Efficacy Of Immune Checkpoint Inhibitors Research Articles

Increasing serum complement component 1q is associated with worse prognosis in advanced non-small cell lung cancer treated with immune checkpoint inhibitors: a single-center, retrospective study.

There is a lack of readily available clinical markers of non-small cell lung cancer (NSCLC) immunotherapy efficacy. Previous studies have found that overexpressed complement component 1q (C1q) promotes macrophage M2 polarization and an immunosuppressive tumor microenvironment. This study aimed to evaluate the association between serum C1q and the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced NSCLC. A total of 168 patients with advanced NSCLC who received ICIs in the Renmin Hospital of Wuhan University were included in this study. Serum C1q levels were collected before and 3 weeks after immunotherapy treatment, together with other data on clinical and demographic characteristics. The primary outcome was overall survival (OS) (months from first dose of ICIs to death, censored at date of last follow-up). Secondary outcome was progression-free survival (PFS) [defined as months from first dose of ICIs to clinical or radiographic progression by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or death, censored at date of last follow-up] and objective response rate (ORR) which was defined as rate of complete response (CR) or partial response (PR) at best response by RECIST 1.1. A total of 168 patients were included in this study, including 127 males (75.60%) and 41 females (24.40%). Thirty-nine patients achieved objective response (2 CR, 37 PR), and 111 patients (66.07%) had stable disease (SD) as best response. The ORR was 23.21% and the disease control rate was 89.28%. The upward trends of serum C1q levels between baseline and post-treatment were strongly associated with the shorter PFS [hazard ratio (HR) =1.554, 95% confidence interval (CI): 1.07-2.10, P=0.01] and OS (HR =1.444, 95% CI: 1.01-1.98, P=0.03). Moreover, taking the median OS 18.9 months as the cut-off of prognosis, receiver operating characteristic (ROC) analysis showed that serum baseline C1q yielded an area under the ROC curve of 0.785 (95% CI: 0.711-0.869). The optimal serum baseline C1q cut-off point to predict immunotherapy prognosis was 216.2 mg/L. These findings suggested that elevated serum C1q after ICIs treatment was related to a worse prognosis in NSCLC. Monitoring the baseline and dynamic data of C1q during hospitalization showed the potential to predict the prognosis of NSCLC patients.

Structure-Based Rational Design of Constrained Peptides as TIM-3 Inhibitors.

Blocking the immunosuppressive function of T-cell immunoglobulin mucin-3 (TIM-3) is an established therapeutic strategy to maximize the efficacy of immune checkpoint inhibitors for cancer immunotherapy. Currently, effective inhibition of TIM-3 interactions relies on monoclonal antibodies (mAbs), which come with drawbacks such as immunogenicity risk, limited tumor penetration, and high manufacturing costs. Guided by the X-ray cocrystal structures of TIM-3 with mAbs, we report an in silico structure-based rational design of constrained peptides as potent TIM-3 inhibitors. The top cyclic peptide from our study (P2) binds TIM-3 with a K D value of 166.3 ± 12.1 nM as determined by surface plasmon resonance (SPR) screening. Remarkably, P2 efficiently inhibits key TIM-3 interactions with natural TIM-3 ligands at submicromolar concentrations in a panel of cell-free and cell-based assays. The capacity of P2 to reverse immunosuppression in T-cell/cancer cell cocultures, coupled with favorable in vitro pharmacokinetic properties, highlights the potential of P2 for further evaluation in preclinical models of immuno-oncology.

Unaddressed Challenges in the Treatment of Cutaneous Melanoma?

Background and Objectives: While the management of noninvasive cutaneous melanoma (CM) is typically limited to a secondary excision to reduce recurrence risk and periodic follow-up, treating patients with advanced melanoma presents ongoing challenges. Materials and Methods: This review provides a comprehensive examination of both established and emerging pharmacologic strategies for advanced CM management, offering an up-to-date insight into the current therapeutic milieu. The dynamic landscape of advanced CM treatment is explored, highlighting the efficacy of immune checkpoint inhibitors and targeted therapies, either in monotherapy or combination regimens. Additionally, ongoing investigations into novel treatment modalities are thoroughly discussed, reflecting the evolving nature of melanoma management. Results: The therapeutic landscape for melanoma management is undergoing significant transformation. Although various treatment modalities exist, there remains a critical need for novel therapies, particularly for certain stages of melanoma or cases resistant to current options. Conclusions: Consequently, further studies are warranted to identify new treatment avenues and optimize the utilization of existing drugs.

Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade.

The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.

Janus kinase inhibitor overcomes resistance to immune checkpoint inhibitor treatment in peritoneal dissemination of gastric cancer in C57BL/6 J mice

BackgroundCancer immunotherapy aims to unleash the immune system’s potential against cancer cells, providing sustained relief for tumors responsive to immune checkpoint inhibitors (ICIs). While promising in gastric cancer (GC) trials, the efficacy of ICIs diminishes in the context of peritoneal dissemination. Our objective is to identify strategies to enhance the impact of ICI treatment specifically for cases involving peritoneal dissemination in GC.MethodsThe therapeutic efficacy of anti-PD1, CTLA4 treatment alone, or in combination was assessed using the YTN16 peritoneal dissemination tumor model. Peritoneum and peritoneal exudate cells were collected for subsequent analysis. Immunohistochemical staining, flow cytometry, and bulk RNA-sequence analyses were conducted to evaluate the tumor microenvironment (TME). A Janus kinase inhibitor (JAKi) was introduced based on the pathway analysis results.ResultsAnti-PD1 and anti-CTLA4 combination treatment (dual ICI treatment) demonstrated therapeutic efficacy in certain mice, primarily mediated by CD8 + T cells. However, in mice resistant to dual ICI treatment, even with CD8 + T cell infiltration, most of the T cells exhibited an exhaustion phenotype. Notably, resistant tumors displayed abnormal activation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway compared to the untreated group, with observed infiltration of macrophages, neutrophils, and Tregs in the TME. The concurrent administration of JAKi rescued CD8 + T cells function and reshaped the immunosuppressive TME, resulting in enhanced efficacy of the dual ICI treatment.ConclusionDual ICI treatment exerts its anti-tumor effects by increasing tumor-specific CD8 + T cell infiltration, and the addition of JAKi further improves ICI resistance by reshaping the immunosuppressive TME.

Hepatocellular Carcinoma: Beyond the Border of Advanced Stage Therapy.

Hepatocellular carcinoma (HCC) is the deadliest emergent health issue around the globe. The stronger oncogenic effect, proteins, and weakened immune response are precisely linked with a significant prospect of developing HCC. Several conventional systemic therapies, antiangiogenic therapy, and immunotherapy techniques have significantly improved the outcomes for early-, intermediate-, and advanced-stage HCC patients, giving new hope for effective HCC management and prolonged survival rates. Innovative therapeutic approaches beyond conventional treatments have altered the landscape of managing HCC, particularly focusing on targeted therapies and immunotherapies. The advancement in HCC treatment suggested by the Food and Drug Administration is multidimensional treatment options, including multikinase inhibitors (sorafenib, lenvatinib, regorafenib, ramucirumab, and cabozantinib) and immune checkpoint inhibitors (atezolizumab, pembrolizumab, durvalumab, tremelimumab, ipilimumab, and nivolumab), in monotherapy and in combination therapy to increase life expectancy of HCC patients. This review highlights the efficacy of multikinase inhibitors and immune checkpoint inhibitors in monotherapy and combination therapy through the analysis of phase II, and III clinical trials, targeting the key molecular pathways involved in cellular signaling and immune response for the prospective treatment of advanced and unresectable HCC and discusses the upcoming combinations of immune checkpoint inhibitors-tyrosine kinase inhibitors and immune checkpoint inhibitors-vascular endothelial growth factor inhibitors. Finally, the hidden challenges with pharmacological therapy for HCC, feasible solutions for the future, and implications of possible presumptions to develop drugs for HCC treatment are reported.

