In human beings heterogenous, pervasive and lethal malignancies of different parts of the gastrointestinal (GI) tract viz., tumours of the oesophagus, stomach, small intestine, colon, and rectum, represent gastrointestinal malignancies. Primary treatment modality for gastric cancer includes chemotherapy, surgical interventions, radiotherapy, monoclonal antibodies and inhibitors of angiogenesis. However, there is a need to improve upon the existing treatment modality due to associated adverse events and the development of resistance towards treatment. Additionally, age has been found to contribute to increasing the incidence of tumours due to immunosenescence-associated immunosuppression. Immunosenescence is the natural process of ageing, wherein immune cells as well as organs begin to deteriorate resulting in a dysfunctional or malfunctioning immune system. Accretion of senescent cells in immunosenescence results in the creation of a persistent inflammatory environment or inflammaging, marked with elevated expression of pro-inflammatory and immunosuppressive cytokines and chemokines. Perturbation in the T-cell pools and persistent stimulation by the antigens facilitate premature senility of the immune cells, and senile immune cells exacerbate inflammaging conditions and the inefficiency of the immune system to identify the tumour antigen. Collectively, these conditions contribute positively towards tumour generation, growth and eventually proliferation. Thus, activating the immune cells to distinguish the tumour cells from normal cells and invade them seems to be a logical strategy for the treatment of cancer. Consequently, various approaches to immunotherapy, viz., programmed death ligand-1 (PD-1) inhibitors, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors etc are being extensively evaluated for their efficiency in gastric cancer. In fact, PD-1 inhibitors have been sanctioned as late late-line therapy modality for gastric cancer. The present review will focus on deciphering the link between the immune system and gastric cancer, and the alterations in the immune system that incur during the development of gastrointestinal malignancies. Also, the mechanism of evasion by tumour cells and immune checkpoints involved along with different approaches of immunotherapy being evaluated in different clinical trials will be discussed.

Cervical cancer (CC) remains a prevalent malignancy among women, with current therapeutic strategies facing significant challenges in curbing its rising incidence. Nano-delivery systems have emerged as a promising approach to hinder CC progression. This review provides a comprehensive examination of CC pathogenesis and its physiological characteristics while focusing on applying various nano-delivery systems in CC therapy. Specifically, it highlights the potential of both internal (e.g., pH, reactive oxygen species, glutathione) and external (e.g., Photo, magnetism, sound waves, microwaves, electricity) stimuli-responsive nano-delivery platforms to enhance therapeutic efficacy. The challenges of nano-delivery systems in CC therapy, encompassing in vivo stability, biosafety, distribution, and metabolic processes, are addressed, along with potential remedies. Additionally, the review underscores recent preclinical advances in nano-delivery systems for CC therapy. By thoroughly exploring nanomaterial applications, this review provides valuable perspectives for advancing CC treatment and stimulating future research and innovation in this domain.

ADVISE (ADaptiVe biomarker trial that InformS Evolution of therapy) (NCT03335540) was a biomarker-adapted feasibility clinical trial of immunohistochemistry (IHC) to inform combination immuno-oncology (I-O) treatment.

To inform I-O combination selection, messenger RNA expression analyses from The Cancer Genome Atlas evaluated associations between programmed death 1/programmed death ligand 1 (PD-1/PD-L1) and other I-O-associated genes. Tumor tissue blocks of melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, and gastroesophageal junction/gastric cancer were stained by IHC to assess expression of CD8, colony-stimulating factor 1 receptor, glucocorticoid-induced tumor necrosis factor receptor (GITR), indoleamine 2,3-dioxygenase 1, lymphocyte-activation gene 3, NKp46, forkhead box P3, and PD-L1. These results facilitated an I-O treatment selection algorithm where patient biopsy results dictated allocation into combinations of nivolumab with cabiralizumab, urelumab, linrodostat mesylate, relatlimab, BMS-986156 (anti-GITR), lirilumab, ipilimumab, or irradiation. The primary endpoint was the proportion of patients with qualified baseline tumor biopsy specimens where decision-enabling biomarker analysis was completed within 12 business days to select an I-O combination therapy.

Correlation of PD-1/L1 and I-O-associated genes varied across the spectrum of T-cell-inflamed versus non-inflamed tumors; however, tumors with low/intermediate PD-L1 expression demonstrated distinct upregulation of immune markers grouped by cell type (T cell, macrophage, etc). IHC analyses of I-O naïve tumors corroborated these findings with distinct immune target upregulation in low-to-intermediate inflamed tumors and significant associations between IHC-detected markers and T-cell inflammation score across most markers. In the clinical trial, 20/23 (87%) of eligible patients were successfully allocated and started on treatment within the 12-day window, meeting the primary endpoint. The safety profile appeared to generally align with those reported for the individual combinations from other trials. No treatment responses occurred. Most patients were allocated to the cabiralizumab treatment arm.

Actualization of a patient-specific I-O combination treatment selection strategy is feasible, however, determination of de novo integral biomarker thresholds of novel I-O targets to facilitate effective treatment of PD-1-refractory cancer remains fraught. These data emphasize the difficulty of integral biomarker development for I-O in translating from immunotherapy treatment-naïve biospecimens to the selection of patients in the PD-1-refractory state.

NCT03335540.

Immune checkpoint inhibitors (ICIs) are becoming more prominent in the treatment of gastric cancer (GC). However, predictive biomarkers of response to ICIs in HER2-negative patients remain incompletely understood.

A total of 47 patients diagnosed with HER2-negative advanced GC who underwent ICI regimens were eligible for this study. Plasma samples with paired white blood cells prior to treatments were collected from these 47 patients. Variations of circulating tumor DNA (ctDNA) was evaluated by next-generation sequencing followed by its significance analysis.

