The COMPASSION-15 trial demonstrated that cadonilimab plus chemotherapy (CAD-CHM) confers clinical benefits over placebo plus chemotherapy (PLA-CHM) as a first-line treatment for human epidermal growth factor receptor 2 (HER2)-negative advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. However, the introduction of cadonilimab substantially elevates treatment costs, and its cost-effectiveness relative to PLA-CHM remains undetermined. This study evaluates the cost-effectiveness of CAD-CHM compared with PLA-CHM from the perspective of the Chinese healthcare system.

A Markov model with three health states was developed to assess the cost-effectiveness of CAD-CHM in HER2-negative advanced G/GEJ adenocarcinoma. Clinical efficacy data were sourced from the COMPASSION-15 trial, while drug costs were calculated based on national tender prices, and additional costs and utility values were extracted from published literature. The analysis encompassed the overall population, as well as subgroups stratified by programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 5 and CPS < 5. Outcomes included total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Sensitivity analyses were conducted to evaluate model robustness.

The ICER of CAD-CHM was $67,378.09 per QALY in the overall population, $48,433.34 per QALY in the PD-L1 CPS ≥ 5 subgroup, and $78,463.86 per QALY in the PD-L1 CPS < 5 subgroup. Key determinants influencing model outcomes included patient weight, cadonilimab cost, and the utility value of progression-free survival. Across all groups, CAD-CHM resulted in an ICER exceeding the willingness-to-pay threshold of $41,511 per QALY, with a 0% probability of cost-effectiveness compared with PLA-CHM.

From the perspective of the Chinese healthcare system, CAD-CHM is not cost-effective as a first-line treatment for HER2-negative advanced G/GEJ adenocarcinoma, either in the overall population or in subgroups stratified by PD-L1 CPS status, compared with chemotherapy alone.

Extremely aggressive prostate cancer, including subtypes like small cell carcinoma and neuroendocrine carcinoma, is associated with poor prognosis and limited treatment options. This study sought to create a robust, interpretable machine learning-based model that predicts 1-, 3-, and 5-year survival in patients with extremely aggressive prostate cancer. Additionally, we sought to pinpoint key prognostic factors and their clinical implications through an innovative method.

This study retrospectively analyzed data from 1,620 patients with extremely aggressive prostate cancer in the SEER database (2000-2020). Feature selection was performed using the Boruta algorithm, and survival predictions were made using nine machine learning algorithms, including XGBoost, logistic regression (LR), support vector machine (SVM), random forest (RF), k-nearest neighbor (KNN), decision tree (DT), elastic network (Enet), multilayer perceptron (MLP) and lightGBM. Model performance was evaluated using metrics such as AUC, accuracy (F1 score), confusion matrix, and decision curve analysis. Additionally, Shapley Additive Explanations (SHAP) were applied to interpret feature importance within the model, revealing the clinical factors that influence survival predictions.

Among the nine models, the lightGBM model exhibited the best performance, with an AUC and F1 score of (0.8, 0.809) for 1-year survival prediction, (0.809, 0.751) for 3-year survival prediction, and (0.773, 0.611) for 5-year survival prediction. SHAP analysis revealed that M stage was the most important feature for predicting 1- and 3-year survival, while PSA level had the greatest impact on 5-year survival predictions. The model demonstrated good clinical utility and predictive accuracy through decision curve analysis and confusion matrix.

The lightGBM model has good predictive power for survival in patients with extremely aggressive prostate cancer. By identifying key clinical factors and providing actionable predictions, the model has the potential to enhance prognostic accuracy and improve patient outcomes.

Patients with small cell lung cancer (SCLC) generally have a poor prognosis, with an exceptionally high proliferative rate and a strong propensity for early metastasis, indicating the urgent need for novel therapies. The development of chimeric antigen receptor (CAR)s targeting solid tumors is limited owing to the lack of target antigens and low efficacy. In this study, we aimed to discover new targets for SCLC CAR-T therapy and develop CAR-T-based combinational treatment against SCLC in preclinical models.

The in vitro antitumor activity of B7H6-specific CAR-T cell was evaluated. Venetoclax-resistant B7H6 CAR-T cell were designed and the synergistic effect of venetoclax and B7-H6 CAR-T cells was tested in vitro and in vivo.

B7H6 is highly expressed in SCLC tumors. CAR-T cell against B7H6 displayed antigen-specific antitumor efficacy. BCL-2(D103E)-expressing CAR-T cells showed resistance to venetoclax-induced apoptosis. The combinational treatment of venetoclax and BCL-2(D103E)-expressing B7H6-targeting showed potent anti-SCLC effect in vitro and in vivo.

Our findings suggest that the combination of BCL-2 mutant-expressing B7H6-targeting CAR-T cells and venetoclax could be a promising novel strategy against B7H6-expressing SCLCs and other solid tumors, providing the foundation for CAR-T cells and proapoptotic small molecules therapy in patients with SCLCs in a clinical trial.

Extensive-stage small cell lung cancer (SCLC) has a dismal prognosis. Despite initial responsiveness to first-line platinum-etoposide chemotherapy, most patients relapse within six months. Managing disease progression, particularly in platinum-resistant or refractory cases, remains challenging. Topotecan is the only drug approved in the European Union for the second-line treatment of SCLC but is associated with modest clinical activity and high rates of hematological toxicities. Temozolomide, an oral alkylating agent, has been investigated as a viable alternative for treating relapsed SCLC. This study presents the largest real-world cohort of SCLC-patients treated with temozolomide.