Evaluating Immune Checkpoint Blockade in Metastatic Castration-Resistant Prostate Cancers with Deleterious CDK12 Alterations in the Phase 2 IMPACT Trial.

CDK12 inactivation in metastatic castration-resistant prostate cancer (mCRPC) may predict immunotherapy responses. This phase 2 trial evaluated the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with CDK12-altered mCRPC. Eligible patients had mCRPC with deleterious CDK12 alterations and any prior therapies except ICI. Cohort A received ipilimumab (1 mg/kg) with nivolumab (3 mg/kg) every 3 weeks for up to four cycles, followed by nivolumab 480 mg every 4 weeks. Cohort C received nivolumab alone 480 mg every 4 weeks. Patients with CDK12-altered nonprostate tumors were enrolled in cohort B and not reported. The primary endpoint was a 50% reduction in PSA (PSA50). Key secondary endpoints included PSA progression-free survival, overall survival, objective response rate, and safety. PSA was evaluable in 23 patients in cohort A and 14 in cohort C. Median lines of prior therapy were two in cohorts A and C, including any prior novel hormonal agent (74% and 79%) and chemotherapy (57% and 36%). The PSA50 rate was 9% [95% confidence interval (CI), 1%-28%] in cohort A with two responders; neither had microsatellite instability or a tumor mutational burden >10 mutations/megabase. No PSA50 responses occurred in cohort C. Median PSA progression-free survival was 7.0 months (95% CI, 3.6-11.4) in cohort A and 4.5 months (95% CI, 3.4-13.8) in cohort C. Median overall survival was 9.0 months (95% CI, 6.2-12.3) in cohort A and 13.8 months (95% CI, 3.6-not reached) in cohort C. There was minimal activity with ICI therapy in patients with CDK12-altered mCRPC.

Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer

POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone+/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P= 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR)= 0.24, 95% confidence interval (CI) 0.08-0.74, P= 0.01] and superior overall survival (OS) (HR= 0.38, 95% CI 0.12-1.18, P= 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR= 0.17, 95% CI 0.04-0.69, P=0.013) and OS (HR= 0.24, 95% CI 0.06-0.98, P= 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

The correlation between immune-related adverse events and efficacy of immune checkpoint inhibitors.

Immune checkpoint inhibitors have revolutionized cancer treatment by targeting the cytotoxic T lymphocyte antigen-4 and programmed death-1/ligand-1. Although immune checkpoint inhibitors show promising therapeutic efficacy, they often cause immune-related adverse events. Immune-related adverse events differ from the side effects of conventional chemotherapy and require vigilant monitoring. These events predominantly affect organs, such as the colon, liver, lungs, pituitary gland, thyroid and skin, with rare cases affecting the heart, nervous system and other tissues. As immune-related adverse events result from immune activation, indicating the reinvigoration of exhausted immune cells that attack both tumors and normal tissues, it is theoretically possible that immune-related adverse events may signal a better response to immune checkpoint inhibitor therapy. Recent retrospective studies have explored the link between immune-related adverse event development and clinical efficacy; however, the predictive value of immune-related adverse events in the immune checkpoint inhibitor response remains unclear. Additionally, studies have focused on immune-related adverse events, timing of onset and immunosuppressive treatments. This review focuses on pivotal studies of the association between immune-related adverse events and outcomes in patients treated with immune checkpoint inhibitors.

Isobutyric acid enhances the anti-tumour effect of anti-PD-1 antibody

The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.

