Efficacy Of Immune Checkpoint Inhibitors Research Articles

Exploring Immunological Effects and Novel Immune Adjuvants in Immunotherapy for Salivary Gland Cancers.

Salivary gland cancer (SGC) is rare and comprises over 20 histological subtypes. Recently, clinical experience regarding immunotherapies for SGCs has been accumulating, yet their efficacy remains controversial. Understanding the tumor microenvironment (TME), including the expression of immune checkpoint molecules in SGC, is crucial to optimizing immunotherapy. In this review, we demonstrate that high-grade mucoepidermoid carcinoma and salivary duct carcinoma generally exhibit immune-hot TME with high immune cell infiltration, frequent genetic mutations, and robust immune checkpoint molecule expression. In contrast, adenoid cystic carcinomas exhibit an immune-cold TME. While the reported efficacy of immune checkpoint inhibitors (ICIs) for SGCs is generally poor, several studies showed promising clinical efficacy of ICIs, with an objective response rate ranging from 20.0-33.3%, indicating that ICIs might be beneficial for a specific population of SGC. Molecule-targeted therapies including anti-human epidermal growth factor receptor 2 and anti-androgen receptor therapies have shown promising clinical efficacy against SGC. Recent evidence indicates that these molecules could be targets for antigen-specific immunotherapies including chimeric antigen receptor-T therapy and cancer vaccines. This review discusses the current understanding and future directions of immunotherapies for SGCs, including ongoing clinical trials.

Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer.

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. In this study, we aim to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefit. We retrospective analyzed 69 GBC patients who had received ICI therapy between January 2016 and December 2020. Tumor samples were obtained for genomic sequencing and immunohistochemical analysis. The median progression-free survival (PFS) and overall survival (OS) was 4.4 months and 8.5 months, respectively. Multivariate analysis indicated that alcohol intake history, carcinoma embryonic antigen (CEA) level ≥100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for PFS. CEA level ≥100 U/mL and cutaneous irAEs were independent prognostic factors for OS. The objective response rate and disease control rate (DCR) were 15.9% and 37.7%, respectively. Patients with cutaneous irAEs, high CD8+ T cell infiltrated or immune inflamed GBCs had higher DCR. Patients with high CD8+ T cell infiltrated or immune inflamed GBCs also had a notably improved prognosis. These results suggest that ICIs were effective in patients with GBC. High CEA level, cutaneous irAEs, high CD8+ T cell infiltration, and immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC.

FASN Inhibition Decreases MHC-I Degradation and Synergizes with PD-L1 Checkpoint Blockade in Hepatocellular Carcinoma.

Inhibition of FASN increases MHC-I protein levels by suppressing its palmitoylation and lysosomal degradation, which stimulates immune activity against hepatocellular carcinoma and enhances the efficacy of immune checkpoint inhibition.

Immune checkpoint inhibitors combined with concurrent chemoradiotherapy in locally advanced esophageal squamous cell carcinoma.

This study aims to evaluate the efficacy of immune checkpoint inhibitors (ICIs) combined with concurrent chemoradiotherapy (CCRT) versus CCRT alone in patients with locally advanced esophageal squamous cell carcinoma. This retrospective cohort study included patients diagnosed with locally advanced esophageal squamous cell carcinoma who received either CCRT alone or CCRT combined with ICIs from April 2019 to February 2023. The primary endpoint was progression-free survival (PFS), and the secondary endpoint was overall survival (OS). A total of 101 patients were enrolled, with 58 undergoing CCRT alone and 43 receiving CCRT+ICI. The CCRT+ICI group demonstrated a higher complete response rate compared to the CCRT alone group (11.6% vs. 1.7%, P = 0.037). However, no significant difference was observed in 1-year PFS (58.9% vs. 55.2%; hazard ratio [HR] = 1.26, 95% confidence interval [CI]: 0.70-2.26; P = 0.445) or 1-year OS (70.8% vs. 75.9%; HR = 1.21, 95% CI: 0.58-2.53; P = 0.613) between CCRT+ICI and CCRT alone groups. The CCRT alone group experienced a higher incidence of leukopenia of any grade (93.1% vs. 76.7%, P = 0.039) but a lower incidence of pneumonitis of any grade (36.2% vs. 65.1%, P = 0.008). CCRT+ICI may not lead to improved survival outcomes compared to CCRT alone in patients with locally advanced esophageal squamous cell carcinoma. These findings indicate the need for further investigation into this treatment approach.

