Death Ligand Research Articles

NIR-II-Responsive Hybrid System Achieves Cascade-Augmented Antitumor Immunity via Genetic Engineering of Both Bacteria and Tumor Cells.

The combination of nanoparticles and tumor-targeting bacteria for cancer immunotherapy can overcome the shortcomings of poor nanoparticle accumulation, limited penetration, and restricted distribution. However, it remains a great challenge for the hybrid system to improve therapeutic efficacy through the simultaneous and controllable regulation of immune cells and tumor cells. Herein, a hybrid therapeutic platform is rationally designed to achieve immune cascade-augmented cancer immunotherapy. To construct the hybrids, photothermal nanoparticles responsive to light in the second near-infrared (NIR-II) region are conjugated onto the surface of engineered bacteria through pH-responsive Schiff base bonds. Taking advantage of the hypoxia targeting and deep penetration characteristics of the bacteria, the hybrids can accumulate at tumor sites. Then nanoparticles detach from the bacteria to realize genetic engineering of tumor cells, which induces tumor cell apoptosis and down-regulate the expression of programmed cell death ligand 1 to alleviate immunosuppressive tumor microenvironment. The mild photothermal heating can not only induce tumor-associated antigen release, but also trigger sustainable expression of cytokine interleukin-2. Notably, a synergistic antitumor effect is achieved between the process of p53 transfection and NIR-II light-activated genetic engineering of bacteria. This work proposes a facile strategy for the construction of hybrid system to achieve cascade-augmented cancer immunotherapy.

Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial

BackgroundWe report 5-year efficacy and safety outcomes from CheckMate 9LA in patients with metastatic non-small cell lung cancer (mNSCLC) and exploratory analyses in key patient subgroups. MethodsAdults with stage IV/recurrent NSCLC and no sensitizing EGFR/ALK alterations were randomized to receive nivolumab plus ipilimumab with chemotherapy (n = 361) or chemotherapy (n = 358). Outcomes were assessed in all randomized patients and subgroups. ResultsWith 57.3 months’ minimum follow-up, patients continued to derive overall survival (OS) benefit with nivolumab plus ipilimumab with chemotherapy over chemotherapy (HR, 0.73; 95% CI, 0.62–0.85; 5-year OS rates, 18% vs. 11%), regardless of tumor programmed death ligand 1 (PD-L1) expression (PD-L1 < 1%, 22% vs. 8%; PD-L1 ≥ 1%, 18% vs. 11%), histology (squamous, 18% vs. 7%; non-squamous, 19% vs. 12%), or presence of baseline brain metastases (20% vs. 6%). Five-year duration of response (DOR) rates were 19% versus 8% with nivolumab plus ipilimumab with chemotherapy versus chemotherapy, with consistent benefit across subgroups. Patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events had a 5-year OS rate of 37%. Five-year progression-free survival and DOR rates in 5-year survivors were 55% versus 38% and 59% versus 46%, respectively. No new safety signals were observed in 5-year survivors, regardless of the number of ipilimumab doses received. ConclusionThis 5-year update supports the long-term, durable OS benefit and improved 5-year survivorship with nivolumab plus ipilimumab with chemotherapy over chemotherapy in patients with mNSCLC, regardless of tumor PD-L1 expression or histology. ClinicalTrials.gov registrationNCT03215706

Correlation between exosomal PD-L1 and prognosis in patients with cancer: a systematic review and meta-analysis.

The predictive role of exosomal programmed cell death ligand l (exoPD-L1) in prognosis has been studied extensively; however, there is still no consensus. Three databases, including EMBASE, PubMed, and Web of Science, were searched through January 4, 2024. The pooled hazard ratios (HRs) with 95% confidence intervals (95%CIs) were used to identify the relationship between circulating exoPD-L1 and prognosis. 15 studies with 1091 patients with cancer were included in this statistical analysis. High exoPD-L1 level was correlated with shorter progression-free survival (PFS) (HR = 2.58, 95% CI: 1.75-3.81) and overall survival (OS) (HR = 1.61, 95% CI: 1.32-1.98). Meanwhile, we found that dynamic upregulation of circulating exoPD-L1 in the early stages of immunotherapy was a favorable factor for prognosis (PFS: HR = 0.34, 95% CI: 0.23-0.51; OS: HR = 0.21, 95% CI: 0.13-0.26). Circulating exoPD-L1 may be a valuable prognostic indicator for patients with cancer and monitoring its changes in the early stages of immunotherapy might be used to predict tumor response and clinical outcome. This conclusion may not apply to superficial tumors.