The later-line efficacy and safety of immune checkpoint inhibitors plus anlotinib in EGFR-mutant patients with EGFR-TKI-resistant NSCLC: a single-center retrospective study

BackgroundEffective treatment after EGFR-TKI resistance is of great clinical concern. We aimed to investigate the efficacy and safety of anlotinib in combination with an anti-PD-1/PD-L1 antibody in later-line therapy for EGFR-mutant NSCLC patients after TKI treatment failure and to explore the independent predictive factors of therapeutic efficacy.MethodsA total of 71 patients with confirmed advanced EGFR-mutated NSCLC who progressed after previous standard EGFR-TKI therapy but still failed after multiline treatments were included retrospectively in this study. Most of the patients had previously received at least three lines of treatment. All were treated with anlotinib combined with anti-PD-1 or anti-PD-L1 therapy. The safety of this combined treatment was assessed by the incidence of adverse events. The efficacy of the regimens was evaluated by survival analysis (OS, PFS, ORR, DCR).ResultsThe median follow-up period was 28.6 months (range: 2.3–54.0 months), and the median number of treatment lines was 4. The overall response rate (ORR) and disease control rate (DCR) were 19.7% and 77.5%, respectively. The median PFS was 5.8 months (95% CI 4.2–7.4 months), and the median OS was 17.1 months (95% CI 12.0–22.3 months). Patients who received immune checkpoint inhibitors plus anlotinib had an encouraging intracranial ORR of 38.5% and a DCR of 80.8%. ECOG performance status < 2 at baseline was independent protective factors of PFS. Metastatic organs and ECOG performance status were independent parameters in predicting OS. Treatment-related adverse events occurred in 66 (93.0%) patients; most of the adverse events were Grade 1–2, and no increase in adverse events was observed compared to monotherapy.ConclusionAnlotinib combined with an anti-PD-1/PD-L1-based regimen exhibited promising efficacy and tolerance in NSCLC patients with EGFR mutations after previous TKI failure. The efficacy of this combined regimen in patients with EGFR mutations should be further evaluated.

Enhancing immunotherapy outcomes by targeted remodeling of the tumor microenvironment via combined cGAS-STING pathway strategies.

Immune checkpoint inhibitors (ICIs) represent a groundbreaking advance in the treatment of malignancies such as melanoma and non-small cell lung cancer, showcasing substantial therapeutic benefits. Nonetheless, the efficacy of ICIs is limited to a small subset of patients, primarily benefiting those with "hot" tumors characterized by significant immune infiltration. The challenge of converting "cold" tumors, which exhibit minimal immune activity, into "hot" tumors to enhance their responsiveness to ICIs is a critical and complex area of current research. Central to this endeavor is the activation of the cGAS-STING pathway, a pivotal nexus between innate and adaptive immunity. This pathway's activation promotes the production of type I interferon (IFN) and the recruitment of CD8+ T cells, thereby transforming the tumor microenvironment (TME) from "cold" to "hot". This review comprehensively explores the cGAS-STING pathway's role in reconditioning the TME, detailing the underlying mechanisms of innate and adaptive immunity and highlighting the contributions of various immune cells to tumor immunity. Furthermore, we delve into the latest clinical research on STING agonists and their potential in combination therapies, targeting this pathway. The discussion concludes with an examination of the challenges facing the advancement of promising STING agonists in clinical trials and the pressing issues within the cGAS-STING signaling pathway research.

New drugs, old problems: immune checkpoint inhibitors and cancer-associated thrombosis

A frequent side effect of cancer treatment is venous thromboembolism (VTE), which is made more likely by systemic anticancer medication. Immune checkpoint inhibitors (ICIs) have emerged as a paradigm-shifting treatment for many cancers. Early trials investigating the efficacy of ICIs did not identify thrombosis as a significant adverse event of concern. An initial meta-analysis reported a 1.1% [95% confidence interval (CI) 0.5-2.1] risk of arterial thromboembolism (ATE) and a 2.7% (95% CI 1.8-4.0) rate of vein thrombosis. ICIs have, however, been linked to ATE and VTE in an increasing number of post-marketing investigations. The reported incidence rates of cumulative VTE range from 5-8% at 6 months to 10-12% at 12 months, while the rates of ATE vary from 1-2% at 6 months to 17 months. Furthermore, a number of studies show a correlation between reduced survival and ICI-related thromboembolism. In order to provide a compiled and thorough narrative on the mechanisms, incidence, risk factors, and survival related to ICI-associated VTE and ATE, this narrative review summarizes the literature.

Immune Checkpoint Inhibitor Score Predicts Survival Benefit of Immunotherapy in Patients with Non-small Cell Lung Cancer.