Targeting YAP1 to improve the efficacy of immune checkpoint inhibitors in liver cancer: mechanism and strategy.

Liver cancer is the third leading of tumor death, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immune checkpoint inhibitors (ICIs) are yielding much for sufferers to hope for patients, but only some patients with advanced liver tumor respond. Recent research showed that tumor microenvironment (TME) is critical for the effectiveness of ICIs in advanced liver tumor. Meanwhile, metabolic reprogramming of liver tumor leads to immunosuppression in TME. These suggest that regulating the abnormal metabolism of liver tumor cells and firing up TME to turn "cold tumor" into "hot tumor" are potential strategies to improve the therapeutic effect of ICIs in liver tumor. Previous studies have found that YAP1 is a potential target to improve the efficacy of anti-PD-1 in HCC. Here, we review that YAP1 promotes immunosuppression of TME, mainly due to the overstimulation of cytokines in TME by YAP1. Subsequently, we studied the effects of YAP1 on metabolic reprogramming in liver tumor cells, including glycolysis, gluconeogenesis, lipid metabolism, arachidonic acid metabolism, and amino acid metabolism. Lastly, we summarized the existing drugs targeting YAP1 in the treatment of liver tumor, including some medicines from natural sources, which have the potential to improve the efficacy of ICIs in the treatment of liver tumor. This review contributed to the application of targeted YAP1 for combined therapy with ICIs in liver tumor patients.

Tumor stroma-derived ANGPTL2 potentiates immune checkpoint inhibitor efficacy.

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic. We recently reported that tumor stroma-derived angiopoietin-like protein 2 (ANGPTL2) has tumor suppressive activity by enhancing dendritic cell-mediated CD8+ T cell anti-tumor immune responses. However, a direct impact of ANGPTL2 on ICI anti-tumor effect remains unclear. Here, we use a murine syngeneic model to show that host ANGPTL2 facilitates CD8+ T cell cross-priming and contributes to anti-tumor responses to ICIs in this context. Importantly, our analysis of public datasets indicated that ANGPTL2 expression is associated with positive responses to ICI therapy by human melanoma patients. We conclude that ANGPTL2-mediated stromal cell crosstalk facilitates anti-tumor immunity and ICI responsiveness. These findings overall provide novel insight into ANGPTL2 anti-tumor function and regulation of ICI-induced anti-tumor immunity.

MCL1 inhibition targets Myeloid Derived Suppressors Cells, promotes antitumor immunity and enhances the efficacy of immune checkpoint blockade

Immune checkpoint inhibitors (ICIs) are now the first-line treatment for patients with advanced melanoma. Despite promising clinical results, many patients fail to respond to these therapies. BH3 mimetics, a novel class of small molecule inhibitors that bind and inhibit anti-apoptotic members of the BCL2 family proteins such as BCL2 or MCL1, have been very successful in treating hematologic malignancies. However, there are limited studies on the immunomodulatory role of the BH3 mimetics. Several factors contribute to ICI resistance including myeloid-derived suppressor cells (MDSCs) that exert immunosuppressive effects through direct and indirect inhibition of antitumor immunity. Thus, targeting MDSCs to enhance antitumor immunity has the potential to enhance the efficacy of ICIs. In this study, we show that the MCL1 inhibitor S64315 reduces melanoma tumor growth in an immune cell-dependent manner in mice. Specifically, S64315 enhances antitumor immunity by reducing MDSC frequency and by promoting the activity of CD8+T cells. Additionally, human MDSCs are 10 times more sensitive to S64315 than cutaneous melanoma lines. Further, we found that a higher expression of MCL1 is associated with poor survival for patients treated with anti-PD-1. Finally, combining S64315 and anti-PD-1 significantly slowed tumor growth compared to either agent alone. Together, this proof-of-concept study demonstrates the potential of combining an MCL1 inhibitor with anti-PD-1 in the treatment of melanoma. It justifies the further development of next generation MCL1 inhibitors to improve efficacy of ICIs in treating malignant melanoma.