Pan-cancer exploration of PNO1: A prospective prognostic biomarker with ties to immune infiltration

The partner of NOB1 homolog (PNO1) is an RNA-binding protein that participates in ribosome biogenesis and protein modification. The functions of this molecule are largely unknown in cancers, particularly breast cancer. We employed bioinformatics methods to probe the putative oncogenic functions of PNO1 based on expression profiles and clinical data from the cancer genome atlas (TCGA), genotype-tissue expression project (GTEx), human protein atlas (HPA), cancer cell line encyclopedia (CCLE), UALCAN, drug sensitivity in cancer (GDSC) and UCSC XENA databases. Our analyses revealed that PNO1 was overexpressed in 31 malignancies, which excluded kidney chromophobe (KICH) and acute myeloid leukemia (LAML). Prognostic assessments have demonstrated that high PNO1 expression was significantly correlated with poor overall and disease-specific survival in various cancers. The promoter methylation level of PNO1 is significantly decreased in breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSC), kidney renal papillary cell carcinoma (KIRP), prostate adenocarcinoma (PRAD), thyroid carcinoma (THCA) and uterine corpus endometrial carcinoma (UCEC). Furthermore, inhibition of PNO1 decreased the viability, migration and invasion of breast cancer cells, and these results were confirmed by mouse xenograft models of breast cancer. In addition, we discovered that tumor microenvironment (TME), immune infiltration, and chemotherapy sensitivity were influenced by PNO1 expression. Concordantly, our analyses revealed a significant positive correlation between PNO1 and programmed cell death ligand 1 (PD-L1) expression across breast carcinoma samples. In conclusion, these findings indicate that PNO1 could act as a promising prognostic biomarker and adjunct diagnostic indicator, because it affects tumor growth and invasion. Our study offers valuable new perspectives on the oncogenic role of PNO1 in various types of cancers.

The Impact of Infections in Patients Treated with Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma.

Background: The therapeutic landscape of unresectable hepatocellular carcinoma (uHCC) continues to evolve. Atezolizumab, an anti-programmed cell death ligand 1 (PD-1) immune checkpoint inhibitor (ICI), in combination with bevacizumab, has substantially improved outcomes. This study aims to evaluate the incidence, risk factors, and outcomes in patients who develop infections while receiving atezolizumab and bevacizumab for uHCC. Methods: Patients who received atezolizumab and bevacizumab for uHCC at a single hospital network were included. Types and rates of infections were reported. Covariates compared among infected and non-infected cohorts included age, sex, race, comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status, immunosuppressive use, chronic infections, number of cycles of ICIs given, antibiotic or antiviral therapies at ICI initiation, and line of therapy (first-line, second-line, greater than second-line). Results: Out of 810 evaluable patients, 34 uHCC patients were treated with atezolizumab plus bevacizumab. The mean ± SD age was 66.29 ± 9.39; 28 (82.35%) were males. There were 17 (50%) patients with reported infection, with bacterial infection occurring in 12 (70.59%) patients and COVID-19 in 4 (23.5%). Of the infected patients, eight (47.06%) had one infection, five (29.41%) had two infections, and two (11.76%) had three or more infections. Infected and non-infected patients received a median of 12 (IQR: 5-17) and 4 (IQR: 3-12) ICI cycles (p = 0.18), respectively. Infections did not negatively impact OS or PFS but resulted in treatment delays and discontinuation in 11 (64.71%) and 7 (41.18%) patients, respectively. At the last follow-up, 19 (55.88%) patients died, 9 (52.94%) in the non-infected group vs. 10 (58.82%) in the infected group (p = 1.0). Conclusions: While a broad array of infections occurred in 50% of the patients in this cohort, it did not negatively impact survival outcomes. However, it did impact morbidity, with more all-cause admissions and treatment delays.