A total of 658 somatic mutations involving 203 genes were identified in all ctDNA. Mutations in MEN1, MLH1, CEBPA, ATR, GNAQ, and FOXL2 genes were more frequent in responders (P < 0.05). Compared with wild-type patients, patients with CEBPA or IRS2 mutations had prolonged median progression-free survival (mPFS, P = 0.0056). Patients with co-occurring mutations in IRS2/CEBPA, IRS2/POLD1, TP53/PIK3CA, or POLD1/CEBPA had longer mPFS compared with others (P = 0.003; 0.006; 0.0166; 0.0315; respectively). Both alteration of CDKN2A alone and co-mutations with MSH6 were significantly associated with superior overall survival (OS, P = 0.0289; 0.0355; respectively). In addition, higher on-treatment ctDNA concentration or variant allele frequency (VAF) were associated with poorer response (P < 0.05). Additionally, the increased molecular alterations of POLE, FGFR2 and MDC1 seemed to indicate the acquired resistance to ICIs.

Variation signatures captured by ctDNA as well as the kinetics of ctDNA could predict the clinical benefits of ICB in HER2-negative GC patients, which was worth further validated in large cohort.

Gastric cancer (GC) is one of the primary contributors to cancer-related mortality on a global scale. It holds a position within the top five most prevalent malignancies both in terms of occurrence and fatality rates. Immunotherapy, as a breakthrough cancer treatment, brings new hope for GC patients. Various biomarkers, such as the expression of programmed death ligand-1 (PD-L1), the microsatellite instability (MSI) status, tumor mutational burden (TMB), and Epstein-Barr virus (EBV) infection, demonstrate potential to predict the effectiveness of immunotherapy in treating GC. Nevertheless, each biomarker has its own limitations, which leads to a significant portion of patients continue to be unresponsive to immunotherapy. With the understanding of the tumor immune microenvironment (TIME), genome sequencing technology, and recent advances in molecular biology, new molecular markers, such as POLE/POLD1mutations, circulating tumor DNA, intestinal flora, lymphocyte activation gene 3 (LAG-3), and lipid metabolism have emerged. This review aims to consolidate clinical evidence to offer a thorough comprehension of the existing and emerging biomarkers. We discuss the mechanisms, prospects of application, and limitations of each biomarker. We anticipate that this review will open avenues for fresh perspectives in the investigation of GC immunotherapy biomarkers and promote the precise choice of treatment modalities for gastric cancer patients, thereby advancing precision immuno-oncology endeavors.

It remains unclear whether adding CTLA-4 blockade to PD-1/PD-L1 blockade improves clinical outcomes in cervical cancer (CC).

In this randomized, double-blind, placebo-controlled, phase 2 study (ClinicalTrials.gov: NCT04590599), patients with recurrent/metastatic CC (R/M CC) who experienced disease progression after or during platinum-based chemotherapy were enrolled from 37 centers across China and randomly assigned (1:1), stratified by PD-L1 expression and prior treatment lines, to receive either IBI310 plus sintilimab or placebo plus sintilimab intravenously every 3 weeks for 12 weeks, followed by sintilimab alone. The primary endpoint was the objective response rate (ORR). Pivotal secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.

205 patients were randomized to receive IBI310-sintilimab (n = 103) or placebo-sintilimab (n = 102). The ORR difference between the IBI310-sintilimab arm (32.3%, 95% confidence interval [CI]: 23.3%-42.5%) and the placebo-sintilimab arm (23.5%, 95% CI: 15.5%-33.1%) was not significant (p = 0.17). IBI310-sintilimab and placebo-sintilimab exhibited median PFS values of 3.6 (95% CI: 2.7-6.3) and 4.2 months (95% CI: 2.8-6.2), respectively (hazard ratio [HR] = 0.91, 95% CI: 0.65-1.27; p = 0.58). The median OSs were 13.9 months (95% CI: 11.5-25.6) in the IBI310-sintilimab arm and 17.2 months (95% CI: 13.7-25.9) in the placebo-sintilimab arm (HR = 1.12, 95% CI: 0.79-1.58; p = 0.54). Adding IBI310 to sintilimab increased the incidence of grade ≥3 treatment-related adverse events (55% versus 19%).

Compared to single-agent PD-1/PD-L1 blockade, dual blockade of CTLA-4 and PD-1/PD-L1 did not significantly improve clinical outcomes in R/M CC.

This work was funded by Innovent Biologics (Suzhou).

Identifying predictive biomarkers for immune checkpoint inhibitor (ICI) treatment is critical for gastric cancer (GC) prognosis. C-X-C motif chemokine ligand 13(CXCL13) plays an important role in immune regulation by binding exclusively to its receptor CXCR5. However, its role, underlying mechanisms, and prognostic significance in ICI-treated GC patients remain controversial.

This study investigated the clinical significance of CXCL13 and its potential immunomodulatory function in GC patients. A total of 144 GC patients from two cohorts, who received a combination of chemotherapy and anti-PD-1 antibody, were analyzed. The expression of CXCL13 was assessed using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay. Associations between CXCL13, CXCR5, CD8, and CD4 were assessed by IHC and immunofluorescence. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards model. The treatment response to CXCL13 and anti-PD-1 antibody was investigated using a subcutaneous xenograft tumor mouse model.

The results suggested that patients with high CXCL13 expression had prolonged survival. High CXCL13 expression exhibited increased infiltration of CXCR5+CD8+ T cells and was associated with better outcomes. The combined assessment of CXCL13, CXCR5, and CD8+ T cells served as an independent predictor of prognosis. Additionally, CXCR5 and CD8+ T cells were enriched in tertiary lymphoid structures (TLSs), which conferred a prognostic benefit in the presence of high CXCL13 expression. CXCL13, in combination with anti-PD-1 therapy, retarded tumor growth in vivo, resulting in increased infiltration of CXCR5+CD8+ T cells.