We performed a retrospective analysis of patients with relapsed SCLC treated with temozolomide at a single academic hospital in Belgium. Temozolomide was administered at a fixed dose of 250 mg orally once daily on days 1-5 of each 28-day cycle. Data on activity (overall response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS) and median overall survival (mOS)) and safety (treatment related adverse events (TRAE)) were collected.

Between February 2011 and May 2023, a total of 48 patients with relapsed SCLC were treated with temozolomide of which 47 patients, median age 61 years, were included in this real-world analysis. The majority of the patients were heavily pretreated with 57.4 % having received two or more prior systemic therapies. An objective response was observed in 14.9 % and the DCR was 23.4 %. The median PFS was 1.7 months (95 % CI 1.5-1.9) and the median OS was 3.2 months (95 % CI 2.3-4.1). Grade 3-4 TRAEs occurred in 34 % of the patients.

Temozolomide demonstrated modest clinical activity in this real-world effectiveness analysis of patients with relapsed SCLC. Nevertheless, given its comparable response rate and milder toxicity profile compared to topotecan, temozolomide should be considered as a viable alternative to topotecan for treating relapsed SCLC.

Progression-free survival (PFS) and overall survival (OS) curves generally approximate first-order kinetics. On log-linear plots, convex curves with downward inflection (indicating late acceleration of progression/death) might arise from stopping effective therapies. We digitized published PFS/OS curves for etoposide/platinum-treated extensive small-cell lung cancer (SCLC) and other malignancies and replotted the curves log-linearly. Of 26 SCLC PFS curves, 21 (81%) were highly convex (with a marked late down-turn), and 26 (100%) were moderately or highly convex vs. 35/888 (4%) highly convex and 186 (21%) moderately/highly convex curves for other cancers (p < 0.0001). For SCLC, all 32 OS curves were moderately or highly convex vs. 87/363 (24%) that were moderately/highly convex for other cancers (p < 0.0001). The SCLC PFS curves had an initial downward inflection at a median of 3.1 months (around the completion of first-line chemotherapy), then a second inflection at 5.4 months, with further acceleration of progression. The median PFS half-life was 11.9 months while receiving treatment vs. 1.7 months after the second inflection point. Immunotherapy benefit appeared to be limited to 6-10% of the population. SCLC PFS/OS curves are more often convex than for other cancers, reflecting SCLC chemotherapy sensitivity but rapid progression following the completion of first-line chemotherapy. Effective maintenance strategies are needed.

DDX5 is a DEAD-box RNA helicase that is overexpressed and implicated in the progression of several cancers, including small cell lung cancer (SCLC). Our laboratory has demonstrated that DDX5 is essential for the invasive growth of SCLC and mitochondrial respiration. SCLC is an extremely lethal, recalcitrant tumor, and currently lacking effective treatments. Supinoxin (RX 5902), a compound having anti-cancer activity, is a known target of phosphor-DDX5. We now report that Supinoxin inhibits the proliferation of chemo-sensitive and chemo-resistant SCLC lines, H69 and H69AR, respectively. Additionally, Supinoxin mitigates both the growth of H69AR xenograft tumors and SCLC PDX tumors in vivo. Finally, we find that Supinoxin inhibits expression of mitochondrial genes and effectively blocks respiration. These studies suggest that Supinoxin functions in anti-tumor progression by reducing cellular energy levels through DDX5.

As the seventh-leading contributor to global cancer-related deaths, esophageal cancer (EC) is one of the most challenging types of cancer. Despite advancements in conventional therapies, including surgery, chemotherapy, and radiotherapy, the five-year survival rate remains low, underscoring the need for the development of more efficacious treatment approaches. Immunotherapy has emerged as a promising treatment approach, offering new hope for EC patients. This review provides an in-depth examination of the latest immunotherapeutic strategies for EC, focusing on immune checkpoint inhibitors, adoptive cell therapy, cancer vaccines, and oncolytic virotherapy. We critically analyze the current clinical data to highlight the progress and pitfalls of each immunotherapeutic approach for EC. Additionally, we explore the potential for combination therapies, which could overcome the resistance often seen with monotherapies. Finally, we discuss the limitations of current treatments and outline key areas for future research to improve patient outcomes and survival.

Small cell lung cancer (SCLC) is characterized by early metastatic potential and poor prognosis. Liver kinase B1 (LKB1) is a tumor suppressor and a cell metabolism regulator. LKB1 downregulation has been associated with a cold tumor immune microenvironment (TIME). We aimed to analyze the role of LKB1 in SCLC in relation to its association with overall survival (OS) and TIME components.

We retrospectively evaluated SCLC patients consecutively treated at our institution from 1996 to 2020 with available tissue. LKB1, PD-L1 on tumor cells and on tumor immune-infiltrating cells, CD8, and FOXP3 were evaluated by immunohistochemistry (IHC), categorized according to predefined cutoffs. The primary endpoint was the description of LKB1 expression, and the secondary endpoints were the association with prognosis and TIME features.

