular insights into BC's post-adjuvant therapy cure remain elusive, necessitating active treatment explorations. Immunotherapy, notably chemotherapy-induced immunogenic cell death (ICD), has emerged as a promising BC therapy. ICD harnesses chemotherapeutics to activate anti-tumor immunity via DAMPs, fostering long-term T-cell memory and primary BC cure. Besides chemotherapy drugs, Nanodrugs, traditional Chinese medicine (TCM) and ICIs also induce ICD, boosting immune response. ICIs, like PD-1/PD-L1 inhibitors, revolutionize cancer treatment but face limited success in cold tumors. Thus, ICD induction combined with ICIs is studied extensively for BC immunotherapy. This article reviews the mechanism of ICD related drugs in BC and provides reference for the research and development of BC treatment, in order to explore more effective clinical treatment of BC, we hope to explore more ICD inducers and make ICIs more effective vaccines. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death worldwide. surgery, transarterial chemoembolization (TACE), systemic therapy, local ablation therapy, radiotherapy, and targeted drug therapy with agents such as sorafenib. However, the tumor microenvironment of liver cancer has a strong immunosuppressive effect. Therefore, new treatments for liver cancer are still necessary. Immune checkpoint molecules, such as programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4), along with high levels of immunosuppressive cytokines, induce T cell inhibition and are key mechanisms of immune escape in HCC. Recently, immunotherapy based on immune checkpoint inhibitors (ICIs) as monotherapy or in combination with tyrosine kinase inhibitors, anti-angiogenesis drugs, chemotherapy agents, and topical therapies has offered great promise in the treatment of liver cancer. In this review, we discuss the latest advances in ICIs combined with targeted drugs (targeted-immune combination) and other targeted-immune combination regimens for the treatment of patients with advanced HCC (aHCC) or unresectable HCC (uHCC), and provide an outlook on future prospects. The literature reviewed spans the last five years and includes studies identified using keywords such as "hepatocellular carcinoma," "immune checkpoint inhibitors," "targeted therapy," "combination therapy," and "immunotherapy". [ABSTRACT FROM AUTHOR]

Objective: To determine the cost-effectiveness of imported immune checkpoint inhibitors (ICIs) such as atezolizumab and durvalumab, and domestic ICIs like serplulimab and adebrelimab, in combination with chemotherapy for extensivestage small cell lung cancer (ES-SCLC) in China. Methods: Using a 21-day cycle length and a 20-year time horizon, a Markov model was established to compare the clinical and economic outcomes of five first-line ICIs plus chemotherapy versus chemotherapy alone, as well as against each other, from the perspective of the Chinese healthcare system. Transition probabilities were estimated by combining the results of the CAPSTONE-1 trial and a published network meta-analysis. Cost and health state utilities were collected from multiple sources. Both cost and effectiveness outcomes were discounted at a rate of 5% annually. The primary model output was incremental cost-effectiveness ratios (ICERs). A series of sensitivity analyses were preformed to assess the robustness of the model. Results: In the base-case analysis, the addition of first-line ICIs to chemotherapy resulted in the ICERs ranged from $80,425.31/QALY to $812,415.46/QALY, which exceeded the willing-to-pay threshold set for the model. When comparing these first-line immunochemotherapy strategies, serplulimab plus chemotherapy had the highest QALYs of 1.51286 and the second lowest costs of $60,519.52, making it is the most cost-effective strategy. Our subgroup-level analysis yielded results that are consistent with the base-case analysis. The sensitivity analysis results confirmed the validity and reliability of the model. Conclusion: In China, the combination of fist-line ICIs plus chemotherapy were not considered cost-effective when compared to chemotherapy alone. However, when these fist-line immunochemotherapy strategies were compared with each other, first-line serplulimab plus chemotherapy consistently demonstrated superiority in terms of cost-effectiveness. Reducing the cost of serplulimab per 4.5 mg/kg would be a realistic step towards making first-line serplulimab plus chemotherapy more accessible and cost-effective. [ABSTRACT FROM AUTHOR]

ObjectiveIn China, lung cancer ranks first in both incidence and mortality among all malignant tumors. Non-small cell lung cancer (NSCLC) constitutes the vast majority of cases, accounting for 80% to 85% of cases. Immune checkpoint inhibitors (ICIs), either as monotherapies or combined with other treatments, have become the standard first-line therapy for NSCLC patients. This study aimed to establish a nomogram model for NSCLC patients receiving immunotherapy incorporating demographic information, clinical characteristics, and laboratory indicators.MethodsFrom January 1, 2019, to December 31, 2022, a prospective longitudinal cohort study involving 1321 patients with NSCLC undergoing immunotherapy was conducted at Chongqing University Cancer Hospital. Clinical and pathological characteristics, as well as follow-up data, were collected and analyzed. To explore prognostic factors affecting overall survival (OS), a Cox regression model was used to test the significance of various variables. Independent prognostic indicators were identified through multivariate analysis and then used to construct a nomogram prediction model. To validate the accuracy and practicality of this model, the concordance index (C-index), area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA) were used to assess the predictive performance of the nomogram.ResultIn the final model, 11 variables from the training cohort were identified as independent risk factors for patients with NSCLC: age, KPS score, BMI, diabetes, targeted therapy, Hb, WBC, LDH, CRP, PLR, and LMR. The C-index for OS in the training cohort was 0.717 (95% CI, 0.689–0.745) and 0.704 (95% CI, 0.660–0.750) in the validation cohort. Calibration curves for survival probability showed good concordance between the nomogram predictions and actual observations. The AUCs for 1-year, 2-year, and 3-year OS in the training cohort were 0.724, 0.764, and 0.79, respectively, and 0.725, 0.736, and 0.818 in the validation cohort. DCA demonstrated that the nomogram model had a greater overall net benefit.ConclusionA prognostic model for OS in NSCLC patients receiving immunotherapy was established, providing a simple and reliable tool for predicting patient survival (https://icisnsclc.shinyapps.io/DynNomapp/). This model offers valuable guidance for clinicians in making treatment decisions and recommendations.

BackgroundThe discovery and development of immune checkpoint inhibitors (ICIs) have resulted in their application as a novel therapeutic strategy for patients with small-cell lung cancer (SCLC). However, a comprehensive analysis of the potential adverse effects of ICIs in patients with SCLC remains to be conducted.MethodsAdverse event (ADE) reports relating to SCLC patients, submitted to the FDA Adverse Event Reporting System (FAERS) from the first quarter of 2013 to the second quarter of 2022, were extracted for analysis. The extracted data were subsequently screened and analyzed using the reporting odds ratio (ROR) method to assess the AE reports.ResultsA total of 4,522 ADE reports were obtained from patients with SCLC who had received either chemotherapy alone or a combination of ICIs with chemotherapy. The ROR analysis identified a total of 91 immune-related adverse events in SCLC patients associated with the ICIs (SCLC-irAEs).ConclusionThis study revealed that the adverse effects resulting from irAEs in SCLC patients predominantly affected the hematologic and gastrointestinal systems, with the most severe cases potentially leading to fatality.