CRISPR/Cas-Mediated Knockdown of PD-L1 and KRAS in Lung Cancer Cells.

Cancer cells can escape death and surveillance by the host immune system in various ways. Programmed cell death ligand 1 (PD-L1) is a transmembrane protein that is expressed by most cell types, including cancer cells, and can provide an inhibitory signal to its receptor PD-1, which is expressed on the surface of activated T cells, impairing the immune response. PD-L1/PD-1-mediated immune evasion is observed in several KRAS-mutated cancers. In the current study, we used the CRISPR/Cas9 system to knock down PD-L1 and KRAS in adenocarcinoma lung cells (A549 and H1975). Knockdown of PD-L1 was validated by qPCR and coculture with lymphocytes. The cells were functionally analyzed for cell cycle, migration and apoptosis. In addition, the effects of PD-L1 and KRAS downregulation on chemotherapy sensitivity and expression of inflammatory markers were investigated. Suppression of PD-L1 and KRAS led to a slowdown of the cell cycle in the G0/G1 phase and reduced migration, increased sensitivity to chemotherapy and triggered apoptosis of cancer cells. In addition, the conditioned medium of the modulated cells significantly affected the native cancer cells and reduced their viability and drug resistance. Our study suggests that dual silencing of PD-L1 and KRAS by CRISPR/Cas9 may be a promising therapeutic approach for the treatment of lung cancer.

Gene and Protein Expression of MAGE and Associated Immune Landscape Elements in Non-Small-Cell Lung Carcinoma and Urothelial Carcinomas.

Melanoma-associated antigen-A (MAGE-A) is expressed in multiple cancers with restricted expression in normal tissue. We sought to assess the MAGE-A3/A6 expression profile as well as immune landscape in urothelial (UC) and non-small cell lung carcinoma (NSCLC). We also assessed co-expression of immune-associated markers, including programmed cell death ligand 1 (PD-L1) in tumor and/or immune cells, and assessed the effect of checkpoint inhibitor treatment on these markers in the context of urothelial carcinoma. We used formalin-fixed paraffin-embedded (FFPE) tissue sections from a variety of tumor types were screened by IHC for MAGE-A and PD-L1 expression. Gene expression analyses by RNA sequencing were performed on RNA extracted from serial tissue sections. UC tumor samples from patients treated with checkpoint inhibitors were assessed by IHC and NanoString gene expression analysis for MAGE-A and immune marker expression before and after treatment. Overall, 84 samples (57%) had any detectable MAGE-A expression. Detectable MAGE-A expression was present at similar frequencies in both tumor tissue types, with 41 (50%) NSCLC and 43 (64%) UC. MAGE-A expression was not significantly changed before and after checkpoint inhibitor therapy by both IHC and NanoString mRNA sequencing. Other immune markers were similarly unchanged post immune checkpoint inhibitor therapy. Stable expression of MAGE-A3/A6 pre and post checkpoint inhibitor treatment indicates that archival specimens harvested after checkpoint therapy are applicable to screening potential candidates for MAGE therapies.