Tissue samples of 138 out of 481 SCLCs were adequate for molecular analyses. Eighty patients had limited stage (LS) at diagnosis and 58 had extended stage (ES). The median LKB1 IHC score was 4. Patients with IHC score >4 (n = 67) were classified as LKB1-positive. The probability of LKB1 positivity was higher in LS [odds ratio 2.78, 95% confidence interval (95% CI) 1.18-7.14]. At the data cutoff (2 January 2024), 123 patients died. The median OS (mOS) was 14.0 months (95% CI 11.5-19.4). mOS was significantly longer in patients with LKB1-positive expression [32.4 months (95% CI 13.6-62.4) vs. 11.2 months (95% CI 8.7-14.7); p < 0.001]. At multivariate analysis, positive LKB1 expression, LS, and no weight loss at diagnosis were confirmed as independent positive prognostic factors. TIME features were evaluated in 70 patients. Unexpectedly, LKB1-negative samples were more likely to show CD8+ tumor-infiltrating lymphocytes (TILs; p = 0.013). No association with PD-L1 expression nor the presence of FOXP3+ TILs was found.

LKB1 expression is a potential positive prognostic marker in SCLC. In this series, LKB1 expression was negatively associated with the presence of CD8+ TILs.

Programmed cell death protein-1 (PD-1) inhibitors plus chemotherapy have been the standard of care in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma; however, the survival benefits are modest in patients with low programmed death ligand 1 (PD-L1) expression. Here we investigated the efficacy and safety of cadonilimab (PD-1/cytotoxic T lymphocyte antigen-4 (CTLA-4) bispecific antibody) plus chemotherapy as first-line treatment in G/GEJ adenocarcinoma. The prespecified interim analysis is reported here. This was a randomized, double-blind, placebo-controlled phase 3 study. Eligible patients were adults with untreated, unresectable, locally advanced or metastatic G/GEJ adenocarcinoma. Patients were randomized 1:1 to receive cadonilimab (10 mg kg-1 every 3 weeks) or placebo plus chemotherapy (every 3 weeks). The primary endpoint was overall survival (OS) in the intention-to-treat population (one-sided significance level, P = 0.025). Secondary endpoints included OS in patients with a PD-L1 combined positive score ≥5, progression-free survival, objective response rate, duration of response and safety. As of 18 August 2023, 610 patients from 75 study centers were randomized to cadonilimab (n = 305) or placebo (n = 305). With a median follow-up of 18.7 months, the cadonilimab group had a significantly longer median OS (14.1 versus 11.1 months; hazard ratio (HR) 0.66; 95% confidence interval (CI) 0.54-0.81; P < 0.001) than the placebo group. The primary endpoint was met. The median progression-free survival was 7.0 months versus 5.3 months (HR 0.53, 95% CI 0.44-0.65). The median OS in patients with a PD-L1 combined positive score ≥5 was 15.3 months versus 10.9 months (HR 0.58, 95% CI 0.41-0.82). The objective response rate was 65.2% versus 48.9% with a median duration of response of 8.8 months versus 4.4 months. Grade ≥3 treatment-related adverse events occurred in 65.9% of the cadonilimab group and 53.6% of the placebo group, and the most common were decreased platelet count, decreased neutrophil count and anemia. Most of the immune-related adverse events were grade 1 or 2. No new safety signals were observed. Cadonilimab plus chemotherapy significantly improved OS with a manageable safety profile in patients with advanced G/GEJ adenocarcinoma. ClinicalTrials.gov registration: NCT05008783 .

Cutaneous immune-related adverse events (cirAEs) represent a prevalent manifestation of adverse reactions linked to immune checkpoint inhibitors (ICIs) therapy, substantially affecting patients' quality of life. This systematic review and meta-analysis aimed to quantify the pooled incidence of cirAEs in this population and strengthen clinical awareness for early recognition and management.

A comprehensive search of PubMed, Embase, CINAHL, Cochrane Library, CBM, CNKI, and Wanfang databases was conducted from inception to December 2022. Literature that reported the incidence of cirAEs in patients with lung cancer receiving ICIs therapy was included. A meta-analysis was conducted using R software, version 4.4.1 to estimate the pooled incidence of cirAEs, and a random-effects model was used for data synthesis. Begg's rank correlation and funnel plots were used to assess publication bias.

A total of 99 articles involving 23,814 patients with lung cancer receiving ICIs therapy were included, with publication dates ranging from 2012 to 2022. The meta-analysis results reveal that the incidence of cirAEs in patients with lung cancer was 20.26% (95% confidence interval [CI (17.12-23.81)]. Significant differences were observed between all subgroups, including continent, study type, combination therapy, dual ICIs therapy, and diagnostic criteria for cirAEs for Grade 1-2 and Grade 3-4 incidences.

The incidence of cirAEs in patients with lung cancer is relatively high, particularly undergoing combined or dual ICIs therapy. To comprehensively characterize cirAEs in patients with lung cancer, large-scale multicenter studies integrating real-world pharmacovigilance data are warranted to establish precise incidence estimates and identify clinically significant risk factors.

This review's insights aroused clinical staff's attention and concern about cirAEs, potentially enhancing the quality of life of patients with cancer.