This study identified CXCL13 as a prognostic factor in GC patients receiving ICI therapy, emphasizing its critical role in the antitumor microenvironment via CXCR5+CD8+ T cells.

Advanced esophageal squamous cell carcinoma (ESCC) patients had poor prognosis and few effective drugs based on the randomized controlled trials (RCTs). In such a circumstance, recent RCTs have shown the clinical efficacy of immune checkpoint inhibitors (ICIs) as first- or second-line treatment for advanced ESCC patients. Tislelizumab is one of the anti-Programmed-Death-1 (PD-1) antibodies; at first, tislelizumab monotherapy showed clinical efficacy as a second-line treatment for advanced ESCC patients based on the results of the RATIONALE-302 trial. Since then, tislelizumab plus doublet chemotherapy has shown superiority in overall survival compared to doublet chemotherapy for untreated advanced ESCC patients in the RATIONALE-306 trial. In this review, we share the overview of the development of tislelizumab and discuss the future perspectives on ICIs for advanced ESCC patients. In our opinion, tislelizumab plus doublet chemotherapy is one of the first-line standard treatments for advanced ESCC patients regardless of Programmed cell Death ligand 1 expression. Some other ICI-containing treatments showed clinical efficacy for untreated ESCC patients; we need further investigation to select these treatments appropriately.

Gastric cancer (GC) represents a global health-care challenge. Recent progress in immunotherapy has elicited attracted considerable attention as a viable treatment option through modulating the host immune system and unleashing pre-existing immunity, which has profoundly revolutionized oncology, especially GC. Nonetheless, low clinical response and intrinsic and acquired resistance remain persistently challenging. The microenvironment of GC comprising multifarious stromal cell types has remarkable immunosuppressive elements that may impact the efficacy of immunotherapy. Immunosenescence is increasingly regarded as a factor that contributes to cancer development, remodels the tumor microenvironment and affects the efficacy of immunotherapy. Natural products are at the forefront of traditional medicine. Senotherapeutics is a class of drugs and natural products capable of delaying, preventing, or reversing the senescence process (i.e., senolytics) or suppressing senescence-associated secretory phenotype (i.e., senomorphics). Emerging evidence supports that natural products can improve the efficacy of existing immunotherapy and expand their indications in GC mainly based upon remodeling the immunosuppressive microenvironment and reversing immunosenescence. The review provides an integrated review of previously reported and ongoing clinical trials with immunotherapeutic regimens in GC and discusses current challenges. Next, we focus on natural compounds that exert anti-GC functions and possess immunomodulatory properties. More attention is paid to the potential of these natural compounds in modulating the immune microenvironment and immunosenescence. Lastly, we discuss the nanomedicine that can overcome the deficiencies of natural products. Altogether, our review suggests the enormous potential of natural compounds in GC immunotherapy, and provides an important direction for future research.

Gastric cancer (GC) is linked to high morbidity and mortality rates. Approximately two-thirds of GC patients are diagnosed at an advanced or metastatic stage. Conventional treatments for GC, including surgery, radiotherapy, and chemotherapy, offer limited prognostic improvement. Recently, immunotherapy has gained attention for its promising therapeutic effects in various tumors. Immunotherapy functions by activating and regulating the patient's immune cells to target and eliminate tumor cells, thereby reducing the tumor burden in the body. Among immunotherapies, immune checkpoint inhibitors (ICIs) are the most advanced. ICIs disrupt the inhibitory protein-small molecule (PD-L1, CTLA4, VISTA, TIM-3 and LAG3) interactions produced by immune cells, reactivating these cells to recognize and attack tumor cells. However, adverse reactions and resistance to ICIs hinder their further clinical and experimental development. Therefore, a comprehensive understanding of the advancements in ICIs for GC is crucial. This article discusses the latest developments in clinical trials of ICIs for GC and examines combination therapies involving ICIs (targeted therapy, chemotherapy, radiotherapy), alongside ongoing clinical trials. Additionally, the review investigates the tumor immune microenvironment and its role in non-responsiveness to ICIs, highlighting the function of tumor immune cells in ICI efficacy. Finally, the article explores the prospects and limitations of new immunotherapy-related technologies, such as tumor vaccines, nanotechnologies, and emerging therapeutic strategies, aiming to advance research into personalized and optimized immunotherapy for patients with locally advanced gastric cancer.

Immune encephalitis (IE) is an immune-mediated adverse events (irAEs) linked to nivolumab therapy, and its clinical characteristics remain unclear. This study aimed to analyze the clinical patterns of nivolumab-induced IE to inform diagnosis, treatment, and prevention strategies. We conducted a retrospective analysis of nivolumab-induced IE by reviewing case reports from the database until October 31, 2024. Among the 86 patients (53.5% male), the median age was 64 years (range 17, 83). The median time to the onset of IE was 38 days (range 4, 1430), and the median treatment cycle was 2 cycles (range 1, 18). The most prevalent symptoms included altered mental status (38.4%) and fever (37.2%). Cerebrospinal fluid analysis revealed elevated protein levels, normal glucose, and pleocytosis. Antineuronal antibodies were present in 29.1% of patients. MRI findings typically showed T2/FLAIR hyperintense signals in 52.3%. EEG results indicated diffuse slowing (16.3%). Following drug discontinuation and treatment, 86% of patients exhibited recovery or improvement, while 5.8% unfortunately succumbed to the condition. IE represents a rare yet severe irAEs associated with nivolumab. Clinicians must remain vigilant for signs of IE in patients undergoing nivolumab treatment. Diagnostic tests for nivolumab-induced IE generally do not reveal specific abnormalities. For individuals diagnosed with IE, it is crucial to initiate systemic steroid treatment without delay.