Efficacy and safety of pembrolizumab as first-line treatment for advanced non-small cell lung cancer complicated with chronic obstructive pulmonary disease: protocol for a prospective, single-arm, single-center, phase II clinical trial.

The first-line standard treatment option for patients with NSCLC complicated with Chronic obstructive pulmonary disease (COPD) is still unclear and relies on the treatment option of NSCLC alone. To date, a limited number of retrospective studies have explored the efficacy and safety of immunotherapy in patients with NSCLC complicated with COPD. We therefore designed this study to further explore the efficacy and safety of first-line immunotherapy in patients with NSCLC complicated with COPD. This study was designed as a single-armed, single-center, prospective, phase II clinical study. It will include 30 advanced (stage IV) NSCLC combined with COPD primary treatment subjects. Each subject's diagnosis will be confirmed by clinical, radiographic, pathologic, and pulmonary function evaluation. A fixed dose of 200 mg pembrolizumab will be administered by intravenous infusion on day1 every 3 weeks (Q3W). The management of stable and acute exacerbations of COPD include home oxygen therapy, and the use of conventional medications are also administered. Imaging evaluation will be performed every 6 weeks for 6 months from the first pembrolizumab dose and approximately every 12 weeks thereafter until disease progression or early withdrawal. COPD status will be evaluated every 3 months by pulmonary function, GOLD grading, mMRC score, CAT score, ABCD grouping, and AECOPD severity. The primary outcome is Progression-free survival. The secondary outcome measures include objective response rate, overall survival, rate of acute exacerbations of COPD (times/year), lung function, mMRC score, CAT score, impact of treatment on patient's health-related quality of life, antibiotic use (including duration and classes), and adverse events associated with immune checkpoint inhibitors. Exploratory endpoint is to explore the association between COPD grade and the degree of immune cell (CD4+ T lymphocytes and CD8+ T lymphocytes) infiltration, as well as the association between COPD grade and the efficacy of immune checkpoint inhibitors. ClinicalTrials.gov, identifier NCT05578222.

Sex-related differences in serum biomarker levels predict the activity and efficacy of immune checkpoint inhibitors in advanced melanoma and non-small cell lung cancer patients

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

HOXC9 characterizes a suppressive tumor immune microenvironment and integration with multiple immune biomarkers predicts response to PD-1 blockade plus chemotherapy in lung adenocarcinoma.

The quest for dependable biomarkers to predict responses to immune checkpoint inhibitors (ICIs) combined with chemotherapy in advanced non-small cell lung cancer remains unfulfilled. HOXC9, known for its role in oncogenesis and creating a suppressive tumor microenvironment (TME), shows promise in enhancing predictive precision when included as a TME biomarker. This study explores the predictive significance of HOXC9 for ICI plus chemotherapy efficacy in lung adenocarcinoma (LUAD). Following the bioinformatic findings, assays were performed to ascertain the effects of Hoxc9 on oncogenesis and response to programmed death 1 (PD-1) blockade. Furthermore, a cohort of LUAD patients were prospectively enrolled to receive anti-PD-1 plus chemotherapy. Based on the expression levels, baseline characteristics, and clinical outcomes, the predictive potential of HOXC9, PD-L1, CD4, CD8, CD68, and FOXP3 was integrally analyzed. HOXC9 not only mediated oncogenesis, but also corelated with suppressive TME. CMT167 and LLC cell lines unveiled the impacts of Hoxc9 on proliferation, invasion, and migration. Subsequently, tumor-bearing murine models were established to validate the inverse relationship between Hoxc9 expression and effective CD8+ T cells. Inhibition of Hoxc9 significantly curtailed tumor growth (P<0.05), independent of PD-1 blockade. In patient studies, while individual markers fell short in prognosticating survival, a notable elevation in CD8-positive expression was observed in responders (P=0.042). Yet, the amalgamation of HOXC9 with other markers provided a more distinct differentiation between responders and non-responders. Notably, patients displaying PD-L1+/HOXC9- and CD8+/HOXC9- phenotypes exhibited significantly prolonged progression-free survival. The expression of HOXC9 may serve as a biomarker to amplifying predictive efficacy for ICIs plus chemotherapy, which is also a viable oncogene and therapeutic target for immunotherapy in LUAD.