Over the past two decades, immunotherapies have increasingly been considered as first-line treatments for most cancers. One such treatment is immune checkpoint blockade (ICB), which has demonstrated promising results against various solid tumors in clinical trials. Monoclonal antibodies (mAbs) are currently available as immune checkpoint inhibitors (ICIs). These ICIs target specific immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Clinical trial results strongly support the feasibility of this immunotherapeutic approach. However, a substantial proportion of patients with cancer develop resistance or tolerance to treatment, owing to tumor immune evasion mechanisms that counteract the host immune response. Consequently, substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), and anti-CTLA-4 treatments. Recently, several immune checkpoint molecular targets have been identified, such as T cell immunoreceptor with Ig and ITIM domains (TIGIT), mucin domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and signal-regulatory protein α (SIRPα). Functional mAbs targeting these molecules are under development. CTLA-4, PD-1/PD-L1, and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of research. This review discusses these structures, as well as clinical progress in mAbs targeting these immune checkpoint molecules and their potential applications.

The relevance of environmental justice in global biodiversity and climate governance has increased as stakeholders’ unequal affectedness by environmental action is becoming ever more obvious. International Cooperative Initiatives (ICIs) play an ever increasing role in addressing global environmental change and biodiversity loss. Yet, the consideration of demands of environmental justice by these non-state or hybrid actors is still under-explored. Informed by a three-pillar environmental justice framework comprising distributive, procedural, and recognition justice, we use content analysis to identify if and how these different pillars are presented on the websites and in the key publications of a sample of 53 ICIs. A majority of these ICIs include references to environmental justice and its different pillars in their description of their work. But environmental justice seems to be neither a central concern nor are the references very nuanced. Distributive justice receives the most attention, whereas aspects of procedural and recognition justice receive less attention. To better anchor environmental justice within global biodiversity and climate governance, we encourage ICIs to thoroughly integrate environmental justice in operational work and to integrate and establish ongoing dialogues with marginalised groups.

Abstract Background Advanced unresectable gastric cancer (GC) patients were previously treated with chemotherapy alone as the first-line therapy. However, with the Food and Drug Administration’s (FDA) 2022 approval of programmed cell death protein 1 (PD-1) inhibitor combined with chemotherapy as the first-li ne treatment for advanced unresectable GC, patients have significantly benefited. However, the significant costs and potential adverse effects necessitate precise patient selection. In recent years, the advent of deep learning (DL) has revolutionized the medical field, particularly in predicting tumor treatment responses. Our study utilizes DL to analyze pathological images, aiming to predict first-line PD-1 combined chemotherapy response for advanced-stage GC. Methods In this multicenter retrospective analysis, Hematoxylin and Eosin (H&E)-stained slides were collected from advanced GC patients across four medical centers. Treatment response was evaluated according to iRECIST 1.1 criteria after a comprehensive first-line PD-1 immunotherapy combined with chemotherapy. Three DL models were employed in an ensemble approach to create the immune checkpoint inhibitors Response Score (ICIsRS) as a novel histopathological biomarker derived from Whole Slide Images (WSIs). Results Analyzing 148,181 patches from 313 WSIs of 264 advanced GC patients, the ensemble model exhibited superior predictive accuracy, leading to the creation of ICIsNet. The model demonstrated robust performance across four testing datasets, achieving AUC values of 0.92, 0.95, 0.96, and 1 respectively. The boxplot, constructed from the ICIsRS, reveals statistically significant disparities between the well response and poor response (all p-values

Objective: To evaluate the cardiovascular safety of anticancer drug immune checkpoint inhibitors (ICIs) used in patients with malignant tumors. Methods: Four clinical research databases that have been completed since their establishment were searched, and the odds ratios and 95% confidence intervals of each indicator were statistically calculated. Results: 62 randomized controlled trial and controlled trials were included. In single drug treatment ICIs group, the overall risk of cardio cerebral Vascular disease at all levels was higher than that in the placebo/chemotherapy group. Especially in all grades of Myocarditis and above grade 3 compared with normal controls, except for pericardial lesions, other indicators have no obvious side effects. Conclusion: Single drug use of an anti-tumor ICIs may increase cardiovascular side effects risk in cancer patients, so we need to strengthen monitoring, identification and management, and timely intervention to manage ICI induced adverse events. [ABSTRACT FROM AUTHOR]

The prognostic factors of ICI-including combined therapy in patients with metastatic renal cell carcinoma were analyzed by systematic review. We searched Web of Science, Cochrane, PubMed, CNKI, Wanfang and other databases for randomized controlled trials and clinical trials of combination therapy including ICIs in the treatment of metastatic renal cell carcinoma. The search time was from the establishment of the database to September 2023. Data were extracted and evaluated with RevMan 5.4 software. Six studies were included, including 4723 patients. The results showed that ① in terms of progression-free survival, the factors of age < 65 years old, male sex, Canada and Western Europe, nephrectomy, different IMDC class, number of organs with metastases and PD-L1 expression ≥ 1% significantly prolonged PFS in patients with metastatic cancer treated by combination therapy including ICIs; ② in terms of overall survival rate, the factors of age < 65 years old, female sex, nephrectomy, different IMDC class and PD-L1 expression ≥ 1% significantly prolonged the OS of patients with metastatic cancer treated by combination therapy including ICIs. Age, sex, region, nephrectomy, different IMDC class, number of organs with metastases and PD-L1 expression are independent factors influencing the efficacy of combination therapy including ICIs in the treatment of metastatic renal cell carcinoma. Systematic evaluation of baseline indicators of patients with metastatic renal cell carcinoma to predict clinical benefits can effectively improve the benefit rate of patients. [ABSTRACT FROM AUTHOR]