The use of immune checkpoint inhibitors (ICIs) in patients with advanced lung cancer is increasing. Despite ongoing studies to predict the efficacy of ICIs, its use in clinical practice remains difficult. Thus, we aimed to discover a predictive marker by analyzing blood cell characteristics and developing a scoring system for patients treated with ICIs. This was a prospective multicenter study in patients with advanced nonsmall cell lung cancer (NSCLC) who received ICIs as second-line treatment from June 2021 to November 2022. Blood cell parameters in routine blood samples were evaluated using an automated hematology analyzer. Immune checkpoint inhibitor score (IChIS) was calculated as the sum of neutrophil count score and immature granulocyte score. A total of 143 patients from four institutions were included. The treatment response was as follows: partial response, 8.4%; stable disease, 37.1%; and progressive disease, 44.8%. Median progression-free survival and overall survival after ICI treatment was 3.0 and 8.3 months, respectively. Median progression-free survival in patients with an IChIS of 0 was 4.0 months, which was significantly longer than 1.9 months in patients with an IChIS of 1 and 1.0 month in those with an IChIS of 2 (p=0.001). The median overall survival in patients with an IChIS of 0 was 10.2 months, which was significantly longer than 6.8 and 1.8 months in patients with an IChIS of 1 and 2, respectively (p&lt;0.001). Baseline IChIS could be a potential biomarker for predicting survival benefit of immunotherapy in NSCLC.

PCDH11X mutation as a potential biomarker for immune checkpoint therapies in lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) have achieved impressive success in lung adenocarcinoma (LUAD). However, the response to ICIs varies among patients, and predictive biomarkers are urgently needed. PCDH11X is frequently mutated in LUAD, while its role in ICI treatment is unclear. In this study, we curated genomic and clinical data of 151 LUAD patients receiving ICIs from three independent cohorts. Relations between PCDH11X and treatment outcomes of ICIs were examined. A melanoma cohort collected from five published studies, a pan-cancer cohort, and non-ICI-treated TCGA-LUAD cohort were also examined to investigate whether PCDH11X mutation is a specific predictive biomarker for LUAD ICI treatment. Among the three ICI-treated LUAD cohorts, PCDH11X mutation (PCDH11X-MUT) was associated with better clinical response compared to wild-type PCDH11X (PCDH11X-WT). While in ICI-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and the non-ICI-treated TCGA-LUAD cohort, no significant differences in overall survival (OS) were observed between the PCDH11X-MUT and PCDH11X-WT groups. PCDH11X mutation was associated with increased PD-L1 expression, tumor mutation burden (TMB), neoantigen load, DNA damage repair (DDR) mutations, and hot tumor microenvironment in TCGA-LUAD cohort. Our findings suggested that the PCDH11X mutation might serve as a specific biomarker to predict the efficacy of ICIs for LUAD patients. Considering the relatively small sample size of ICI-treated cohorts, future research with larger cohorts and prospective clinical trials will be essential for validating and further exploring the role of PCDH11X mutation in the context of immunotherapy outcomes in LUAD. KEY MESSAGES: PCDH11X mutation is associated with better clinical response compared to wild type PCDH11X in three ICIs-treated LUAD cohorts. In ICIs-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and non-ICIs-treated TCGA-LUAD cohortsPCDH11X mutation is not associated with better clinical response, suggesting PCDH11X mutation might be a specific biomarker to predict the efficacy of ICIs treatment for LUAD patients. PCDH11X mutation is associated with increased PD-L1 expression, tumor mutation burden, and neoantigen load in TCGA-LUAD cohort. PCDH11X mutation is associated with hot tumor microenvironment in TCGA-LUAD cohort.