Immune Checkpoint Inhibitor–Induced Cardiotoxicity

Immune checkpoint inhibitors (ICIs) improve outcomes in a wide range of cancers; however, serious adverse effects, including cardiovascular adverse effects (CVAEs), can occur. To determine the incidence of CVAEs and analyze data on the management of myocarditis in patients exposed to ICIs. PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception were searched on April 4, 2023. Two separate studies were performed. Key inclusion criteria for study 1 were phases 1 to 4 trials involving adults with malignant neoplasms treated with an ICI and toxicity data; for study 2, publications (case reports and retrospective analyses) on clinical manifestations and treatment of patients with ICI-induced CVAEs. Studies with dose escalation or fewer than 11 patients in each group and all case reports, retrospective analyses, letters, reviews, and editorials were excluded from study 1. Studies not published in English were excluded from study 2. The PRISMA guidelines and Cochrane Handbook for Systematic Reviews were followed. Data were extracted independently by 2 researchers. A meta-analysis of the incidence of CVAEs in clinical trials and a systematic review of the evidence for the management of myocarditis were performed. Data were pooled using a random-effects model. In study 1, the primary outcome was incidence CVAEs in clinical trials with ICIs and ICI combination therapies. Study 2 examined evidence supporting specific management strategies that may decrease the mortality rate of myocarditis. The primary outcomes were planned before data collection began. In study 1, a total of 83 315 unique participants in 589 unique trials were included in the meta-analysis. Incidence of CVAEs induced by anti-programmed cell death 1 and/or programmed cell death ligand 1 was 0.80% (95% CI, 0%-1.66%) in clinical trials, with no differences between the compounds, except for cemiplimab, which was associated with a higher risk of CVAEs. Incidence of CVAEs following ipilimumab treatment was 1.07% (95% CI, 0%-2.58%). The incidence of myocarditis was significantly higher following treatment with dual ICIs. However, CVAE incidence was not higher with dual ICIs, ICI combination with chemotherapy, or tyrosine kinase inhibitors. Evidence from randomized clinical trials on recommended monitoring and treatment strategies for ICI-induced myocarditis was lacking. Study 2 showed that myocarditis-associated mortality occurred in 83 of 220 patients (37.7%). Prospective data from 40 patients with myocarditis indicated that systematic screening for respiratory muscle involvement, coupled with active ventilation, prompt use of abatacept, and the addition of ruxolitinib, may decrease the mortality rate. Immune checkpoint inhibitor-induced CVAEs and/or myocarditis were recorded in 1.07% of patients in clinical trials. The CVAE mortality risk remains high, justifying the need for monitoring and management strategies for which evidence from randomized clinical trials is absent. Early recognition, ICI therapy cessation, prompt initiation of corticosteroid therapy, and escalation of therapy are all crucial elements for achieving optimal outcomes. Prospective clinical trials or at least prospective registration of treatments and outcomes are highly warranted.

Genomic correlates of the response to first-line PD-1 blockade plus chemotherapy in patients with advanced non-small-cell lung cancer.

Programmed death 1 (PD-1) blockade plus chemotherapy has become the new first-line standard of care for patients with advanced non-small-cell lung cancer (NSCLC). Yet not all NSCLC patients benefit from this regimen. This study aimed to investigate the predictors of PD-1 blockade plus chemotherapy in untreated advanced NSCLC. We integrated clinical, genomic, and survival data from 287 patients with untreated advanced NSCLC who were enrolled in one of five registered phase 3 trials and received PD-1 blockade plus chemotherapy or chemotherapy alone. We randomly assigned these patients into a discovery cohort (n=125), a validation cohort (n=82), and a control cohort (n=80). The candidate genes that could predict the response to PD-1 blockade plus chemotherapy were identified using data from the discovery cohort and their predictive values were then evaluated in the three cohorts. Immune deconvolution was conducted using transcriptome data of 1014 NSCLC patients from The Cancer Genome Atlas dataset. A genomic variation signature, in which one or more of the 15 candidate genes were altered, was correlated with significantly inferior response rates and survival outcomes in patients treated with first-line PD-1 blockade plus chemotherapy in both discovery and validation cohorts. Its predictive value held in multivariate analyses when adjusted for baseline parameters, programmed cell death ligand 1 (PD-L1) expression level, and tumor mutation burden. Moreover, applying both the 15-gene panel and PD-L1 expression level produced better performance than either alone in predicting benefit from this treatment combination. Immune landscape analyses revealed that tumors with one or more variation in the 15-gene panel were associated with few immune infiltrates, indicating an immune-desert tumor microenvironment. These findings indicate that a 15-gene panel can serve as a negative prediction biomarker for first-line PD-1 blockade plus chemotherapy in patients with advanced NSCLC.