Background: Advanced unresectable gastric cancer (GC) patients were previously treated with chemotherapy alone as the first-line therapy. However, with the Food and Drug Administration's (FDA) 2022 approval of programmed cell death protein 1 (PD-1) inhibitor combined with chemotherapy as the first-li ne treatment for advanced unresectable GC, patients have significantly benefited. However, the significant costs and potential adverse effects necessitate precise patient selection. In recent years, the advent of deep learning (DL) has revolutionized the medical field, particularly in predicting tumor treatment responses. Our study utilizes DL to analyze pathological images, aiming to predict first-line PD-1 combined chemotherapy response for advanced-stage GC. Methods: In this multicenter retrospective analysis, Hematoxylin and Eosin (H&E)-stained slides were collected from advanced GC patients across four medical centers. Treatment response was evaluated according to iRECIST 1.1 criteria after a comprehensive first-line PD-1 immunotherapy combined with chemotherapy. Three DL models were employed in an ensemble approach to create the immune checkpoint inhibitors Response Score (ICIsRS) as a novel histopathological biomarker derived from Whole Slide Images (WSIs). Results: Analyzing 148,181 patches from 313 WSIs of 264 advanced GC patients, the ensemble model exhibited superior predictive accuracy, leading to the creation of ICIsNet. The model demonstrated robust performance across four testing datasets, achieving AUC values of 0.92, 0.95, 0.96, and 1 respectively. The boxplot, constructed from the ICIsRS, reveals statistically significant disparities between the well response and poor response (all p-values < = 0.001). Conclusion: ICIsRS, a DL-derived biomarker from WSIs, effectively predicts advanced GC patients' responses to PD-1 combined chemotherapy, offering a novel approach for personalized treatment planning and allowing for more individualized and potentially effective treatment strategies based on a patient's unique response situations. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cell-based anti-hepatocellular carcinoma (HCC) therapy is an increasingly attractive approach that warrants further study. Siglec-9 interacts with its ligand (Siglec-9L) and restrains NK cell functions, suggesting it is a potential therapeutic target. However, in situ Siglec-9/Siglec-9L interactions in HCC have not been reported, and a relevant interventional strategy is lacking. Herein, we aim to illustrate Siglec-9/Siglec-9L-mediated cell sociology and identify small-molecule inhibitors targeting Siglec-9 that could improve the efficacy of NK cell-based immunotherapy for HCC. Multiplexed immunofluorescence staining was performed to analyze the expression pattern of Siglec-7, -9 and their ligands in HCC tissues. Then we conducted docking-based virtual screening combined with bio-layer interferometry assays to identify a potent small-molecule Siglec-9 inhibitor. The therapeutic potential was further evaluated in vitro and in hepatoma-bearing NCG mice. Siglec-9 expression, rather than Siglec-7, was markedly upregulated on tumor-infiltrating NK cells, which correlated significantly with reduced survival of patients with HCC. Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival, further suggesting that Siglec-9/Siglec-9L interactions are a potential therapeutic target in HCC. In addition, we identified a small-molecule Siglec-9 inhibitor MTX-3937 which inhibited phosphorylation of Siglec-9 and downstream SHP1 and SHP2. Accordingly, MTX-3937 led to considerable improvement in NK cell function. Notably, MTX-3937 enhanced cytotoxicity of both human peripheral and tumor-infiltrating NK cells. Furthermore, transfer of MTX-3937-treated NK92 cells greatly suppressed the growth of hepatoma xenografts in NCG mice. Our study provides the rationale for HCC treatment by targeting Siglec-9 on NK cells and identifies a promising small-molecule inhibitor against Siglec-9 that enhances NK cell-mediated HCC surveillance. Herein, we found that Siglec-9 expression is markedly upregulated on tumor-infiltrating natural killer (TINK) cells and correlates with reduced survival in patients with hepatocellular carcinoma (HCC). Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival. More importantly, we identified a small-molecule inhibitor targeting Siglec-9 that augments NK cell functions, revealing a novel immunotherapy strategy for liver cancer that warrants further clinical investigation. [Display omitted] • Upregulated Siglec-9, a sialic acid-binding receptor on NK cells within HCC tissues, correlates with poor patient prognosis. • Expression of Siglec-9 ligands on cells neighboring to Siglec-9+ NK cells is significantly increased in HCC tissues. • The small-molecule Siglec-9 inhibitor, MTX-3937, enhances the functions and homeostasis of NK cells. • MTX-3937 remarkably improves NK cell-mediated anti-tumor efficacy against liver cancer in vivo. [ABSTRACT FROM AUTHOR]

Primary malignant melanoma of the esophagus (PMME) is an extremely rare but highly aggressive malignancy with a poor prognosis. Due to the scarcity of driver gene alterations, there is a need for more clinical data to comprehensively depict its molecular alterations. This study reviewed 26 PMME cases from three medical centers. Hybrid capture‐based targeted sequencing of 295 and 1021 genes was performed in 14 and 12 cases, respectively. We found that PMME patients had a relatively low tumor mutation burden (median, 2.88 mutations per Mb) and were simultaneously accompanied by mutations in genes such as KIT (6/26, 23%), TP53 (6/26, 23%), SF3B1 (4/26, 15%), and NRAS (3/26, 12%). KIT, NRAS, and BRAF were mutually exclusive, and SF3B1 co‐occurred with KIT mutation and amplification. The most common pathways affected were the mitogen‐activated protein kinases and DNA damage response (DDR) pathways. Stage IV was a risk factor for both progression‐free survival (hazard ratio [HR] = 5.14, 95% confidence interval [CI] = 1.32–19.91) and overall survival (OS), HR = 4.33, 95% CI = 1.22–15.30). Treatment with immune‐checkpoint inhibitors (ICIs) was an independent factor for favorable OS (HR = 0.10, 95% CI = 0.01–0.91). Overall, PMME is a complex malignancy with diverse gene alterations, especially with harboring DDR alterations for potentially response from ICIs. [ABSTRACT FROM AUTHOR]

Currently lacking research to explore the correlation between inflammatory markers and the efficacy of immune checkpoint inhibitors (ICIs) combined with chemotherapy in the treatment of advanced gastric cancer. This study is a retrospective study and included patients with advanced gastric cancer who receiving ICIs combined with chemotherapy from January 2020 to December 2022. We analysed the relationship between systemic inflammatory markers and the efficacy of ICIs combined chemotherapy and constructed a clinical prediction model. A nomogram was constructed based on the results of the bidirectional stepwise regression model. A total of 197 patients were enrolled in the training group, with a median follow‐up period of time 26 months. Kaplan Meier analysis showed that the median OS of patients with low systemic immune‐inflammatory index (SII) and low platelet to lymphocyte ratio (PLR) was superior to those with high SII and PLR. Univariate and multivariate Cox regression analysis showed that SII, NLR, PLR, and N stage as independent prognostic factors for OS. Adding SII to the conventional model improved the predictive ability of the 12‐month OS. A total of 95 patients were included in the validation group, and external validation of the SII‐based nomogram showed favourable predictive performance. Baseline SII, PLR, and N stage may serve as independent predictive factors for survival outcomes in advanced gastric cancer patients undergoing ICIs combined with chemotherapy. The SII‐based nomogram can provide intuitive and accurate prognosis prediction of individual patients. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by producing remarkable clinical outcomes for patients with various cancer types. However, only a subset of patients benefits from immunotherapeutic interventions due to the primary and acquired resistance to ICIs. Myeloid-derived suppressor cells (MDSCs) play a crucial role in creating an immunosuppressive tumor microenvironment (TME) and contribute to resistance to immunotherapy. V-domain Ig suppressor of T cell activation (VISTA), a negative immune checkpoint protein highly expressed on MDSCs, presents a promising target for overcoming resistance to current ICIs. This article provides an overview of the evidence supporting VISTA's role in regulating MDSCs in shaping the TME, thus offering insights into how to overcome immunotherapy resistance.