The widespread use of immune checkpoint inhibitors (anti-CTLA4 or PD-1) has opened a new chapter in tumor immunotherapy by providing long-term remission for patients. Unfortunately, however, these agents are not universally available and only a minority of patients respond to them. Therefore, there is an urgent need to develop novel therapeutic strategies targeting other co-inhibitory molecules. However, comprehensive information on the expression and prognostic value of co-inhibitory molecules, including co-inhibitory receptors and their ligands, in different cancers is not yet available.

We investigated the expression, correlation, and prognostic value of co-inhibitory molecules in different cancer types based on TCGA, UCSC Xena, TIMER, CellMiner datasets. We also examined the associations between the expression of these molecules and the extent of immune cell infiltration. Besides, we conducted a more in-depth study of VISTA.

The results of differential expression analysis, correlation analysis, and drug sensitivity analysis suggest that CTLA4, PD-1, TIGIT, LAG3, TIM3, NRP1, VISTA, CD80, CD86, PD-L1, PD-L2, PVR, PVRL2, FGL1, LGALS9, HMGB1, SEMA4A, and VEGFA are associated with tumor prognosis and immune cell infiltration. Therefore, we believe that they are hopefully to serve as prognostic biomarkers for certain cancers. In addition, our analysis indicates that VISTA plays a complex role and its expression is related to TMB, MSI, cancer cell stemness, DNA/RNA methylation, and drug sensitivity.

These co-inhibitory molecules have the potential to serve as prognostic biomarkers and therapeutic targets for a broad spectrum of cancers, given their strong associations with key clinical metrics. Furthermore, the analysis results indicate that VISTA may represent a promising target for cancer therapy.

Treatment with cadonilimab and chemotherapy has shown promise as a first-line treatment for gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. However, its application in neoadjuvant settings has not yet been documented.

This multicenter, phase 2 trial (ChiCTR2200066893) was conducted at four hospitals across China. Treatment-naive patients with locally advanced G/GEJ adenocarcinoma (cT3/4, N+, M0) and who were human epidermal growth factor receptor 2 negative received 3-cycle or 4-cycle neoadjuvant treatment of cadonilimab plus FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy, followed by gastrectomy and 4-cycle adjuvant FLOT chemotherapy. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included major pathological response (MPR), overall response rate (ORR), disease control rate (DCR), R0 resection rate, downstaging rate, and safety.

Between December 23, 2022, and December 15, 2023, 32 of 38 patients completed the scheduled treatment, achieving an R0 resection rate of 100% (32/32). The pCR rate was 21.1% (8/38, 90% confidence interval [CI]: 9.7-32.4), and the MPR rate was 44.7% (17/38, 90% CI: 30.9-58.5). Radiological evaluations were available for 28 of 38 patients by blinded independent central review. The ORR was 60.7% (17/28, 90% CI: 44.7-76.7), and the DCR was 100.0% (28/28, 90% CI: 100.0-100.0). Tumor downstaging occurred in 71.9% of patients (23/32), with consistent efficacy across all populations observed in the subgroup analysis. Grade 3 adverse events occurred in 31.6% of patients without severe safety issues.

Neoadjuvant cadonilimab plus FLOT chemotherapy treatment exhibits promising efficacy with manageable toxicities in locally advanced G/GEJ adenocarcinoma, providing preliminary evidence for further investigation.

This study was funded by Akeso Biopharma.

Background/Objectives: Immune checkpoint inhibitors (ICIs) have generated a revolutionary approach in the treatment of cancer, but their effectiveness has been compromised by immune-related adverse events, including renal damage. Although rare, these effects are relevant because they have been related to poor patient prognoses. The objective of this review was to estimate the current incidence of nephrotoxicity in patients treated with single and double ICI therapies. Methods: A total of 1283 potential articles were identified, which were reduced to 50 after applying the exclusion and inclusion criteria. Results: This study reveals the increase in acute kidney injury associated with these drugs in the last decade and shows that, interestingly, combined therapies with ICIs does not lead to an increase in kidney damage compared with anti-CTLA-4. It also suggests that kidney damage could be underdiagnosed when it comes to interstitial nephritis, because definitive evidence requires a renal biopsy. Conclusions: In perspective, these conclusions could guide clinicians in making decisions for therapy personalization and highlight the need to search for new diagnostic systems that are more sensitive and specific to the type of damage and could replace the biopsy.

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.

SCLC has limited second-line treatment options after chemotherapy. We assessed the efficacy and safety of lurbinectedin combined with pembrolizumab in relapsed SCLC patients who had not received prior immunotherapy, aiming to prevent early progression and achieve sustained responses.

The LUPER trial (NCT04358237) is a phase I/II, single-arm, open-label, multicenter study. Phase I established the recommended phase II dose. The primary endpoint of phase II was the investigator-confirmed objective response rate. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Patients were categorized as platinum-sensitive (chemotherapy-free interval ≥ 90 d) or platinum-resistant (<90 d).

The recommended phase II dose was 3.2 mg/m2 lurbinectedin and 200 mg pembrolizumab IV every three weeks. Phase II included 28 patients, 50% of whom were platinum-resistant. The objective response rate was 46.4% (95% confidence interval: 27.5-66.1, p < 0.001), including three complete responses, with two complete metabolic responses post-treatment completion at 35 cycles. The median duration of response was 7.8 months, with 40% of patients maintaining responses for 12 months or longer. The median PFS was 4.6 months, and the median OS was 10.5 months. Platinum-sensitive patients had significantly better PFS (8.0 versus 2.8 mo, p = 0.012) and numerically superior OS (15.7 versus 7.1 mo, p = 0.058). Grade 3 or higher treatment-related adverse events occurred in 71.4% of patients, with transient neutropenia being the most common. Immune-related adverse events were consistent with prior pembrolizumab studies.