Impact of lymph node dissection on the efficacy of immune checkpoint inhibitors in patients with postoperative recurrence of non-small cell lung cancer.

The effect of lymph node dissection (LND) on the efficacy of immune checkpoint inhibitor (ICI) remains unclear. The purpose of this study was to examine the difference in the effect of ICI between patients with non-small cell lung cancer (NSCLC) according to the extent of LND performed in surgery prior to postoperative recurrence. A total of 134 patients with postoperative recurrence (surgery group, n=26) or unresectable advanced lung cancer (non-surgery group, n=108) who were treated with ICIs between January 2016 and December 2022 were included for analysis. In the surgery group, 16 patients underwent systematic LND, whereas the remaining 10 patients underwent selective LND. Progression-free survival with ICI treatment (ICI-PFS) and overall survival (OS) were compared between the surgery and non-surgery groups and between the systematic and selective LND groups using the inverse probability of treatment weighting (IPTW) method to adjust for patient background characteristics. In the IPTW-adjusted analysis, the 2-year PFS rate with ICI treatment was 31.2% in the surgery group and 27.3% in the non-surgery group (P=0.19); the corresponding 2-year OS rates were 69.6% and 62.2%, respectively (P=0.10). In the surgery group, the 2-year PFS rates under ICI were 20.0% in the systematic LND group and 45.7% in the selective LND group (P=0.03). IPTW-adjusted analysis indicated no difference in prognosis between patients with postoperative recurrence and those with advanced unresectable lung cancer. However, in patients with postoperative recurrence, the extent of LND was a significant predictor of ICI-PFS. These findings suggest that systematic LND may reduce the efficacy of ICI, indicating that preoperative ICI administration may be warranted.

Associations of concomitant medications with immune-related adverse events and survival in advanced cancers treated with immune checkpoint inhibitors: a comprehensive pan-cancer analysis

BackgroundWhile concomitant medications can affect the efficacy of immune checkpoint inhibitors (ICIs), few studies have assessed associations of concomitant medications with the occurrence and profile of immune-related adverse events (irAEs).MethodsThis...

Unraveling the role of M1 macrophage and CXCL9 in predicting immune checkpoint inhibitor efficacy through multicohort analysis and single-cell RNA sequencing.

The exact function of M1 macrophages and CXCL9 in forecasting the effectiveness of immune checkpoint inhibitors (ICIs) is still not thoroughly investigated. We investigated the potential of M1 macrophage and C-X-C Motif Chemokine Ligand 9 (CXCL9) as predictive markers for ICI efficacy, employing a comprehensive approach integrating multicohort analysis and single-cell RNA sequencing. A significant correlation between high M1 macrophage and improved overall survival (OS) and objective response rate (ORR) was found. M1 macrophage expression was most pronounced in the immune-inflamed phenotype, aligning with increased expression of immune checkpoints. Furthermore, CXCL9 was identified as a key marker gene that positively correlated with M1 macrophage and response to ICIs, while also exhibiting associations with immune-related pathways and immune cell infiltration. Additionally, through exploring RNA epigenetic modifications, we identified Apolipoprotein B MRNA Editing Enzyme Catalytic Subunit 3G (APOBEC3G) as linked to ICI response, with high expression correlating with improved OS and immune-related pathways. Moreover, a novel model based on M1 macrophage, CXCL9, and APOBEC3G-related genes was developed using multi-level attention graph neural network, which showed promising predictive ability for ORR. This study illuminates the pivotal contributions of M1 macrophages and CXCL9 in shaping an immune-active microenvironment, correlating with enhanced ICI efficacy. The combination of M1 macrophage, CXCL9, and APOBEC3G provides a novel model for predicting clinical outcomes of ICI therapy, facilitating personalized immunotherapy.