ObjectiveTo determine the cost-effectiveness of imported immune checkpoint inhibitors (ICIs) such as atezolizumab and durvalumab, and domestic ICIs like serplulimab and adebrelimab, in combination with chemotherapy for extensive-stage small cell lung cancer (ES-SCLC) in China.MethodsUsing a 21-day cycle length and a 20-year time horizon, a Markov model was established to compare the clinical and economic outcomes of five first-line ICIs plus chemotherapy versus chemotherapy alone, as well as against each other, from the perspective of the Chinese healthcare system. Transition probabilities were estimated by combining the results of the CAPSTONE-1 trial and a published network meta-analysis. Cost and health state utilities were collected from multiple sources. Both cost and effectiveness outcomes were discounted at a rate of 5% annually. The primary model output was incremental cost-effectiveness ratios (ICERs). A series of sensitivity analyses were preformed to assess the robustness of the model.ResultsIn the base-case analysis, the addition of first-line ICIs to chemotherapy resulted in the ICERs ranged from $80,425.31/QALY to $812,415.46/QALY, which exceeded the willing-to-pay threshold set for the model. When comparing these first-line immunochemotherapy strategies, serplulimab plus chemotherapy had the highest QALYs of 1.51286 and the second lowest costs of $60,519.52, making it is the most cost-effective strategy. Our subgroup-level analysis yielded results that are consistent with the base-case analysis. The sensitivity analysis results confirmed the validity and reliability of the model.ConclusionIn China, the combination of fist-line ICIs plus chemotherapy were not considered cost-effective when compared to chemotherapy alone. However, when these fist-line immunochemotherapy strategies were compared with each other, first-line serplulimab plus chemotherapy consistently demonstrated superiority in terms of cost-effectiveness. Reducing the cost of serplulimab per 4.5 mg/kg would be a realistic step towards making first-line serplulimab plus chemotherapy more accessible and cost-effective.

Abstract Background Immune Checkpoint Inhibitors (ICIs) lead to durable response and a significant increase in long-term survival in patients with advanced malignant melanoma (MM) and Non-Small Cell Lung Cancer (NSCLC). The identification of serum cytokines that can predict their activity and efficacy, and their sex interaction, could improve treatment personalization. Methods In this prospective study, we enrolled immunotherapy-naïve patients affected by advanced MM and NSCLC treated with ICIs. The primary endpoint was to dissect the potential sex correlations between serum cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, GM-CSF, MCP-1, TNF-ɑ, IP-10, VEGF, sPD-L1) and the objective response rate (ORR). Secondly, we analyzed biomarker changes during treatment related to ORR, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Blood samples, collected at baseline and during treatment until disease progression (PD) or up to 2 years, were analyzed using Luminex xMAP or ELLA technologies. Results Serum samples from 161 patients (98 males/63 females; 92 MM/69 NSCLC) were analyzed for treatment response. At baseline, IL-6 was significantly lower in females (F) versus males (M); lower levels of IL-4 in F and of IL-6 in both sexes significantly correlated with a better ORR, while higher IL-4 and TNF-ɑ values were predictive of a lower ORR in F versus M. One hundred and sixty-five patients were evaluable for survival analysis: at multiple Cox regression, an increased risk of PD was observed in F with higher baseline values of IL-4, sPD-L1 and IL-10, while higher IL-6 was a negative predictor in males. In males, higher levels of GM-CSF predict a longer survival, whereas higher IL-1β predicts a shorter survival. Regardless of sex, high baseline IL-8 values were associated with an increased risk of both PD and death, and high IL-6 levels only with shorter OS. Conclusions Serum IL-1β, IL-4, IL-6, IL-10, GM-CSF, TNF-ɑ, and sPD-L1 had a significant sex-related predictive impact on ORR, PFS and OS in melanoma and NSCLC patients treated with ICIs. These results will potentially pave the way for new ICI combinations, designed according to baseline and early changes of these cytokines and stratified by sex.

Abstract Background Immune checkpoint inhibitors (ICIs) have revolutionized the prognosis of cancer. Diabetes mellitus (DM) has been shown to have a negative effect on patients treated with ICIs. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective antidiabetic therapies associated with reduced all-cause mortality and cardiovascular (CV) outcomes. Objective To evaluate the prognostic value of SGLT2i on all-cause mortality and cardiotoxicity among patients treated with ICIs. Methods We performed a retrospective analysis of patients diagnosed with cancer and type 2 DM (DM2) and treated with ICIs at our center. Patients were divided into two groups according to baseline treatment with or without SGLT2i. The primary endpoint was all-cause mortality and the secondary endpoint was MACE, including myocarditis, acute coronary syndrome, heart failure, and arrhythmia. Results The cohort included 119 patients, with 24 (20%) patients assigned to the SGLT2i group. Both groups exhibited a comparable prevalence of cardiac risk factors, although the SGLT2i group displayed a higher incidence of ischemic heart disease. Over a median follow-up of 28 months, 61 (51%) patients died, with a significantly lower all-cause mortality rate in the SGLT2i group (21% vs. 59%, p = 0.002). While there were no significant differences in MACE, we observed zero cases of myocarditis and atrial fibrillation in the SGLT2i, compared to 2 and 6 cases in the non-SGLT2i group. Conclusions SGLT2i therapy was associated with a lower all-cause mortality rate in patients diagnosed with cancer and DM2 and treated with ICIs. Further studies are needed to understand the mechanism and evaluate its benefit on cardiotoxicity. Graphical Abstract

Immunotherapy has revolutionized the cancer treatment landscape by opening up novel avenues for intervention. As the use of immune checkpoint inhibitors (ICIs) has exponentially increased, so have immune-related adverse events (irAEs). The mechanism of irAEs may involve the direct damage caused by monoclonal antibodies and a sequence of immune responses triggered by T cell activation. Common side effects include dermatologic toxicity, endocrine toxicity, gastrointestinal toxicity, and hepatic toxicity. While relatively rare, neurotoxicity, cardiotoxicity, and pulmonary toxicity can be fatal. These toxicities pose a clinical dilemma regarding treatment discontinuation since they can result in severe complications and necessitate frequent hospitalization. Vigilant monitoring of irAEs is vital in clinical practice, and the principal therapeutic strategy entails the administration of oral or intravenous glucocorticoids (GSCs). It may be necessary to temporarily or permanently discontinue the use of ICIs in severe cases. Given that irAEs can impact multiple organs and require diverse treatment approaches, the involvement of a multidisciplinary team of experts is imperative. This review aims to comprehensively examine the pathogenesis, clinical manifestations, incidence, and treatment options for various irAEs. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy based on immune checkpoint inhibitors (ICIs) has become the first-line treatment for unresectable hepatocellular carcinoma (uHCC). However, only a small portion of patients are responsive to ICIs. It is important to identify the patients who are likely to benefit from ICIs in clinical practice. We aimed to examine the significance of serum IL-6 and CRP levels in predicting the effectiveness of ICIs for uHCC. Methods: We retrospectively recruited 222 uHCC patients who received ICIs treatment (training cohort: 124 patients, validation cohort: 98 patients). In the training cohort, patients are categorized into the response group (R) and noresponse group (NR). The levels of serum IL-6 and CRP were compared between the two groups. Internal validation was performed in the validation cohort. Survival analysis was carried out using the Kaplan-Meier method and Cox proportional hazard regression model. The nomograms were developed and assessed using the consistency index (C-index) and calibration curve. Results: Serum levels of IL-6 and CRP were significantly lower in the R group than in the NR group (9.94 vs. 36.85 pg/ml, p< 0.001; 9.90 vs. 24.50 mg/L, p< 0.001, respectively). An ROC curve was employed to identify the optimal cut-off values for IL-6 and CRP in both groups, resulting in values of 19.82 pg/ml and 15.50 mg/L, respectively. Multivariate Cox regression analysis revealed that MVI (HR 1.751, 95%CI 1.059-2.894, p=0.029; HR 1.530, 95%CI 0.955-2.451, p=0.077), elevated IL-6 (HR 1.624, 95%CI 1.016-2.596, p=0.043; HR 2.146, 95%CI 1.361-3.383, p =0.001) and high CRP (HR 1.709, 95%CI 1.041-2.807, p=0.034; HR 1.846, 95%CI 1.128-3.022, p = 0.015) were independent risk factors for PFS and OS, even after various confounders adjustments. Nomograms are well-structured and validated prognostic maps constructed from three variables, as MVI, IL6 and CRP. Conclusion: Low levels of IL-6 and CRP have a positive correlation with efficacy for uHCC patients receiving ICIs. [ABSTRACT FROM AUTHOR]