Lurbinectedin plus pembrolizumab reported promising efficacy in relapsed SCLC, particularly for platinum-sensitive patients, with a known and manageable safety profile. These results support further exploration of this combination in SCLC treatment.

Background: Small cell lung cancer (SCLC) is an aggressive cancer with rapid progression, limited treatment success, and high relapse rates. Chemotherapy and radiation are standard treatments but often result in chemoresistance. PD-L1 inhibitors have gained attention for their role in enhancing tumor immunity. Methods: This review summarizes clinical trials involving PD-L1 inhibitors, such as atezolizumab, durvalumab, pembrolizumab, and nivolumab, in SCLC treatment. Key trials include IMpower133, CASPIAN, KEYNOTE-604, and CheckMate 331, focusing on survival outcomes and treatment efficacy. Results: Studies such as IMpower133 and CASPIAN demonstrate improved overall survival when PD-L1 inhibitors were added to platinum-based chemotherapy. However, outcomes in trials such as KEYNOTE-604 and CheckMate 331 varied, showing the need for refined patient selection. Adverse events (AEs) associated with these treatments were also noted. PD-L1 inhibitors offer promise in SCLC treatment, but efficacy varies across trials and patient groups. Future research should focus on better patient selection and overcoming resistance mechanisms. Addressing immune-related AEs is essential for optimizing treatment strategies.

Small-cell lung cancer accounts for about 15% of lung cancers with an extremely poor prognosis. The incorporation of immunotherapy to platinum-based chemotherapy offers sustained overall survival benefits and become the standard for the first-line setting of extensive-stage small-cell lung cancer. However, only a limited number of patients derive prolonged benefits. Although novel immunomodulatory agents and combination strategies are currently under investigation, identifying patients who are likely to obtain clinical benefits from this therapeutic approach is urgently needed. The modest therapeutic response to immunotherapy can be explained by various mechanisms. Traditional biomarkers do not guide immunotherapeutic decision-making in small-cell lung cancer. Notably, recent progress in the understanding of the molecular typing of small-cell lung cancer based on multi-omics data might bring new sights. This review summarizes the potential biomarkers for small-cell lung cancer immunotherapy based on clinical trials and preclinical studies. Moreover, important constraints in identifying biomarkers for small-cell lung cancer treatment are discussed.

Nivolumab and ipilimumab combination immunotherapy has become a standard treatment option for certain cancers. However, the benefits of combination therapy compared to nivolumab monotherapy in lung cancer patients are not entirely clear. We aimed to evaluate whether nivolumab plus ipilimumab improves clinical outcomes in lung cancer patients compared to nivolumab monotherapy.

A literature search was performed on PubMed, Web of Science, and Scopus from inception until November 2024 to identify relevant randomized controlled trials. The Cochrane risk of bias tool was used to assess the risk of bias, the hazard ratio (HR) was calculated for survival, risk ratios (RRs) were calculated for response rate and safety outcomes, and a random effects model meta-analysis was performed to estimate the safety and efficacy of the treatments.

Seven trials comprising 2134 patients were included. Compared with patients receiving nivolumab monotherapy, non-small cell lung cancer patients who received combination therapy had better progression-free survival (HR = 0.82, 95% CI 0.71; 0.93, P < 0.01, low certainty), and there were no significant differences in overall survival (HR = 0.95, 95% CI 0.86; 1.0, P = 0.31, moderate certainty), or objective response rate (RR = 1.36, 95% CI 0.91; 2.02, P = 0.14 very low certainty). The combination group had a significantly greater risk of grade 3-4 adverse events (RR = 2.77, 95% CI 1.38; 5.56, P < 0.01, low certainty).

Although combination treatment significantly improved progression-free survival in NSCLC patients, it was also associated with a greater risk of adverse events and treatment-related mortality than nivolumab monotherapy. The current evidence is insufficient for choosing combination treatment over nivolumab monotherapy.

Colorectal neuroendocrine tumors with liver metastases (CRNELM) are associated with a poorer prognosis compared to their nonmetastatic counterparts. A comprehensive understanding of the tumor microenvironment (TME) heterogeneity between primary lesions (PL) and liver metastases (LM) could provide crucial insights for enhancing clinical management strategies for these patients.

We utilized single-cell RNA sequencing to analyze fresh tissue samples from CRNELM patients, aiming to elucidate the variations in TME between PL and LM. Complementary multidimensional validation was achieved through spatial transcriptomics, bulk RNA sequencing, and multiplex immunohistochemistry/immunofluorescence.