Clinical evidence for the prognostic impact of metformin in cancer patients treated with immune checkpoint inhibitors

BackgroundPreclinical studies suggest that metformin might enhance the efficacy of immune checkpoint inhibitors (ICIs) and potentially influence the prognoses of cancer patients undergoing ICIs treatment. This study endeavors to assess the prognostic significance of metformin in cancer patients undergoing ICIs therapy, aiming to furnish evidence-based insights for clinical practice. MethodsA thorough literature search was conducted across electronic databases to encompass all potential records published before November 20th, 2023. A meta-analysis was executed utilizing Stata 17.0 to derive pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for both overall survival (OS) and progression-free survival (PFS). ResultsA total of 22 studies encompassing 9,011 patients met the inclusion criteria. Meta-analyses revealed a significant correlation between metformin use and poorer OS (HR, 1.13; 95 %CI, 1.04–1.23; P = 0.004) rather than PFS (HR, 1.04; 95 %CI, 0.96–1.14; P = 0.345) among cancer patients undergoing ICIs treatment. Subgroup analysis delineated that the concurrent administration of metformin and ICIs significantly associated with adverse prognoses in the European population (OS: HR, 1.23; 95 %CI, 1.10–1.39; P = 0.001; PFS: HR, 1.14; 95 %CI, 1.02–1.28; P = 0.024). ConclusionBased on current clinical evidence, concomitant metformin use does not appear to improve the prognostic outcomes for cancer patients undergoing ICIs therapy and may potentially correlate with inferior prognoses. Further studies are imperative to comprehensively elucidate the impact of metformin within the realm of ICIs therapy.

Efficacy of immune-checkpoint inhibitors combined with cytotoxic chemotherapy in advanced or recurrent endometrial cancer: A systematic review and meta-analysis

BackgroundThe combination of immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy has emerged as a highly promising primary option for advanced or recurrent endometrial cancer (EC). The study aimed to evaluate treatment efficacy of ICIs with cytotoxic chemotherapy in EC. MethodsWe conducted a comprehensive review of randomized controlled trials up to November 11, 2023, focusing on immunotherapy combined with chemotherapy versus chemotherapy alone for EC. The primary endpoint was the pooled hazard ratio (HR), which was further analyzed across subgroups based on mismatch repair (MMR) status, race, histology, and programmed death-ligand 1 (PD-L1) status. The protocol was registered in PROSPERO (CRD42023475669). FindingsFour trials with 2335 patients were analyzed. ICIs with chemotherapy significantly prolonged progression-free survival (PFS) (HR, 0.70; 95% CI, 0.62–0.79) and overall survival (OS) (HR, 0.75; 95% CI, 0.63–0.89) compared to chemotherapy alone. Stratification by MMR status showed substantial benefits for dMMR (PFS; HR, 0.33; 95% CI, 0.26–0.43; OS; HR, 0.37; 95% CI, 0.22–0.91) over pMMR cohorts in both PFS and OS. In the subgroup analysis, there was significant PFS advantage in Caucasian (HR, 0.63; 95% CI, 0.54–0.72) over non-Caucasian, in endometrioid histology (HR, 0.66; 95% CI, 0.56–0.78) over non-endometrioid, and in PD-L1 positive (HR, 0.39; 95% CI, 0.19–0.81) over PD-L1 negative population. InterpretationICIs combined with platinum-based chemotherapy significantly prolonged PFS and OS in patients with advanced or recurrent EC. Patients with dMMR status, Caucasians, endometrioid histology, and positive PD-L1 status showed significant PFS benefits, emphasizing the need for personalized treatment approaches to improve outcomes.

Assessment of PSA responses and changes in the rate of tumor growth (g-rate) with immune checkpoint inhibitors in US Veterans with prostate cancer