Gastric cancer remains one of the most prevalent and lethal malignancies worldwide, characterized by poor survival rates, particularly in advanced stages. In recent years, a paradigm shift in gastric cancer treatment has been witnessed with the introduction of immunotherapy and targeted therapies. This review provides a detailed examination of current immunotherapeutic strategies, including adoptive cell therapy (ACT), immune checkpoint inhibitors (ICIs), and cancer vaccines. Additionally, it explores advancements in targeted therapies, focusing on the human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor receptor (VEGFR) signaling pathways, as well as emerging targets such as claudin 18.2. Clinical trials investigating chimeric antigen receptor T-cell (CAR-T) therapy, T-cell receptor-engineered T-cell (TCR-T) therapy, and natural killer (NK) cell-based treatments have shown promise, particularly when combined with conventional chemotherapeutic regimens. However, challenges such as cytokine release syndrome, immune-related toxicities, and scalability issues remain significant. The combination of immunotherapy with targeted therapies represents a promising approach to enhance treatment outcomes. Future directions emphasize the need to overcome resistance mechanisms and refine treatment strategies to improve efficacy while reducing adverse effects. This review aims to elucidate the current landscape of immunotherapy and targeted therapy in gastric cancer and to explore their potential in shaping the future of clinical management for this devastating disease.

Gastric adenocarcinoma (GAC) remains a significant global public health challenge, characterized by high incidence and mortality rates. Progress in tumor immunology has introduced immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways, demonstrating substantial potential in GAC therapy. Clinical research indicates that ICIs, particularly when combined with chemotherapy or targeted therapies, significantly enhance treatment efficacy in advanced GAC and specific molecular subtypes, including microsatellite instability-high (MSI-H) and human epidermal growth factor receptor 2 (HER2)-positive patients. However, immunotherapy is also associated with a range of immune-related adverse events (irAEs), necessitating effective management strategies to ensure treatment safety and maintain patients' quality of life. Future studies should focus on identifying new therapeutic targets, optimizing patient selection, and developing personalized treatment approaches to further improve the efficacy and safety of immunotherapy in GAC.

Gastric cancer (GC) is a highly aggressive malignancy associated with poor prognosis, particularly in its advanced stages. Neutrophil extracellular traps (NETs) have been implicated in cancer progression and immune therapy responses; however, the role of NETs-related long non-coding RNAs (lncRNAs) in GC remains poorly understood. This study used data from the Cancer Genome Atlas (TCGA) and previous research to identify NETs-related lncRNAs in GC. A prognostic signature comprising four NETs-related lncRNAs (NlncSig) was developed and validated, serving as a predictor for patient survival and response to immunotherapy. The NlncSig was correlated with poorer outcomes in high-risk patients and demonstrated that those with lower risk scores exhibited more favorable responses to immunotherapy. In vitro experiments confirmed that LINC01150 enhances GC cell proliferation, migration, and invasion. This robust NlncSig provides a reliable tool for predicting survival and immune characteristics in GC, with the potential to guide personalized therapeutic approaches and improve patient care.

A 77-year-old man with large-cell gastric neuroendocrine carcinoma underwent palliative total gastrectomy after 10 cycles of carboplatin and etoposide chemotherapy for severe tumor bleeding. Despite a histological grade 0 therapeutic effect, the remnant lesions were treated with paclitaxel and ramucirumab, but progression occurred after two cycles. Nivolumab monotherapy was then initiated, resulting in complete remission after three cycles. Nivolumab was discontinued because of immune-related psoriasis, but complete remission persisted for at least 16 months. This is the first reported case of nivolumab monotherapy achieving complete remission in gastric neuroendocrine carcinoma with the patient surviving 28 months.

Esophageal cancer is one of the most common and deadliest cancers worldwide. Rates of esophageal cancer worldwide have been steadily rising over the past decade due to higher incidence of gastroesophageal reflux disease (GERD). Current therapies include surgical resection, chemotherapy, and limited targeted therapies. One obstacle to care is tumor cells' ability to evade immune surveillance, which can render certain therapeutics ineffective. Immunotherapy provides a new paradigm to cancer treatment, which has proven to be effective in evasive tumors. In recent years, PD-1/PD-L1 and CLTA-4 inhibitors have been used as frontline treatment and have shown to be extremely effective in the treatment of hard-to-treat tumors. Here, we aim to analyze the current literature regarding current therapeutics along with emerging techniques and future receptor targets for immunotherapy.

CD8+ T lymphocytes greatly affect the efficacy of immunotherapy, displaying promising potential in various tumors. Here, we aimed to identify immune subtypes associated with CD8+ T cell-related genes to predict the efficacy of treatment in esophageal cancer (ESCA).

We obtained 13 immune cell-related datasets from the Gene Expression Omnibus (GEO) database and removed batch effects. Weighted correlation network analysis (WGCNA) and co-expression analysis were performed to identify highly correlated CD8+ T cell genes. Cox analysis was used to process ESCA clinical information, and the immune clusters (ICs) were constructed through consensus cluster analysis. Furthermore, we constructed an immune risk score model to predict the prognosis of ESCA based on these CD8+ T cell genes. This model was verified using the IMvigor210 dataset, and we functionally validated the immune risk score model in vitro.

The results revealed significant correlations between CD8+ T cell-related genes and immune-related pathways. Three ICs were identified in ESCA, with IC3 demonstrating the most favorable prognosis. The final 6-gene prognostic risk model exhibited stable predictive performance in datasets across different platforms. Compared with that in normal esophageal epithelial (HEEC cells), CHMP7 in the 6-gene prognostic risk model was upregulated in KYSE150 and TE-1 cells. Si-CHMP7 transfection led to a decrease in tumor cell migration, invasion, and proliferation, accompanied by an accelerated apoptotic process.

Collectively, we identified the immune subtypes of CD8+ T cell-related genes with different prognostic significance. We designated CHMP7 in the 6-gene prognostic risk model as a potential target to improve tumor cell prognosis. These insights provide a strong basis for improving prognosis and facilitating more personalized and accurate treatment decisions for the immunotherapy of ESCA.