Our single-cell RNA sequencing analysis revealed that LM harboured a higher proportion of CD8 + T cells, CD4 + T cells, NK cells, NKT cells, and B cells exhibiting a stress-like phenotype compared to PL. RGS5 + pericytes may play a role in the stress-like phenotype observed in immune cells within LM. MCs in PL (PL_MCs) and LM (LM_MCs) exhibit distinct activation of tumor-associated signaling pathways. Notably, COLEC11 + matrix cancer-associated fibroblasts (COLEC11_mCAFs) were found to be significantly associated with LM_MCs. Cell communication analysis unveiled potential targetable receptor-ligand interactions between COLEC11_mCAFs and LM_MCs. Multidimensional validation confirmed the prominence of the characteristic stress-like phenotypes, including HSPA6_CD8_Tstr, HSPA6_NK, and COLEC11_mCAFs in LM. Moreover, a higher abundance of COLEC11_mCAFs correlated with poorer survival rates in the neuroendocrine tumor patient cohort.

Overall, our study provides the first single-cell analysis of the cellular and molecular differences between PL and LM in CRNELM patients. We identified distinct cell subsets and receptor-ligand interactions that may drive TME discrepancies and support metastatic tumor growth. These insights highlight potential therapeutic targets and inform strategies for better managing CRNELM patients.

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but can trigger immune-related encephalitis. We report one of the largest case series of patients with immune-related encephalitis and review of the literature.

Retrospective series of patients with immune-related encephalitis and literature review.

Fourteen patients with cancer treated with ICI (50% combination therapy) developed immune-related encephalitis. Diagnostic testing revealed cerebral spinal fluid (CSF) lymphocytic pleocytosis (85%) and elevated protein (69%), abnormal brain magnetic resonance imaging(MRI) (33%) or brain FDG-PET (25%), electroencephalogram (EEG) abnormalities (30%), and autoantibodies (31%). Encephalitis treatment included: corticosteroids (86%), intravenous immunoglobulin (IVIg) (36%), plasmapheresis (7%), and rituximab (29%). There were no deaths and 12 patients had significant recovery, although long-term complications were observed. All patients discontinued ICI. Longitudinal follow-up demonstrated anti-cancer response to ICI at 3 months (85%) and 6 months post-ICI initiation (77%). A literature review identified 132 patients with immune-related encephalitis. Most were treated with PD-1 inhibitors (18% combination). Common abnormalities included elevated CSF protein (84%) or pleocytosis (77%), abnormal brain MRI (65%), or autoantibodies (47%). Nearly all were treated with corticosteroids, many required additional therapy with IVIg (26%) or rituximab (12%). Most patients had clinical improvement (81%) but a minority (10%) had a clinical relapse after completing corticosteroid taper. ICIs were resumed in 7 patients (5%), with relapse in 3.

Immune-related encephalitis is treatable and improves with corticosteroids in most cases but may require additional immunosuppression. Re-emergence of encephalitis is rare and does not typically result in adverse outcomes, and this should be considered in neurological immune-related adverse event management guidelines.

BackgroundExtensive-stage small cell lung cancer (ES-SCLC) is a highly aggressive malignancy with poor prognosis. This study aimed to assess the efficacy of combining immunotherapy (IT) with Anlotinib in ES-SCLC patients.MethodsThis study was a multicenter retrospective cohort analysis. Survival outcomes were evaluated using Kaplan-Meier curves and Cox proportional hazards regression models.ResultsA total of 147 patients were included in the analysis. The median overall survival (mOS) for the cohort was 15.5 months (95% CI: 13.9-17.1). Patients in the chemotherapy(CT) plus IT group had an mOS of 17.8 months, compared to 12.6 months in the CT-alone group (p = 0.055). When stratified into CT + IT + Anlotinib, CT + IT, and CT-alone groups, the mOS were 18.5, 16.3, and 12.6 months, respectively, with the CT + IT + Anlotinib group demonstrating significantly improved OS compared to CT-alone (p = 0.044). The ORR and DCR for the entire cohort were 71.4% and 85.7%, respectively. Subgroup analysis revealed ORRs of 74.1% (CT + IT + Anlotinib), 73.9% (CT + IT), and 70.1% (CT-alone), with corresponding DCRs of 92.6%, 91.3%, and 82.5%. Multivariate analysis revealed that radiotherapy (RT, p = 0.003) and IT (p = 0.021) were independent prognostic factors for OS, while liver metastasis (p = 0.023) and RT (p = 0.018) were associated with PFS. Patients receiving RT in combination with CT showed markedly improved OS (17.5 vs 12.5 months; p = 0.002) and PFS (7.3 vs 6.3 months; p = 0.004). The incidence of adverse events was comparable across all groups (p = 0.721).ConclusionThe combined application of Anlotinib with IT and the combination of CT with RT both significantly improved survival outcomes in patients with ES-SCLC while maintaining a favorable safety profile. These findings warrant further investigation in future studies.

Immune checkpoint inhibitors (ICIs) are crucial in cancer treatment, and the associated immune-related adverse events (irAEs) have garnered significant attention, yet reports on associated immune related gastritis are limited. The diagnosis of immune related gastritis remains predominantly exclusionary, meanwhile its management diverges significantly from that of conventional gastritis. Current guidelines lack standardized grading criteria, and substantial data from large-scale, tertiary clinical studies are absent, therefore we conducted a systematic review of Medline, Web of Science, and Embase databases, identifying 31 articles from 2017 to December 31, 2023, involving 258 patients. Clinical manifestations included epigastric pain (53.1%), mucosal erythema (56.1%), and lymphocyte infiltration (48.6%). Corticosteroid therapy was common (94.7%), with 86.7% experiencing post-treatment improvement. 80% of patients can be diagnosed through endoscopy and pathology, while the remaining 20% may require PET-CT. Hormonal therapy is favored but diverges from standard management. Accurate diagnosis is crucial in managing immune related gastritis effectively.