Efficacy and safety of first-line PD-L1/PD-1 inhibitors in limited-stage small cell lung cancer: a multicenter propensity score matched retrospective study.

The prognosis of small cell lung cancer (SCLC) patients is poor, and the standard first-line treatment for limited-stage small cell lung cancer (LS-SCLC) is still chemotherapy and thoracic radiotherapy. The primary objectives of our study were to confirm the superior efficacy of first-line immune checkpoint inhibitors (ICIs) plus etoposide and platinum (EP) for LS-SCLC and find crucial biomarkers. We analyzed LS-SCLC patients from three medical centers, employing propensity score matching for group comparability. Survival outcomes were estimated by Kaplan-Meier and Cox regression analyses. Additionally, we conducted univariate and multivariate analyses to investigate potential predictive factors. Among 150 patients in our study, we successfully matched 41 pairs. The median overall survival (OS) was 29.5 months in the EP + ICIs group and 20.0 months in the EP group {hazard ratio (HR) =0.64 [95% confidence interval (CI): 0.41-1.02], P=0.059}. The median progression-free survival (PFS) was significantly extended in the EP + ICIs group (14.6 months), compared to the EP group (8.6 months) [HR =0.42 (95% CI: 0.28-0.63), P<0.001]. After matching, patients receiving chemo-immunotherapy had a median OS of 36.1 months, significantly surpassing those receiving chemotherapy alone (19.0 months) [HR =0.51 (95% CI: 0.28-0.93), P=0.02]. And the patients in the EP + ICIs group also had longer PFS after matching [HR =0.42 (95% CI: 0.25-0.71), P=0.001]. No significant difference in the objective response rate (ORR) and treatment-related adverse events (trAEs) between the two groups was found (ORR: EP: 81.0%, EP + ICIs: 90.0%, P=0.14; trAEs: EP: grade 1-2, 49.3%; grade 3-4, 42.5%; EP + ICIs: grade 1-2, 40.0%; grade 3-4, 49.1%, P=0.62). The multivariate analysis presented that the history of immunotherapy [EP + PD-1 inhibitors: HR =0.33 (95% CI: 0.17-0.62), P=0.001; EP + PD-L1 inhibitors: HR =0.18 (95% CI: 0.06-0.60), P=0.005] and baseline lung immune prognostic index (LIPI) [intermediate: HR =2.22 (95% CI: 1.20-4.13), P=0.01; poor: HR =2.03 (95% CI: 0.71-5.77), P=0.18] were independent prognostic factors for PFS among all LS-SCLC cases. However, no independent prognostic factor was identified for OS. Our real-world data showed promising clinical efficacy and tolerable safety of first-line programmed cell death protein 1 (PD-1) inhibitors or programmed cell death ligand 1 (PD-L1) inhibitors in cases with LS-SCLC. Additionally, LIPI may serve as a valuable prognostic factor.

Immune-Related Adverse Event-Related Adrenal Insufficiency Mediates Immune Checkpoint Inhibitors Efficacy in Cancer Treatment.

Immune checkpoint inhibitors (ICIs) have significantly improved the outcomes of patients with cancer; however, these agents may initiate immune-related adverse events (irAEs). Previous studies have demonstrated a robust correlation between disease prognosis and the occurrence of irAEs, specifically skin or endocrine irAEs. Herein, we aimed to evaluate the correlation between irAE-related adrenal insufficiency (AI) and ICI treatment efficacy. Patients diagnosed with gastrointestinal, respiratory, head and neck, urological, skin and gynecologic cancers treated with anti-programmed cell death 1 (PD-1)/anti-programmed cell death ligand 1 (PD-L1) antibody as monotherapy or combined therapy (combined with chemotherapy or targeted therapy) were divided into irAE-A (patients with irAE-related AI), irAE-B (patients with other irAEs) and non-irAE groups. Immunotherapy efficacy was assessed based on the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Survival probabilities were estimated using the Kaplan-Meier method with the log-rank test. Of the 192 patients enrolled in our study, 17 developed irAE-related AI and 83 developed other irAEs. The DCR of the irAE-A and irAE-B groups were higher than that of the non-irAE group (P<0.05). Multiple extended Cox regression analyses showed that irAE status (irAE-A vs non-irAE, P=0.008; irAE-B vs non-irAE, P=0.020), Eastern Cooperative Oncology Group (ECOG) status (P=0.045), tumor-node-metastasis (TNM) stage (P=0.000), and treatment line (P=0.002) were independent predictors of PFS. Contrarily, irAE status (irAE-A vs non-irAE, P=0.009; irAE-B vs non-irAE, P=0.013), ECOG status (P=0.007), TNM stage (P=0.035), treatment line (P=0.001) and treatment modality (P=0.008) were independent predictors for OS. IrAE-related AI was significantly associated with ICI treatment efficacy in patients with cancer, which could be a potentially predictable marker. Due to the destruction of adrenal tissue by T cells with enhanced activity, AI reflects enhanced T cell activity to some extent.