Introduction: Immunotherapy has become more widely accepted and used by medical oncologists. Radiologists face challenges in assessing tumor response and becoming more involved in the management of treatment. We aimed to assess the agreement between immune-related response criteria (irRC), immune-related RECIST (irRECIST), and immune RECIST (iRECIST) to correlate the response measured by them with overall survival (OS), and to determine the confirmation rate of progressive disease (PD). Methods: A total of 43 patients (28 men, 15 women; average age = 54.6 ± 15.7 years) treated with immunotherapy were included in this study. Pairwise agreements between iRECIST, irRC, and irRECIST were calculated using Cohen's kappa statistics. The correlation of the criteria-based response and OS was evaluated using the Kaplan-Meier method and log-rank test. A confirmation rate with 95% confidence intervals (CI) was calculated in patients with PD. Results: The kappa values between iRECIST and irRC, iRECIST and irRECIST, and irRC and irRECIST were 0.961 (almost perfect; P < 0.001), 0.961 (almost perfect; P < 0.001), and 0.922 (almost perfect; P < 0.001), respectively. The Kaplan-Meier method and log-rank test showed for each criterion a statistically significant correlation with OS (P < 0.05). The confirmation rates of PD for irRC, irRECIST, and iRECIST were 95% (19/20; 95% CI = 76.4-99.1%), 90% (18/20; 95% CI = 69.9-97.2%), and 90.5% (19/21; 95% CI = 71.1-97.4%), respectively. Conclusion: There was an almost perfect and statistically significant agreement between iRECIST, irRC, and irRECIST. The measurements performed with them significantly correlated with the OS; their confirmation rates were similar. iRECIST and irRECIST might be favored over irRC because of their relative ease of use. [ABSTRACT FROM AUTHOR]

Abstract T-cell exhaustion (TEX) and high heterogeneity of cancer stem cells (CSCs) are associated with progression, metastasis, and treatment resistance in hepatocellular carcinoma (HCC). Here, we aim to characterize TEX-stemness-related genes (TEXSRGs) and screen for HCC patients who are more sensitive to immunotherapy. The immune cell abundance identifier (ImmuCellAI) was utilized to precisely evaluate the abundance of TEX and screen TEX-related genes. The stemness index (mRNAsi) of samples was analyzed through the one-class logistic regression (OCLR) algorithm. Application of the non-negative matrix decomposition algorithm (NMF) for subtype identification of HCC samples. The different subtypes were assessed for differences in prognosis, tumor microenvironment (TME) landscape, and immunotherapy treatment response. Then, the TEXSRGS-score, which can accurately forecast the survival outcome of HCC patients, was built by LASSO-Cox and multivariate Cox regression, and experimentally validated for the most important TEXSRGs. We also analyzed the expression of TEXSRGs and the infiltration of CD8+ T cells in clinical samples using qRT-PCR and immunohistochemistry (IHC). Based on 146 TEXSRGs, we found two distinct clinical phenotypes with different TEX infiltration abundance, tumor stemness index, enrichment pathways, mutational landscape, and immune cell infiltration through the non-negative matrix decomposition algorithm (NMF), which were confirmed in the ICGC dataset. Utilizing eight TEXSRGs linked to clinical outcome, we created a TEXSRGs-score model to further improve the clinical applicability. Patients can be divided into two groups with substantial differences in the characteristics of immune cell infiltration, TEX infiltration abundance, and survival outcomes. The results of qRT-PCR and IHC analysis showed that PAFAH1B3, ZIC2, and ESR1 were differentially expressed in HCC and normal tissues and that patients with high TEXSRGs-scores had higher TEX infiltration abundance and tumor stemness gene expression. Regarding immunotherapy reaction and immune cell infiltration, patients with various TEXSRGs-score levels had various clinical traits. The outcome and immunotherapy efficacy of patients with low TEXSRGs-score was favorable. In conclusion, we identified two clinical subtypes with different prognoses, TEX infiltration abundance, tumor cell stemness index, and immunotherapy response based on TEXSRGs, and developed and validated a TEXSRGs-score capable of accurately predicting survival outcomes in HCC patients by comprehensive bioinformatics analysis. We believe that the TEXSRGs-score has prospective clinical relevance for prognostic assessment and may help physicians select prospective responders in preference to current immune checkpoint inhibitors (ICIs).

Abstract Objectives ICIs have become the standard treatment for advanced NSCLC patients. Currently, PD-L1 is the most widely useful biomarker to predict ICI efficacy, but the sensitivity and specificity are limited. Therefore, the useful predictive biomarkers of ICI efficacy is urgently needed. BMI is an internationally used measure of body health. Obesity may affect ICI efficacy by changing T cell functions. This meta-analysis aimed to clarify the relationship between BMI and survival outcomes of NSCLC patients treated with ICIs. Methods A systematic review was conducted to identify studies that assessed the association between BMI and survival outcomes in patients treated with ICIs. OS was the primary endpoint, and PFS was the secondary endpoint. Random-effect models or fixed-effect models were utilized to combine study effects according to the Cochran Q and I 2 tests. Results Nine studies, including 4602 NSCLC patients treated with ICIs, that met the inclusion criteria were selected for this meta-analysis. There was no significant difference in PFS (HR 0.885; 95% CI 0.777–1.009, p = 0.068) or OS (HR 0.947; 95% CI 0.789–1.137, p = 0.560) between the low BMI group and the high BMI group. However, in the subgroup analysis, compared with normal-weight patients, overweight and obese patients achieved prolonged PFS (HR 0.862; 95% CI 0.760–0.978, p = 0.021) and OS (HR 0.818; 95% CI 0.741–0.902, p

Abstract Background Cutaneous melanoma (CM) has an overall poor prognosis due to a high rate of metastasis. This study aimed to explore the role of hypoxia-related genes (HRGs) in CM. Methods We first used on-negative matrix factorization consensus clustering (NMF) to cluster CM samples and preliminarily analyzed the relationship of HRGs to CM prognosis and immune cell infiltration. Subsequently, we identified prognostic-related hub genes by univariate COX regression analysis and the least absolute shrinkage and selection operator (LASSO) and constructed a prognostic model. Finally, we calculated a risk score for patients with CM and investigated the relationship between the risk score and potential surrogate markers of response to immune checkpoint inhibitors (ICIs), such as TMB, IPS values, and TIDE scores. Results Through NMF clustering, we identified high expression of HRGs as a risk factor for the prognosis of CM patients, and at the same time, increased expression of HRGs also indicated a poorer immune microenvironment. Subsequently, we identified eight gene signatures (FBP1, NDRG1, GPI, IER3, B4GALNT2, BGN, PKP1, and EDN2) by LASSO regression analysis and constructed a prognostic model. Conclusion Our study identifies the prognostic significance of hypoxia-related genes in melanoma and shows a novel eight-gene signature to predict the potential efficacy of ICIs.