The limited success of immune checkpoint inhibitors (ICIs) in the adjuvant setting for glioblastoma highlights the need to explore administering ICIs prior to immunosuppressive radiation. To address the feasibility and safety of this approach, we conducted a phase I study in patients with newly diagnosed Grade 3 and Grade 4 gliomas. Patients received nivolumab 300 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity. Fifteen patients were treated, with four patients on dexamethasone at treatment initiation and five tumors having MGMT promoter methylated. Treatment began a median of 38 days post-surgery. The most common treatment-related adverse events (AEs) were rash, pruritus, fatigue, nausea, and anorexia. Grade 3 AEs were lipase increased (n = 2), anorexia (n = 1), pruritus (n = 1), and rash (n = 3), and one Grade 4 cerebral edema occurred. Median progression-free survival (mPFS) was 1.3 months and median overall survival (mOS) was 19.3 months (95% CI, 12.9-NA). Three patients deferred conventional radiochemotherapy for over seven months while ten eventually received it. Progressing tumors tended to exhibit higher LAG-3 levels at baseline compared to shrinking tumors. Analysis of paired pre-treatment and post-progression tissue (n = 5) showed trends of up-regulated TGF-β, ERBB2, ERBB3, and ERBB4 signaling pathways, downregulated PPAR signaling, decreased B cell proportions, and increased monocytes proportions in tumors post-treatment. We show nivolumab plus ipilimumab can be safely administered prior to standard radiotherapy for newly diagnosed gliomas and is operationally feasible. Clinicaltrials.gov NCT03425292 registered February 7, 2018.

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a poor prognosis. Although the addition of immunotherapy to chemotherapy has modestly improved outcomes, most patients rapidly develop resistance. Resistance to immunotherapy can be broadly categorized into primary resistance and acquired resistance, as proposed by the Society for Immunotherapy of Cancer (SITC) consensus definition. Primary resistance occurs in the setting of failure to respond to immune checkpoint inhibitors (ICIs), while acquired resistance develops after initial response. The mechanisms of acquired and primary resistance to ICI are not well understood in SCLC, denoting an area of critical unmet need. Both intrinsic and extrinsic mechanisms play significant roles in immunotherapy resistance. Intrinsic mechanisms include defects in antigen presentation, mutations in key genes, reduced tumor immunogenicity, and epigenetic alterations. Extrinsic mechanisms involve the tumor microenvironment (TME), which is a complex interplay of both tumor- and immunosuppressive immune cells, vasculature, and microbiome. An understanding of these resistance mechanisms is crucial for developing novel therapeutic strategies to advance effective immunotherapy in patients with SCLC, a critical area of unmet need.

The therapeutic efficacy and prognosis of various tumors can be assessed using the systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI). Despite their potential, no studies have investigated the prognostic value of the combined SII-PNI score for outcomes in patients with extensive small cell lung cancer (ES-SCLC) treated with chemotherapy and immune checkpoint inhibitors (ICIs).

Our study retrospectively examined 213 ES-SCLC patients treated with chemotherapy and ICIs across two institutions. The patients were divided into three groups based on their SII-PNI scores. Cox regression analysis was employed to identify independent prognostic factors. A nomogram was constructed based on these independent factors. With 1000 repeated samples, the bootstrap method was used to validate the nomogram model internally. The model's performance was assessed using calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA).

Before and after chemotherapy with immune checkpoint inhibitors (ICIs), SII was significantly higher in the PD group compared with the PR group (both p < 0.05). In the meantime, PNI was considerably lower in the PD group than in the PR group (both p < 0.01). Kaplan-Meier curves demonstrated that patients with a low SII-PNI had prolonged progression-free survival (PFS) and overall survival (OS) compared to those with a high SII-PNI (all p < 0.01). Multivariate Cox analysis showed that PS = 1, bone metastasis, brain metastasis, and SII-PNI = 1,2 after four treatment cycles were independent risk factors for shorter OS and were included in the nomogram model. The ROC curves, C-index, and DCA curves confirm that the SII-PNI scores-based nomograms have strong predictive accuracy for OS.

There was a significant correlation between pre- and post-treatment SII-PNI and treatment effect in ES-SCLC. The SII-PNI score after four treatment cycles is a useful prognostic indicator for ES-SCLC patients receiving chemotherapy combined with immune checkpoint inhibitors (ICIs).

The immune system relies on a delicate balance between attacking harmful pathogens and preserving the body's own tissues, a balance maintained by immune checkpoints. These checkpoints play a critical role in preventing autoimmune diseases by restraining excessive immune responses while allowing the immune system to recognize and destroy abnormal cells, such as tumors. In recent years, immune checkpoint inhibitors (ICIs) have become central to cancer therapy, enabling the immune system to target and eliminate cancer cells that evade detection. Traditional antibodies, such as IgGs, have been widely used in immune therapies but are limited by their size and complexity. Nanobodies (Nbs), derived from camelid heavy-chain-only antibodies, offer a promising alternative. These small, stable antibody fragments retain the antigen-binding specificity of traditional antibodies but have enhanced solubility and the ability to target otherwise inaccessible epitopes. This review explores the use of Nbs as ICIs, emphasizing their potential in cancer immunotherapy and other immune-related treatments. Their unique structural properties and small size make Nbs highly effective tools for modulating immune responses, representing a novel approach in the evolving landscape of checkpoint inhibitor therapies.