BUB1B, a member of the spindle assembly checkpoint family known as BUB1 mitotic checkpoint serine/threonine kinase B, has been associated with the promotion of tumor progression. Nevertheless, its specific contributions to tumorigenesis remain largely unexplored. This study seeks to offer a systematic and comprehensive analysis of the role of BUB1B in the progression of various cancers, with a particular focus on lung adenocarcinoma, utilizing a range of databases. We investigated BUB1B's role in pan-cancer using TCGA data, analyzing it with platforms like HPA, TIMER, TISIDB, GEPIA, cBioPortal, GDC, LinkedOmics, and CancerSEA. Additionally, we assessed BUB1B's impact on lung adenocarcinoma proliferation and migration through CCK-8, wound healing, transwell assays and Western blot analysis. This study found that BUB1B was upregulated in most cancers and was significantly linked to patient prognosis. Its expression correlated with immune cell infiltration and genetic markers of immunomodulators across different cancers. BUB1B was involved in the acute inflammatory response and IgA production pathways but negatively correlated with inflammation in lung adenocarcinoma. Moreover, the siRNA-mediated knockdown of BUB1B resulted in the inhibition of proliferation and migration of lung cancer cells in vitro. This study underscores the potential of BUB1B as a biomarker and a promising therapeutic target for patients with lung adenocarcinoma.

Microsatellite instability-high (MSI-H) gastric cancer (GC) is recognized as a unique subtype of gastric cancer. While patients with advanced MSI-H gastric cancer may respond favorably to a combination of immune checkpoint inhibitors and chemotherapy in first-line treatment, no definitive recommendations exist regarding the optimal regimen for subsequent therapy. Cadonilimab, a PD-1 and CTLA-4 bispecific antibody, has shown encouraging efficacy and safety in the first-line treatment of advanced gastric cancer. However, its utility in the MSI-H gastric cancer subtype following multiple lines of therapy remains uncertain. This case report describes a patient with advanced MSI-H gastric adenocarcinoma that progressed after multiple treatments and achieved notable efficacy with a combination of cadonilimab and apatinib. By examining the current therapeutic landscape for MSI-H gastric cancer, this study explores the potential of combining PD-1/CTLA-4 dual-immunity with anti-vascular therapy as salvage treatment for this gastric cancer subtype. The findings provide valuable reference points for future clinical trials, offering a promising perspective on backline therapeutic strategies for MSI-H gastric cancer and highlighting the potential of integrating bispecific antibodies with anti-vascular therapies.

The administration of second-line or subsequent immune checkpoint inhibitors (ICIs) in previously treated patients with advanced solid cancers has been clinically investigated. However, previous clinical trials lacked an appropriate primary endpoint for efficacy assessment. This systematic review aimed to explore the most optimal early efficacy endpoint for such trials.

Phase 2 or 3 clinical trials involving patients with advanced solid cancers with disease progression following standard first-line therapy receiving second-line or subsequent ICI administration, with adequate survival outcome data, were included from PubMed, Embase, Web of Science, and Cochrane Library databases before February 2023. Quality assessment was conducted using the Cochrane tool and Newcastle-Ottawa Quality Assessment Scale for Cohort Studies for randomized controlled trials (RCTs) and non-randomized trials, respectively. Objective response rate (ORR) and progression-free survival (PFS) at 3, 6, and 9 months were investigated as potential early efficacy endpoint candidates for 12-month overall survival (OS), with a strong correlation defined as Pearson's correlation coefficient r ≥ 0.8.

A total of 64 RCTs comprising 22,725 patients and 106 non-randomized prospective trials involving 10,608 participants were eligible for modeling and external validation, respectively. RCTs examined 15 different cancer types, predominantly non-small-cell lung cancer (NSCLC) (17, 28%), melanoma (9, 14%), and esophageal squamous cell carcinoma (5, 8%). The median sample size of RCTs was 124 patients, and the median follow-up time was 3.2-57.7 months. The ORR (r = 0.38; 95% confidence interval [CI], 0.18-0.54) and PFS (r = 0.42; 95% CI, 0.14-0.64) exhibited weak trial-level correlations with OS. Within ICI treatment arms, the r values of ORR and 3-, 6-, and 9-month PFS with 12-month OS were 0.61 (95% CI, 0.37-0.79), 0.78 (95% CI, 0.62-0.88), 0.84 (95% CI, 0.77-0.90), and 0.86 (95% CI, 0.79-0.90), respectively. External validation of 6-month PFS indicated an acceptable discrepancy between actual and predicted 12-month OS.

In non-randomized phase 2 trials on second-line or subsequent ICI therapy in patients with advanced solid cancers, 6-month PFS could serve as an early efficacy endpoint. However, early efficacy endpoints are not recommended in RCTs to replace OS.