Immune checkpoint inhibitors (ICIs) have shown great promise as immunotherapy for restoring T cell function and reactivating anti-tumor immunity. The US Food and Drug Administration (FDA) approved the first immune checkpoint inhibitor, ipilimumab, in 2011 for advanced melanoma patients, leading to significant improvements in survival rates. Subsequently, other immune checkpoint-targeting antibodies were tested. Currently, seven ICIs, namely ipilimumab (anti-cytotoxic T lymphocyte-associated protein 4 [CTLA4]), pembrolizumab, nivolumab (anti-programmed cell death protein 1 [PD-1]), atezolizumab, avelumab, durvalumab, and cemiplimab (anti-PD-L1), have been approved for various cancer types. However, the efficacy of antibodies targeting CTLA4 or PD-1/programmed death-ligand 1 (PD-L1) remains suboptimal. Consequently, ongoing studies are evaluating the next generation of ICIs, such as lymphocyte activation gene-3 (LAG3), T cell immunoglobulin and mucin-domain containing 3 (TIM3), and T cell immunoglobulin and ITIM domain (TIGIT). Our review provides a summary of clinical trials evaluating these novel immune checkpoints in cancer treatment.

Bladder cancer (BC) is one of the most prevalent malignancies in men. Understanding molecular characteristics via studying signaling pathways has made tremendous breakthroughs in BC therapies. Thus, targeted therapies including immune checkpoint inhibitors (ICIs), antibody–drug conjugates (ADCs), and tyrosine kinase inhibitor (TKI) have markedly improved advanced BC outcomes over the last few years. However, the considerable patients still progress after a period of treatment with current therapeutic regimens. Therefore, it is crucial to guide future drug development to improve BC survival, based on the molecular characteristics of BC and clinical outcomes of existing drugs. In this perspective, we summarize the applications and benefits of these targeted drugs and highlight our understanding of mechanisms of low response rates and immune escape of ICIs, ADCs toxicity, and TKI resistance. We also discuss potential solutions to these problems. In addition, we underscore the future drug development of targeting metabolic reprogramming and cancer stem cells (CSCs) with a deep understanding of their signaling pathways features. We expect that finding biomarkers, developing novo drugs and designing clinical trials with precisely selected patients and rationalized drugs will dramatically improve the quality of life and survival of patients with advanced BC. [ABSTRACT FROM AUTHOR]

T-cell exhaustion (TEX) and high heterogeneity of cancer stem cells (CSCs) are associated with progression, metastasis, and treatment resistance in hepatocellular carcinoma (HCC). Here, we aim to characterize TEX-stemness-related genes (TEXSRGs) and screen for HCC patients who are more sensitive to immunotherapy. The immune cell abundance identifier (ImmuCellAI) was utilized to precisely evaluate the abundance of TEX and screen TEX-related genes. The stemness index (mRNAsi) of samples was analyzed through the one-class logistic regression (OCLR) algorithm. Application of the non-negative matrix decomposition algorithm (NMF) for subtype identification of HCC samples. The different subtypes were assessed for differences in prognosis, tumor microenvironment (TME) landscape, and immunotherapy treatment response. Then, the TEXSRGS-score, which can accurately forecast the survival outcome of HCC patients, was built by LASSO-Cox and multivariate Cox regression, and experimentally validated for the most important TEXSRGs. We also analyzed the expression of TEXSRGs and the infiltration of CD8+ T cells in clinical samples using qRT-PCR and immunohistochemistry (IHC). Based on 146 TEXSRGs, we found two distinct clinical phenotypes with different TEX infiltration abundance, tumor stemness index, enrichment pathways, mutational landscape, and immune cell infiltration through the non-negative matrix decomposition algorithm (NMF), which were confirmed in the ICGC dataset. Utilizing eight TEXSRGs linked to clinical outcome, we created a TEXSRGs-score model to further improve the clinical applicability. Patients can be divided into two groups with substantial differences in the characteristics of immune cell infiltration, TEX infiltration abundance, and survival outcomes. The results of qRT-PCR and IHC analysis showed that PAFAH1B3, ZIC2, and ESR1 were differentially expressed in HCC and normal tissues and that patients with high TEXSRGs-scores had higher TEX infiltration abundance and tumor stemness gene expression. Regarding immunotherapy reaction and immune cell infiltration, patients with various TEXSRGs-score levels had various clinical traits. The outcome and immunotherapy efficacy of patients with low TEXSRGs-score was favorable. In conclusion, we identified two clinical subtypes with different prognoses, TEX infiltration abundance, tumor cell stemness index, and immunotherapy response based on TEXSRGs, and developed and validated a TEXSRGs-score capable of accurately predicting survival outcomes in HCC patients by comprehensive bioinformatics analysis. We believe that the TEXSRGs-score has prospective clinical relevance for prognostic assessment and may help physicians select prospective responders in preference to current immune checkpoint inhibitors (ICIs). [ABSTRACT FROM AUTHOR]

Objectives: ICIs have become the standard treatment for advanced NSCLC patients. Currently, PD-L1 is the most widely useful biomarker to predict ICI efficacy, but the sensitivity and specificity are limited. Therefore, the useful predictive biomarkers of ICI efficacy is urgently needed. BMI is an internationally used measure of body health. Obesity may affect ICI efficacy by changing T cell functions. This meta-analysis aimed to clarify the relationship between BMI and survival outcomes of NSCLC patients treated with ICIs. Methods: A systematic review was conducted to identify studies that assessed the association between BMI and survival outcomes in patients treated with ICIs. OS was the primary endpoint, and PFS was the secondary endpoint. Random-effect models or fixed-effect models were utilized to combine study effects according to the Cochran Q and I2 tests. Results: Nine studies, including 4602 NSCLC patients treated with ICIs, that met the inclusion criteria were selected for this meta-analysis. There was no significant difference in PFS (HR 0.885; 95% CI 0.777–1.009, p = 0.068) or OS (HR 0.947; 95% CI 0.789–1.137, p = 0.560) between the low BMI group and the high BMI group. However, in the subgroup analysis, compared with normal-weight patients, overweight and obese patients achieved prolonged PFS (HR 0.862; 95% CI 0.760–0.978, p = 0.021) and OS (HR 0.818; 95% CI 0.741–0.902, p<0.0001). Conclusion: Overweight and obese NSCLC patients tend to achieve prolonged survival time with ICI regimens. Further prospective studies are needed to strengthen the association between ICI outcomes and BMI levels. [ABSTRACT FROM AUTHOR]

Abstract Background Triple‐negative breast cancer (TNBC) is the most aggressive type of breast cancer. Immune checkpoint inhibitors (ICIs) have been widely used to treat various tumors and have changed the landscape of tumor management, but the data from real‐world studies of ICIs for TNBC treatment remain limited. The aim of this study was to evaluate the efficacy of ICIs in the treatment of patients with advanced TNBC in a real‐world setting and to explore possible correlates. Methods The clinical data of advanced TNBC patients who received ICI treatment in the Chinese People's Liberation Army (PLA) General Hospital were collected. Treatment responses, outcomes and adverse events (AEs) were assessed. Results Eighty‐one patients were included in the study. The confirmed objective response rate (ORR) was 32.1%, and the disease control rate (DCR) was 64.2%. The median progression‐free survival (PFS) was 4.2 months, and the median overall survival (OS) was 11.0 months. PFS and OS were longer in patients who achieved clinical benefit from ICIs and shorter in patients who received later‐line ICIs and higher levels of inflammation; specifically, patients with higher TILs had longer PFS. Overall AEs were tolerable. Conclusions ICIs are effective in the treatment of advanced TNBC, and the adverse reactions are tolerable. A panel of biomarkers including LDH, ALP, and bNLR were identified to predict the efficacies of ICIs in TNBC treatment.