There is a strong association between inflammation and the formation, progression, and metastasis of malignant tumors, according to earlier studies. Some composite inflammation-nutritional indicators, such as the systemic immune-inflammation index (SII) and the prognostic nutritional index (PNI), have a certain predictive effect on the prognosis of patients with small cell lung cancer (SCLC). However, the relationship between these indicators and the efficacy of immunotherapy in SCLC patients is still not well understood. Therefore, the purpose of this study was to explore how the pre-treatment SII-PNI score can predict the tumor response and prognosis of extensive-stage SCLC patients treated with PD-L1 inhibitors and first-line chemotherapy.

This research conducted a retrospective review of 70 ES- SCLC patients from December 2019 to January 2023. According to the SII-PNI score, all patients were categorized into three groups. Overall survival (OS) was assessed by implementing the Kaplan Meier and Cox regression models. In addition, we devised a nomogram and scrutinized its accuracy in prediction through receiver operating characteristic (ROC) curve analysis and visualized it by calibration plots. Subsequently, a risk classification system was established.

Patients with higher SII-PNI scores exhibited notably poorer survival outcomes compared to their counterpart with low SII-PNI score (p=0.008), as well as poorer short-term curative effects (p=0.004). The results of the multivariate analysis revealed that the SII-PNI score (p=0.036) had an independent association with a less favorable OS. The nomogram has been demonstrated to be a reliable prognostic tool for ES-SCLC patients. A notable difference was identified between the two different levels of risk.

The baseline SII-PNI score can serve as a reliable prognostic indicator for ES-SCLC patients receiving immunotherapy. Higher SII-PNI scores imply a worse prognosis.

Lung cancer, both non-small cell and small cell, harbors a high propensity for spreading to the central nervous system. Radiation therapy remains the backbone of the management of brain metastases. Recent advances in stereotactic radiosurgery have expanded its indications and ongoing studies seek to elucidate optimal fractionation and coordination with systemic therapies, especially targeted inhibitors with intracranial efficacy. Efforts in whole-brain radiotherapy aim to preserve neurocognition and to investigate the need for prophylactic cranial irradiation. As novel combinatorial strategies are tested and prognostic/predictive biomarkers are identified and tested, the management of brain metastases in lung cancer will become increasingly personalized to optimally balance intracranial efficacy with preserving neurocognitive function and patient values.

The maintenance of intestinal homeostasis is a fundamental process critical for organismal integrity. Sitting at the interface of the gut microbiome and mucosal immunity, adaptive and innate lymphoid populations regulate the balance between commensal micro-organisms and pathogens. Checkpoint inhibitors, particularly those targeting the CTLA-4 pathway, disrupt this fine balance and can lead to inflammatory bowel disease and immune checkpoint colitis. Here, we show that CTLA-4 is expressed by innate lymphoid cells and that its expression is regulated by ILC subset-specific cytokine cues in a microbiota-dependent manner. Genetic deletion or antibody blockade of CTLA-4 in multiple in vivo models of colitis demonstrates that this pathway plays a key role in intestinal homeostasis. Lastly, we have found that this observation is conserved in human IBD. We propose that this population of CTLA-4-positive ILC may serve as an important target for the treatment of idiopathic and iatrogenic intestinal inflammation.

Total baseline tumor size (BTS) is a prognostic factor for programmed death 1 and programmed death-ligand 1 (PD-L1) inhibitor treatments. However, the prognostic value of total BTS for patients with small-cell lung cancer (SCLC) who receive chemotherapy plus PD-L1 inhibitor remains unknown. Thus, in this study, we aimed to determine whether total BTS is associated with prognosis in patients with SCLC who receive chemotherapy plus PD-L1 inhibitor as first-line therapy.

This study included patients with extensive-stage SCLC or post-chemoradiotherapy recurrence of limited-stage SCLC who received chemotherapy plus PD-L1 inhibitor as first-line therapy from August 2019 to December 2022. The two lesions with the largest diameter among the measurable lesions in each organ were selected from up to five organs (maximum of 10 lesions), and the sum of all diameters was defined as total BTS. The patients were divided into two groups, large or small, with total BTS using X-tile software. Median survival was analyzed using the Kaplan-Meier method, and the groups were compared using the log-rank test. Univariate and multivariate analyses examined the association between total BTS and prognosis.

Fifty patients were included; 14% had large total BTS (>183.2 mm) and 86% had small total BTS (≤183.2 mm). The median observation period was 10.5 months. The large total BTS group showed significantly worse overall survival than the small total BTS group (median: 26.8 months vs. 5.7 months, P = 0.0003). The multivariate analysis indicated that large total BTS was an independent negative predictor of overall survival (hazard ratio: 7.14, 95% confidence interval: 1.89-26.96).

Total BTS is a potentially useful prognostic factor for patients with advanced SCLC who receive chemotherapy plus PD-L1 inhibitor as first-line therapy.