Gastric cancer (GC) is one of the most common malignant tumors worldwide, and its treatment has been a focus of medical research. Herein we systematically review the current status of and advancements in targeted therapy and immunotherapy for GC, which have emerged as important treatment strategies in recent years with great potential, and summarize the efficacy and safety of such treatments. Targeted therapies against key targets in GC, including epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR), have shown remarkable therapeutic efficacies by inhibiting tumor progression and/or blood supply. In particular, markable breakthroughs have been made in HER2-targeting drugs for HER2-positive GC patients. To address intrinsic and acquired resistances to HER2-targeting drugs, novel therapeutic agents including bispecific antibodies and antibody-drug conjugates (ADC) targeting HER2 have been developed. Immunotherapy enhances the recognition and elimination of cancer cells by activating body anticancer immune system. Programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) antibodies are the most commonly used immunotherapeutic agents and have been used with some success in GC treatment. Innovative immunotherapy modalities, including adoptive immune cell therapy, tumor vaccines, and non-specific immunomodulators therapy, and oncolytic viruses have shown promise in early-stage clinical trials for GC. Clinical trials have supported that targeted therapy and immunotherapy can significantly improve the survival and quality of life of GC patients. However, the effects of such therapies need to be further improved and more personalized, with advancement in researches on tumor immune microenvironment. Further studies remain needed to address the issues of drug resistance and adverse events pertaining to such therapies for GC. The combined application of such therapies and individualized treatment strategies should be further explored with novel drugs developed, to provide more effective treatments for GC patients.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited treatment options in advanced stages. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD1/PD-L1, has emerged as a promising therapeutic approach. However, a significant proportion of patients exhibit primary or acquired resistance, limiting the overall efficacy of immunotherapy. This review provides a comprehensive analysis of the mechanisms underlying immunotherapy resistance in GC, including the role of the tumor immune microenvironment, dynamic PD-L1 expression, compensatory activation of other immune checkpoints, and tumor genomic instability. Furthermore, the review explores GC-specific factors such as molecular subtypes, unique immune evasion mechanisms, and the impact of Helicobacter pylori infection. We also discuss emerging strategies to overcome resistance, including combination therapies, novel immunotherapeutic approaches, and personalized treatment strategies based on tumor genomics and the immune microenvironment. By highlighting these key areas, this review aims to inform future research directions and clinical practice, ultimately improving outcomes for GC patients undergoing immunotherapy.

Patients with gastro-oesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastro-oesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and resection.

VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastro-oesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1 : 1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg intravenously (i.v.) every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, locoregional and distant failure rates, and safety according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0.

The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months [95% confidence interval (CI) 8.4-16.8 months] versus 20.8 months (95% CI 15.0-29.9 months) for the chemotherapy group, hazard ratio 1.55 (95% CI 1.07-2.25, one-sided P = 0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations.

Nivolumab/ipilimumab did not improve disease-free survival compared with chemotherapy in patients with ypN+ and/or R1 gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery.

This review addresses the current treatment paradigm and new advancements in the management of microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) esophagogastric cancer (EGC).

While chemotherapy and surgery remain the cornerstone of EGC treatment, MSI-H/dMMR tumors harbor high tumor mutational burden and represent a subset of patients who benefit from immune checkpoint inhibitors (ICI). ICI has been incorporated in the front line setting with and without chemotherapy for advanced disease. Recently, ICI has been studied in the perioperative setting for resectable disease. Though perioperative ICI results in improved response rates, it is not yet clear whether this translates to a survival benefit. Despite high response rates with ICI in this patient population, many do not respond to therapy, representing a major challenge in treatment. Preclinical studies have highlighted potential mechanisms of resistance which will guide drug development and clinical trials.

Nivolumab-based therapies are efficacious with acceptable safety in patients with gastric cancer (GC) and gastroesophageal junction cancer (GEJC). Novel nivolumab-based combination immunotherapies may offer enhanced efficacy in these indications. FRACTION-GC was a signal-seeking, randomized, open-label, phase II adaptive-design trial assessing efficacy and safety of nivolumab in combination with ipilimumab [cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody], relatlimab (lymphocyte-activation gene 3 antibody), or IDO1i (BMS986205, an indoleamine-2,3-dioxygenase-1 inhibitor) in patients with unresectable, advanced/metastatic GC/GEJC.

Previously treated patients with GC/GEJC were randomized to receive nivolumab + ipilimumab, nivolumab + relatlimab, or nivolumab + IDO1i across two tracks: anti-programmed death-(ligand) 1/anti-CTLA-4-naïve (track 1) and -experienced (track 2). Primary endpoints were objective response rate (ORR) by investigator per RECIST v1.1, duration of response, and progression-free survival (PFS) rate at 24 weeks. Secondary endpoint was safety.

Eighty-one patients in track 1 and 81 in track 2 received one combination therapy. With a median follow-up of 50.2 months, ORR [95% confidence interval (CI)] by investigator for nivolumab + ipilimumab, nivolumab + relatlimab, and nivolumab + IDO1i in track 1 was 4% (0.1% to 21.9%), 5% (0.1% to 24.9%), and 13% (4.4% to 28.1%), and for track 2 was 9% (1.1% to 28.0%), 6% (0.7% to 18.7%), and 0% (0% to 15.4%), respectively. PFS rate at 24 weeks (95% CI) was 24% (11% to 39%) for nivolumab + IDO1i track 1, 17% (16% to 32%) for nivolumab + relatlimab track 2, and not estimable for other treatment arms. Grade 3/4 treatment-related adverse events were reported in 22%, 5%, and 18% of patients receiving nivolumab + ipilimumab, nivolumab + relatlimab, and nivolumab + IDO1i in track 1 and in 35%, 11%, and 18% of patients in track 2, respectively. No treatment-related deaths were reported.

While ORR did not meet prespecified expansion criteria in any treatment arm, the safety profile of the combinations was manageable. FRACTION-GC represents a novel adaptive protocol for testing multiple combination immunotherapies.

Notable advances have been made in immune checkpoint inhibitors (ICIs) for cancer treatment. However, the adverse effects of ICIs, especially hepatotoxicity, remain a challenging problem. Whether patients in hepatitis B virus (HBV)-endemic areas are prone to developing hepatic adverse events during ICI treatment warrants further exploration.

From 2014 to 2020, the data of all patients with cancer who received ICI treatment at Taipei Veterans General Hospital were retrospectively reviewed. The incidence of and risk factors for hepatic adverse events, including hepatitis flare, immune-related hepatitis (irHepatitis) and HBV reactivation (HBVr), were analysed through a Cox proportional hazard regression model.