We examined data from US Veterans with prostate cancer (PC) to assess disease response to immune checkpoint inhibitors (ICI) as monotherapy or combined with abiraterone or enzalutamide to assess ICI efficacy in the real-world. We queried the VA corporate data warehouse (CDW) to identify Veterans with a diagnosis of PC who received ICI for any malignancy and had ≥1 PSA measurement while receiving ICI. To evaluate ICI monotherapy, we restricted analysis to Veterans who had not received LHRH agonists/antagonists, PC-directed medical therapy, or radiation/extirpative surgery of the bladder/prostate within and preceding the duration of ICI administration. For ICI combination analysis, we identified Veterans who received abiraterone or enzalutamide for PC while on ICI. We calculated rates of tumor (PSA) growth (g-rates), comparing them to a 1:2 matched reference cohort. We identified 787 Veterans with PC and ≥1 PSA measurement while receiving an ICI. Median duration of ICI therapy was 155 days. 223 Veterans received ICI monotherapy, with only 17(8%) having a reduction in PSA (median decline = 43%). 12 (5%) had PSA declines >30% (PSA30) which included 6 (3%) who had PSA reductions greater than 50% (PSA50). Median g-rates for ICI plus abiraterone (n = 20) or enzalutamide (n = 31) were 0.000689/d-1 and 0.002819/d-1, respectively, and were statistically insignificant compared to g-rates of matched cohorts receiving abiraterone (g = 0.000925/d-1, P = 0.73) or enzalutamide (g = 0.001929/d-1, P = 0.58) alone. Our data align with clinical trial data in PC, demonstrating limited benefit from ICI monotherapy and predicting no survival benefit from simultaneous abiraterone or enzalutamide with an ICI using g-rate.

Efficacy of Pembrolizumab vs. Nivolumab Plus Ipilimumab in Metastatic NSCLC in Relation to PD-L1 and TMB Status.

The efficacy of immune checkpoint inhibitor (ICI) therapy concerning programmed death ligand 1 (PD-L1) status is well established in patients diagnosed with non-small cell lung cancer (NSCLC). However, there remains a paucity of evidence regarding the efficacy concerning tumor mutational burden (TMB) in both clinical trials and real-world data (RWD). In the current article, clinicopathological and molecular epidemiological data were meticulously collected, and treatment modalities were meticulously recorded. The final analysis included a study population of 194 patients. Median age was 67 years (range 37-86), with the majority being male (71.13%), and 85.71% of patients were either current or former smokers at diagnosis. Adenocarcinoma accounted for most diagnoses (71.65%), followed by squamous cell carcinoma (24.23%). In terms of PD-L1 status, 42.78% had an expression level below 1%, 28.35% had an expression between 1-49%, and 28.87% had an expression above 50%. The TMB ranged from 0 to 75, with a median of 10.31 (range 0-75) for PD-L1 expression below 1%, with a median of 9.73 (range 0.95-39.63) for PD-L1 expression between 1-49%, and a median of 9.72 (range 0.95-48) for PD-L1 expression above 50%. Corresponding to patients with low PDL-1 less than 1% and low TMB (0-5), the median overall survival (mOS) was 16 (p = 0.18), and 15 months (p = 0.22), patients with medium PDL-1 (1-49%) and medium TMB (5-10), the mOS was 15 (p = 0.18) and 16 months (p = 0.22), patients with high PDL-1 (>50) and high TMB (>10), the mOS was 24 (p = 0.18) and 21 (p = 0.22) months. This study represents the largest academic RWD dataset concerning PD-L1 and TMB status in patients with locally advanced and metastatic NSCLC.

Assessing the role of programmed cell death signatures and related gene TOP2A in progression and prognostic prediction of clear cell renal cell carcinoma

Kidney Clear Cell Carcinoma (KIRC), the predominant form of kidney cancer, exhibits a diverse therapeutic response to Immune Checkpoint Inhibitors (ICIs), highlighting the need for predictive models of ICI efficacy. Our study has constructed a prognostic model based on 13 types of Programmed Cell Death (PCD), which are intertwined with tumor progression and the immune microenvironment. Validated by analyses of comprehensive datasets, this model identifies seven key PCD genes that delineate two subtypes with distinct immune profiles and sensitivities to anti-PD-1 therapy. The high-PCD group demonstrates a more immune-suppressive environment, while the low-PCD group shows better responses to PD-1 treatment. In particular, TOP2A emerged as crucial, with its inhibition markedly reducing KIRC cell growth and mobility. These findings underscore the relevance of PCDs in predicting KIRC outcomes and immunotherapy response, with implications for enhancing clinical decision-making.