Association between sex and efficacy of immune checkpoint inhibitors: a systematic review and meta-analysis.

Aim: To explore the association between sex and immune checkpoint inhibitors (ICIs). Materials & methods: We assessed the difference in survival outcomes from ICIs between sexes using an interaction test. Results: 108 studies representing 70,243 patients were included. In the first-line setting, the pooled interaction HR was 0.97 (95% CI: 0.91-1.04). In the subsequent-line setting, the pooled interaction HR was 0.85 (95% CI: 0.77-0.95). When ICIs were given as perioperative therapy or as systemic therapy in patients with positive PD-L1 expression, both men and women obtained equal survival benefits. Conclusion: Both sex, line of therapy, cancer (sub)type and PD-L1 status should be taken into account in the assessment of risk versus benefit when deciding to offer ICIs to patients.

Alpha-fetoprotein predicts the treatment efficacy of immune checkpoint inhibitors for gastric cancer patients

BackgroundImmune checkpoint inhibitors (ICIs) are commonly used in conjunction with chemotherapy to improve treatment outcomes for patients with gastric cancer. Since AFP could influence immunity by both inhibiting natural killer (NK) cells and regulating negatively the function of dendritic cells, we evaluated the influence of baseline serum alpha-fetoprotein (AFP) levels on the curative effect of ICIs in advanced gastric cancer (AGC) patients.MethodsA retrospective analysis was conducted on 158 AGC patients who underwent ICI treatment. The patients were divided into high and low groups based on the AFP threshold of 20 ng/ml. The efficacy of ICI treatment was assessed using objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).ResultsThe higher levels of baseline AFP were found to be associated with a decrease in the effectiveness of ICIs, as evidenced by a DCR of 50.0% in the group with high AFP levels compared to 87.7% in the group with low AFP levels (P < 0.001). Further analysis using Kaplan-Meier survival techniques indicated that a high AFP level was linked to shorter progression-free survival (PFS) (P < 0.001) and overall survival (OS) (P = 0.001) in AGC individuals receiving ICIs. After propensity score matching, a log rank test revealed that the high AFP group had a decrease in median PFS (P = 0.011) and median OS (P = 0.036) compared to the low AFP group. The high AFP levels also showed its association with shorter PFS and OS in the subgroup analysis of ICI plus chemotherapy patients.ConclusionsBaseline AFP levels may predict immune checkpoint inhibitor treatment efficacy in AGC patients.

Efficacy of immune checkpoint inhibitors in SMARCA4-deficient and TP53 mutant undifferentiated lung cancer.