A total of 1283 patients with cancer (190 hepatocellular carcinoma [HCC] patients and 1093 patients with non-HCC malignancies) were eligible for analysis, of whom 283 (22.1%) were HBsAg-positive. The incidence of hepatitis flare events of any grade was significantly higher in HCC patients than in non-HCC patients (45.8% vs. 25.6%, p < 0.001). HCC and baseline alanine aminotransferase (ALT) > 40 U/L were independent risk factors for ≥ grade 3 hepatitis flare events. No difference was observed in irHepatitis risk between HCC patients and non-HCC patients. ALT > 40 U/L was an independent risk factor for irHepatitis. Among 283 HBsAg-positive patients, six patients (2.1%) experienced HBVr. HCC patients had a higher risk of HBVr than non-HCC patients (4.4% vs. 0.6%). No specific risk factor for HBVr could be identified. However, none of the patients under nucleos/tide analogue (NUC) prophylaxis experienced HBVr in this study.

Under ICI treatment, HCC patients had a higher risk of hepatitis flare events than non-HCC patients. Abnormal baseline ALT levels are a risk factor for hepatic adverse events. NUC prophylaxis can minimise the risk of HBVr.

We carried out the meta-analysis to determine the predictive value of baseline neutrophil to lymphocyte ratio (NLR) and derived neutrophil to lymphocyte ratio (dNLR) levels in patients with gastroesophageal junction or gastric cancer (GJGC) who underwent immune checkpoint inhibitor (ICI) treatment.

Eligible articles were obtained through PubMed, the Cochrane Library, EMBASE, and Google Scholar, until April 15, 2023. The clinical outcomes evaluated in this study encompassed overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR).

A total of 24 articles with 2221 patients were included in this meta-analysis. The pooled results demonstrated that patients with high NLR levels had significantly poorer OS (HR: 1.860, 95% CI: 1.564-2.213, p < 0.001) and PFS (HR: 1.678, 95% CI: 1.354-2.079, p < 0.001), and lower ORR (OR: 0.754, 95% CI: 0.621-0.915, p = 0.004) and DCR (OR: 0.391, 95% CI: 0.262-0.582, p < 0.001). Besides, we also found that high dNLR levels were significantly associated with shorter OS (HR: 2.117, 95% CI: 1.590-2.820, p < 0.001) and PFS (HR: 1.803, 95% CI: 1.415-2.297, p < 0.001).

Low baseline (Derived) NLR has the potential to predict the good efficacy of ICIs and survival outcomes in patients with GJGC. (Derived) NLR could be useful in determining the optimal treatment strategies for these patients.

Esophageal cancer (EC) is the seventh-most prevalent cancer worldwide and is a significant contributor to cancer-related mortality. Metabolic reprogramming in tumors frequently coincides with aberrant immune function alterations, and extensive research has demonstrated that perturbations in energy metabolism within the tumor microenvironment influence the occurrence and progression of esophageal cancer. Current treatment modalities for esophageal cancer primarily include encompass chemotherapy and a limited array of targeted therapies, which are hampered by toxicity and drug resistance issues. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway, has exhibited promising results; however, a substantial proportion of patients remain unresponsive. The optimization of these immunotherapies requires further investigation. Mounting evidence underscores the importance of modulating metabolic traits within the tumor microenvironment (TME) to augment anti-tumor immunotherapy.

We selected relevant studies on the metabolism of the esophageal cancer tumor microenvironment and immune cells based on our searches of MEDLINE and PubMed, focusing on screening experimental articles and reviews related to glucose metabolism, amino acid metabolism, and lipid metabolism, as well their interactions with tumor cells and immune cells, published within the last five years. We analyzed and discussed these studies, while also expressing our own insights and opinions.

A total of 137 articles were included in the review: 21 articles focused on the tumor microenvironment of esophageal cancer, 33 delved into research related to glucose metabolism and tumor immunology, 30 introduced amino acid metabolism and immune responses, and 17 focused on the relationship between lipid metabolism in the tumor microenvironment and both tumor cells and immune cells.

This article delves into metabolic reprogramming and immune alterations within the TME of EC, systematically synthesizes the metabolic characteristics of the TME, dissects the interactions between tumor and immune cells, and consolidates and harnesses pertinent immunotherapy targets, with the goal of enhancing anti-tumor immunotherapy for esophageal cancer and thereby offering insights into the development of novel therapeutic strategies.

PD-1 inhibitors have shown promising efficacy in enhancing OS and AEs as second-line therapies for patients with advanced esophageal squamous cell carcinoma (ESCC). However, there remains no clear consensus on which PD-1 inhibitor provides the best balance between efficacy and safety. To address this key issue in the second-line treatment of ESCC, we conducted a network meta-analysis (NMA) with a focus on OS benefits, particularly in patients with different levels of PD-L1 expression.

A systematic search of relevant literature was conducted in Web of Science, Embase, PubMed, and Cochrane Library, covering publications from the inception of these database to June 2024. The evaluated endpoints included OS, progression-free survival (PFS), objective response rate (ORR), AEs, and Grade ≥ 3 adverse events (Grade ≥ 3 AEs). A systematic review and Bayesian network meta-analysis were performed to assess the efficacy and safety of various immunotherapy regimens in patients with advanced ESCC. To ensure transparency, novelty, and reliability, this study was prospectively registered in the systematic review registry (CRD42024540581).