Abstract Background Anti-PD-1 antibodies have been approved for treating several cancer. However, data regarding the safety and efficacy of these agents in HIV-infected patients with cancer is lacking, because these patients are frequently omitted from clinical trials. Objectives The primary aim of our research is to assess the safety, activity, and long-term outcomes of PD-1 inhibitors in the treatment of HIV-infected patients with advanced cancer. Method We retrospectively analyzed data from HIV-infected patients with advanced cancers who were treated with PD-1 inhibitors at Shanghai Public Health Clinical Center, Shanghai, China. Results Fifteen HIV-infected patients (all are men; asian; median age, 44) with cancer who were treated with chemotherapy and/or combined the other oncology treatments [along with combined antiretroviral therapy (cART)] prior to Sintilimab (12 out of 15) or Nivolumab (1 out of 11) or Camrelizumab (2 out of 11) injection were identified. Eight patients responded to treatment (disease control rate 53.3%), with 1 got partial response (PR) and 7 were stable. Most treatment-emergent adverse events (TEAEs) were grade 1 or 2 including anemia, leukopenia, hyperglycemia, granulocytopenia, and thrombocytopenia. Eight patients (53.3%) experienced treatment-related AEs (TRAEs) with grades 3/4including myelosuppression, infection, and neurological disorders. CD4+ T cell count and plasma HIV RNA remained stable throughout the treatment. Conclusions When used in HIV-infected patients with advanced malignancies, PD-1 inhibitors tend to have favorable efficacy, manageable side effects, and no deteriorated impacts on plasma HIV-RNA and CD4+ T cell count.

Anqi Lin,1,&ast; Jiarong Yao,1,&ast; Quan Cheng,2,3 Zaoqu Liu,4 Peng Luo,1 Jian Zhang1 1Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 3National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 4Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Peng Luo; Jian Zhang, Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China, Tel +86-18588447321 ; +86-13925091863, Email luopeng@smu.edu.cn; zhangjian@i.smu.edu.cnPurpose: In recent years, tumour immunotherapy has ushered in a new era of oncology treatment. However, the use of immune checkpoint inhibitors (ICIs) in the treatment of CRC remains limited. There is an urgent clinical need for precise biomarkers that can aid in the screening and treatment of CRC subtypes. Therefore, we focused on the NOTCH pathway mutation status and conducted a systematic analysis for its predictive value of ICI therapy efficacy.Methods: We collected mutational and clinical data from cohorts of CRC patients treated with ICIs. The relationship between NOTCH pathway mutations (NOTCH-MT) and CRC immunotherapy prognosis was analysed using univariate and multivariate Cox regression models. CRC cohort data from The Cancer Genome Atlas (TCGA) database were combined to obtain a comprehensive overview of immunogenicity and tumour microenvironment (TME) differences among different NOTCH pathway mutation statuses.Results: We observed greater infiltration of M1 macrophages, CD8+ T cells, neutrophils, and activated natural killer (NK) cells with NOTCH-MT status. Immunogenicity was also significantly higher in patients with NOTCH-MT, as were tumour mutational burden (TMB), neoantigen load (NAL), and the number of mutations in DNA damage repair (DDR) pathways.Conclusion: NOTCH-MT status was strongly associated with the prognosis of CRC patients treated with ICIs and is expected to serve as a novel biomarker and therapeutic target for CRC.Keywords: NOTCH, CRC, ICIs, biomarker, tumour microenvironment

Abstract Bladder cancer (BC) is one of the most prevalent malignancies in men. Understanding molecular characteristics via studying signaling pathways has made tremendous breakthroughs in BC therapies. Thus, targeted therapies including immune checkpoint inhibitors (ICIs), antibody–drug conjugates (ADCs), and tyrosine kinase inhibitor (TKI) have markedly improved advanced BC outcomes over the last few years. However, the considerable patients still progress after a period of treatment with current therapeutic regimens. Therefore, it is crucial to guide future drug development to improve BC survival, based on the molecular characteristics of BC and clinical outcomes of existing drugs. In this perspective, we summarize the applications and benefits of these targeted drugs and highlight our understanding of mechanisms of low response rates and immune escape of ICIs, ADCs toxicity, and TKI resistance. We also discuss potential solutions to these problems. In addition, we underscore the future drug development of targeting metabolic reprogramming and cancer stem cells (CSCs) with a deep understanding of their signaling pathways features. We expect that finding biomarkers, developing novo drugs and designing clinical trials with precisely selected patients and rationalized drugs will dramatically improve the quality of life and survival of patients with advanced BC.

نقاط کنترل ایمنی (Immune checkpoints) مجموعه ای از گیرنده های تنظیمی می باشند که باعث کنترل پاسخ های ایمنی، حفظ تولرانس و هموستاز می شود. سلول های توموری می توانند با به خدمت گرفتن این نقاط از دسترس پاسخ های اختصاصی ضد تومورال بگریزند و گسترش پیدا کنند. از مهم ترین نقاط وارسی مسیر PD-1/PD-L1 است. PD-L1 توسط تمام سلول های توموری بیان شده و اتصال آن به PD-1 روی لنفوسیت های T سایتوتوکسیک (CTL) اختصاصی تومور، منجر به سرکوب CTL می شود. در واقع PD-L1 به عنوان یک فاکتور تومورزا عمل می کند که به طور چشمگیری تومورزایی و متاستاز را افزایش می دهد. همچنین میزان بیان PD-1 و PD-L1 یک بیومارکر پروگنوستیک در انواع تومورها می باشد و می تواند پیش آگهی بیماری را پیش بینی کند. در نتیجه یکی از جدیدترین و مهمترین روش های ایمونوتراپی سرطان برای ایجاد یک پاسخ ایمنی ضد تومورال قوی استفاده از مهارکننده های نقاط کنترل ایمنی (ICIs) و به طور ویژه مهارکننده های مسیر PD-1/PD-L1 است. از سال 2014 تاکنون هفت دارو برپایه آنتی بادی های مونوکلونال ضد PD-1 و PD-L1 توسط سازمان غذا و داروی آمریکا برای استفاده بالینی در طیف وسیعی از سرطان ها تایید گردیده است. شناخت مکانیسم های دقیق مسیر PD-1/PD-L1 به عنوان یک نقطه کنترل ایمنی مهم در سرطان مورد نیاز می باشد. مطالعه مروری حاضر به بررسی برهمکنش های این مسیر با سلول های توموری و همچنین تاثیر مهار کننده های PD-1/PD-L1 بر سلول های توموری می پردازد.