The present study was conducted to characterize the clinicopathologic characteristics, immunohistochemical staining results, and immune checkpoint inhibitors (ICIs) efficacy in patients with SMARCA4-deficient/TP53 mutant lung cancer. Patients diagnosed with advanced or metastatic undifferentiated lung cancer harboring SMARCA4-deficient and TP53 mutations, however, without targetable sensitive mutations were retrieved from the electronic medical record system. Descriptive statistics were used to describe the baseline characteristics and clinical features including age, gender, eastern cooperative oncology group performance status, disease stage, smoking status, chief complaint, site of the primary mass, tumor size, gross type, symptoms, local invasion, and metastatic sizes. Immunological markers and potential drive genes were detected by immunohistochemical staining and next generation sequencing. Efficacy and safety profile of ICIs in included patients was evaluated with progression-free survival and overall survival. Between January 2019 and September 2022, there were 4 patients included within the inclusion criteria in the present study. Biomarkers including CK, CK7, and integrase interactor 1 were detected positive, however, other immunological markers including CK20, CD56, P63, P40, NapsinA, TTF-1, CgA, Syn, BRG1, or PD-L1 were detected negative among them. Results of next generation sequencing panel were failed to discover any targetable sensitive mutations. A total of 4 mutation types of TP53, including p.C141Y, p.S240G, p.E339X (terminator acquired), and p.L130F detected for the patients, respectively. Microsatellite stability status, as well as low tumor mutation burden was identified among all the patients. Median progression-free survival for ICIs as first line treatment and median overall survival were 3.25 months (range from 1.3 to 6.8 months), and 6.0 months (range from 2.7 to 9.6 months), respectively. Our results indicated that advanced lung cancer patients harboring co-occurring SMARCA4-deficient/TP53 mutations might respond to ICIs treatment, though within negative programmed cell death-ligand 1 expression or low tumor mutation burden. However, hyperprogressive disease by ICIs may also happen for such patients. The mutation types of TP53 might play a role during the exposure of ICIs, however, need further identification in basic experiments.

The Efficacy and Safety of Immune Checkpoint Inhibitors in Adrenocortical Carcinoma: A Systematic Review and Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of different malignancies. However, their efficacy in advanced adrenocortical carcinoma (ACC) remains uncertain. Thus, we conducted a systematic review and meta-analysis to summarize the efficacy and tolerability of ICIs in patients with advanced ACC. We searched PubMed, Scopus, and CENTRAL for studies that used ICIs in ACC. Studies with more than five patients were included in the meta-analysis of the objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and grade 3/4 adverse events. Twenty studies with 23 treatment arms and 250 patients were included. Single-agent anti-PD1 or anti-PD-L1 treatment was utilized in 13 treatment arms, whereas an anti-PD1 or anti-PD-L1 and anti-CTLA4 combination was used in 4 treatment arms. Other anti-PD1- or anti-PD-L1-based combinations were used in five treatment arms. The ORR was 14% (95% CI = 10-19%, I2 = 0%), and the DCR was 43% (95% CI = 37-50%, I2 = 13%). The combination anti-PD1- or anti-PD-L1-based treatment strategies did not correlate with higher responses compared with monotherapy. The median OS was 13.9 months (95% CI = 7.85-23.05), and the median PFS was 2.8 months (95% CI = 1.8-5.4). ICIs have a modest efficacy in advanced ACC but a good OS. Further studies are needed to investigate predictive biomarkers for ICI response and to compare ICI-based strategies with the current standard of care.

Special populations in metastatic renal cell carcinoma.

This review focuses on special populations poorly represented in current evidence-based practice for metastatic renal cell carcinoma (mRCC). This includes the elderly and frail, patients on immunosuppression or with autoimmune diseases, patients with brain, liver, and/or bone metastases, and RCC with sarcomatoid features. Certain populations are poorly represented in current trials for mRCC. Patients with central nervous system (CNS) metastases are often excluded from first-line therapy trials. Modern doublet systemic therapy appears to benefit patients with bone or liver metastases, but data supporting this conclusion is not robust. Post-hoc analyses on patients with sarcomatoid differentiation have shown improved response to modern doublet therapy over historical treatments. The elderly are underrepresented in current clinical trials, and most trials exclude all but high-performing (nonfrail) patients, though true frailty is likely poorly captured using the current widely adopted indices. It is difficult to make conclusions about the efficacy of modern therapy in these populations from subgroup analyses. Data from trials on other malignancies in patients with autoimmune diseases or solid organ transplant recipients on immunosuppression suggest that immune checkpoint inhibitors (ICIs) may still have benefit, though at the risk of disease flare or organ rejection. The efficacy of ICIs has not been demonstrated specifically for RCC in this group of patients. The elderly, frail, and immunosuppressed, those with tumors having aggressive histologic features, and patients with brain, bone, and/or liver metastases represent the populations least understood in the modern era of RCC treatment.