Five randomized controlled trials (RCTs), encompassing 2,078 patients and six treatment regimens, were included in this study. Among advanced ESCC patients not selected based on PD-L1 expression, Sintilimab demonstrated the greatest OS benefit (HR = 0.70, 95% CI: 0.50-0.98). Camrelizumab showed the most favorable improvement in PFS compared to chemotherapy (HR = 0.64, 95% CI: 0.47-0.87) and also achieved the best ORR benefit (OR = 3.72, 95% CI: 1.98-6.99). In terms of safety, Nivolumab (OR = 0.10, 95% CI: 0.05-0.19) and Tislelizumab (OR = 0.18, 95% CI: 0.10-0.33) exhibited significant safety advantages over chemotherapy concerning AEs. Moreover, Nivolumab (OR = 0.13, 95% CI: 0.08-0.20) was associated with a markedly lower risk of Grade ≥ 3 AEs compared to chemotherapy. Subgroup analysis based on PD-L1 expression revealed that Tislelizumab (HR = 0.53, 95% CI: 0.37-0.76) offered the greatest OS benefit for patients with PD-L1 ≥ 10%, while Camrelizumab (HR = 0.71, 95% CI: 0.57-0.89) was the most likely regimen to provide an OS advantage for patients with PD-L1 < 10%.

Compared to chemotherapy, PD-1 inhibitors may provide improved survival outcomes for patients with advanced ESCC. Among patients not selected based on PD-L1 expression, Sintilimab is most likely to deliver the best survival benefit. For patients with PD-L1 expression ≥ 10%, Tislelizumab is expected to offer the greatest efficacy, while Camrelizumab appears to be the most effective for those with PD-L1 < 10%.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024540581.

Gastric Cancer (GC) is the 5th most prevalent and 4th most deadly neoplasm globally. Immunotherapy has emerged as a promising treatment approach in GC, potentially improving positive clinical outcomes while addressing the limitations of conventional therapies. GC immunotherapy modalities consist of adoptive cell therapy (ACT), cancer vaccines, and immune checkpoint inhibitors (ICI).

This systematic review aims to provide an overview of the advances in immune-based therapeutic approaches in GC, highlighting the potential of this therapy as a strategy for GC treatment.

Key studies investigating several immunotherapeutic agents and combination therapies were searched in PUBMED and included in this study. Specific cancer outcomes related to disease progression or survival were analyzed.

After screening 236 studies, the results revealed that immunotherapy, particularly the ICI pembrolizumab, demonstrated promising efficacy in the treatment of GC, as several studies reported improved OS, PFS, and objective response rate with the use of pembrolizumab alone or in combination with other treatment modalities.

Safety analysis showed that immunotherapy was mostly well-tolerated, with manageable adverse events and relatively good safety profiles. Nonetheless, further research is required to understand the mechanisms of tumor resistance better and identify predictive biomarkers that can direct treatment optimization.

Gastric cancer is a common malignant tumor of the digestive tract, and its treatment remains a significant challenge. In recent years, the role of various immune cells in the tumor microenvironment in cancer progression and treatment has gained increasing attention. Immunotherapy, primarily based on immune checkpoint inhibitors, has notably improved the prognosis of patients with gastric cancer; however, challenges regarding therapeutic efficacy persist. Histological features within the tumor microenvironment, such as tertiary lymphoid structures (TLSs), tumor-infiltrating lymphocytes, and the proportion of intratumoral stroma, are emerging as potentially effective prognostic factors. In gastric cancer, TLSs may serve as local immune hubs, enhancing the ability of immune cells to interact with and recognize tumor antigens, which is closely linked to the effectiveness of immunotherapy and improved survival rates in patients. However, the specific cell type driving TLS formation in tumors has not yet been elucidated. Mature TLSs are B-cell regions containing germinal centers. During germinal center formation, B cells undergo transformations to become mature cells with immune function, exerting anti-tumor effects. Therefore, targeting B cells within TLSs could provide new avenues for gastric cancer immunotherapy. This review, combined with current research on TLSs and B cells in gastric cancer, elaborates on the relationship between TLSs and B cells in the prognosis and immunotherapy of patients with gastric cancer, aiming to provide effective guidance for precise immunotherapy.

Gastrointestinal (GI) cancers represent a significant global health burden, and the need for more effective treatment options is exceptionally pressing. The present meta-analysis aimed to explore the efficacy and safety of the combination of nivolumab and ipilimumab in treating GI cancers.

A systematic search of four databases (PubMed, Embase, Web of Science, and Cochrane Library) was conducted for articles on the treatment of GI cancers with nivolumab combined with ipilimumab, published from 2014 up to 30 August 2024. The inclusion criteria were designed according to the principles of Participants, Intervention, Control, Outcomes, and Study (PICOS). The control group was chemotherapy or nivolumab monotherapy or nivolumab in combination with other drugs. We extracted data from 10 randomized controlled trials and utilized a random effects model to assess the objective response rate (ORR), median progression-free survival (mPFS), median overall survival (mOS), median duration of response (mDOR), and treatment-related adverse events (TRAEs). The data analysis was conducted using Review Manager version 5.4 and Stata version 12.0.

Overall, the combination of nivolumab and ipilimumab demonstrated superior outcomes, including a higher ORR (OR = 1.69, P = 0.01), prolonged mOS (MD = 1.74, P = 0.04) and extended mDOR (MD = 5.64, P < 0.00001) compared to the control group. Subgroup analysis demonstrated that the ORR (OR = 1.75, P = 0.02) and mOS (MD = 5.02, P = 0.003) were significantly improved in patients with esophageal cancer. Notably, the ORR in patients with biliary cancer was significantly lower (OR = 0.11, P = 0.04). Additionally, the ORR was significantly higher in the NIVO1 + IPI3group (OR = 2.82, P = 0.01) and NIVO3 + IPI1 group (OR = 1.62, P = 0.01). Regarding safety, there was no statistically significant difference between the combination regimen and the control group in terms of any grade (OR = 0.72, P = 0.26) or grade 3-4 TRAEs (OR = 1.36, P = 0.14).

Nivolumab in combination with ipilimumab demonstrated significant efficacy in GI cancers (especially esophageal cancer) without causing more adverse reactions. However, its efficacy in biliary cancer still needs to be further proven.

https://www.crd.york.ac.uk/prospero/, identifier CRD42024590994.