Background: Glioma is the most common primary brain tumor. Traditional treatments for glioma include surgical resection, radiotherapy, chemotherapy, and bevacizumab therapy, but their efficacies are limited. Immunotherapy provides a new direction for glioma treatment. This study aimed to summarize the knowledge structure and research hotspots of glioma immunotherapy through a bibliometric analysis. Method: Publications pertaining to glioma immunotherapy published during the period from 1st January 1990 to 27th March 2023 were downloaded from the Web of Science Core Collection (WoSCC). Bibliometric analysis and visualization were performed using the CiteSpace, VOSviewer, Online Analysis Platform of Literature Metrology, and R software. The hotspots and prospects of glioma immunotherapy research were illustrated via analyzing the countries, institutions, journals, authors, citations and keywords of eligible publications. Results: A total of 1,929 publications pertaining to glioma immunotherapy in 502 journals were identified as of 27th March 2023, involving 9,505 authors from 1,988 institutions in 62 countries. Among them were 1,285 articles and 644 reviews. Most of publications were produced by the United States. JOURNAL OF NEURO-ONCOLOGY published the majority of publications pertaining to glioma immunotherapy. Among the authors, Lim M contributed the largest number of publications. Through analyzing keyword bursts and co-cited references, immune-checkpoint inhibitors (ICIs) were identified as the research focus and hotspot. Conclusion: Using a bibliometric analysis, this study provided the knowledge structure and research hotspots in glioma immunotherapy research during the past 33 years, with ICIs staying in the current and future hotspot. Our findings may direct the research of glioma immunotherapy in the future. [ABSTRACT FROM AUTHOR]

Objective: The development and advance of gastric cancer are inextricably linked to oxidative and antioxidant imbalance. Although immunotherapy has been shown to be clinically effective, the link between oxidative stress and gastric cancer patients treated with immune checkpoint inhibitor (ICIs) remains unknown. This study aims at looking into the prognostic value of oxidative stress scores in gastric cancer patients treated with ICIs. Methods: By taking the propagation to receiver operating characteristic (ROC) we got the best cut-off values, and divided 265 patients receiving ICIs and chemotherapy into high and low GC-Integrated Oxidative Stress Score (GIOSS) groups. We also used Kaplan-Meier and COX regression models to investigate the relationship between oxidative stress biomarkers and prognosis. Results: Through both univariate and multivariate analyses, it’s shown that GIOSS severs as an independent prognostic factor for progression-free survival (PFS) and Overall survival (OS). Based on GIOSS cutoff values, patients with high GIOSS levels, compared to those with low levels exhibited shorter PFS and OS, both in the high GIOSS group, which performed poorly in the ICIs subgroup and other subgroup analyses. Conclusion: GIOSS is a biomarker that responds to systemic oxidative stress in the body and can predict prognosis in patients with gastric cancer who are taking ICIs. Additionally, it might come to medical professionals’ aid in making more effective or more suitable treatment plans for gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Non-Small Cell Lung Cancer (NSCLC) is one of the most prevalent malignancies globally, accounting for 85% of lung cancer cases. The rapid advancements in immunotherapy have significantly improved the prognosis of NSCLC patients. Methods: This article provides a comprehensive review of the clinical applications and latest research on commonly used immune checkpoint inhibitors as well as emerging immune checkpoint inhibitors and agonists in NSCLC treatment, providing valuable clinical guidance. Results: Immune checkpoint inhibitors, including PD-1/PD-L1 inhibitors and CTLA-4 inhibitors, have been widely utilized in NSCLC treatment, leading to substantial increases in patient survival and improvements in quality of life. However, challenges persist in terms of tumor complexity, interindividual variability, drug resistance, and adverse reactions. The emergence of novel immune checkpoints, such as LAG-3, TIM-3, OX-40, and ICOS, opens up new research directions to address these issues. Conclusion: Immune checkpoint inhibitors play a crucial role in the treatment of NSCLC, and the investigation of emerging immune checkpoint inhibitors and agonists presents promising therapeutic opportunities. A comprehensive evaluation of the efficacy and safety of these drugs contributes to the development of personalized treatments, ultimately enhancing treatment outcomes and prognosis for NSCLC patients. [ABSTRACT FROM AUTHOR]

Objective: Genomic biomarkers predicting immune checkpoint inhibitor (ICI) treatment outcomes for Asian metastatic melanoma have been rarely reported. This study presents data on next‐generation sequencing (NGS) and tumour microenvironment biomarkers in 33 cases. Methods: Thirty‐three patients with advanced melanoma, who underwent ICI treatment at the Chang Gung Memorial Hospital in Taiwan, were recruited. The study evaluated clinical outcomes, including response rate, disease control rate, progression‐free survival (PFS) rate and overall survival (OS) rate. Archived tissue samples from 33 cases were subjected to NGS by ACTOnco, and ACTTME was employed in 25 cases. Results: The most prevalent driver mutations were BRAF mutations (24.2%), followed by NRAS (15.2%), KIT (12.1%), KRAS (9.1%) and NF1 (9.1%) mutations. Acral/mucosal melanomas exhibited distinct mutation patterns compared to non‐acral melanomas. Tumour mutational burden estimated using ACTOnco was not associated with ICI efficacy. Notably, genetic alterations in the p53 pathway (CDKNA2 loss, MDM2 gain/amplification and TP53 mutation) accounted for 36.4% and were significantly associated with unfavourable PFS (median PFS 2.7 months vs. 3.9 months, P = 0.0394). Moreover, 26 genes were identified as differentially expressed genes that were upregulated in patients with clinical benefits compared to those without benefits. Four genes, GZMH, GZMK, AIM2 and CTLA4, were found to be associated with both PFS and OS. Conclusion: Genetic alterations in the p53 pathway may be critical in Asian patients with melanoma undergoing ICI treatment. Further investigation is required to explore this mechanism and validate these findings. [ABSTRACT FROM AUTHOR]

The advent of immune checkpoint inhibitors (ICIs) has led to noteworthy progressions in the management of diverse cancer types, as evidenced by the pioneering "ipilimumab" medication authorized by US FDA in 2011. Importantly, ICIs agents have demonstrated encouraging potential in bringing about transformation across diverse forms of cancer by selectively targeting the immune checkpoint pathways that are exploited by cancerous cells for dodging the immune system, culminating in progressive and favorable health outcomes for patients. The primary mechanism of action (MOA) of ICIs involves blocking inhibitory immune checkpoints. There are three approved categories including Programmed Death (PD-1) inhibitors (cemiplimab, nivolumab, and pembrolizumab), Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (Ipilimumab), and Programmed Death-Ligand 1 (PDL-1) (Avelumab). Although ICIs promisingly increase therapeutic response and cancer survival rates, using ICIs has demonstrated some limitations including autoimmune reactions and toxicities, requiring close monitoring. The present review endeavors to explicate the underlying principles of the MOA and pharmacokinetics of the approved ICIs in the realm of cancer induction, including an appraisal of their level of practice-based evidence. [ABSTRACT FROM AUTHOR]