Bioorthogonal Diels-Alder Click Chemistry-Based Pretargeted PET Imaging Strategy for Monitoring Programmed Death-Ligand 1 Expression.

The development of antibody tracers for positron emission tomography (PET) imaging enables real-time monitoring of tumor expression of programmed cell death ligand 1 (PD-L1) in vivo, aiming to facilitate the selection of immunotherapy responders. However, the slow pharmacokinetics of the antibodies in vivo limits their applications in PET imaging with commonly used radionuclides with short half-lives. In this study, we developed a pretargeted PET imaging strategy based on Diels-Alder (IEDDA) click chemistry to overcome these limitations. Atezolizumab and durvalumab, the most commonly used PD-L1 antibodies in cancer immunotherapy, were selected and compared in the development of the pretargeted PET imaging strategy. Fluorine-18-labeled derivatives of methyl tetrazine ([18F]Tz, [18F]PEG6-Tz, and [18F]PEG12-Tz) were tested in biodistribution and PET imaging of A549-PDL1 xenografts (PD-L1 positive) pretargeted with the trans-cyclooctene (TCO)-functionalized atezolizumab/durvalumab. The biodistribution and imaging results indicated that atezolizumab-TCO/[18F]PEG12-Tz was more suitable for pretargeted PET imaging strategy, and the optimal interval time was 48 h after atezolizumab-TCO administration, where the atezolizumab-TCO/[18F]PEG12-Tz pretargeted approach clearly delineated the A549-PDL1 tumor with a tumor-to-muscle ratio of 5.33, while the ratios are 3.39 and 2.39 for durvalumab/[18F]PEG12-Tz and mock-pretargeting controls, respectively. In conclusion, a pretargeted 18F-immuno-PET imaging technology was successfully established on atezolizumab. The high-contrast PET images of the A549-PDL1 tumor models demonstrate that the pretargeting strategy incorporating short-lived fluorine-18 is viable in identifying tumors with high PD-L1 expression, marking this strategy as a potential candidate for further clinical translation.

Update on the Mechanism of Action of Intravesical BCG Therapy to Treat Non-Muscle-Invasive Bladder Cancer.

While more than four decades have elapsed since intravesical Bacillus Calmette-Guérin (BCG) was first used to manage non-muscle invasive bladder cancer (NMIBC), its precise mechanism of anti-tumor action remains incompletely understood. Besides the classic theory that BCG induces local (within the bladder) innate and adaptive immunity through interaction with multiple immune cells, three new concepts have emerged in the past few years that help explain the variable response to BCG therapy between patients. First, BCG has been found to directly interact and become internalized within cancer cells, inducing them to act as antigen-presenting cells (APCs) for T-cells while releasing multiple cytokines. Second, BCG has a direct cytotoxic effect on cancer cells by inducing apoptosis through caspase-dependent pathways, causing cell cycle arrest, releasing proteases from mitochondria, and inducing reactive oxygen species-mediated cell injury. Third, BCG can increase the expression of programmed death ligand 1 (PD-L1) on both cancer and infiltrating inflammatory cells to impair the cell-mediated immune response. Current data has shown that high-grade recurrence after BCG therapy is related to CD8+ T-cell anergy or 'exhaustion'. High-field cancerization and subsequently higher neoantigen presentation to T-cells are also associated with this anergy. This may explain why BCG therapy stops working after a certain time in many patients. This review summarizes the detailed immunologic reactions associated with BCG therapy and the role of immune cell subsets in this process. Moreover, this improved mechanistic understanding suggests new strategies for enhancing the anti-tumor efficacy of BCG for future clinical benefit.

Combination Therapy of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel for Metastatic Non-squamous Non-small Cell Lung Cancer With Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor Resistance and EGFR Mutations.

Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) combination therapyhas a potential efficacy in a specific subset of non-squamous non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations following tyrosine kinase inhibitor (TKI) treatment. However, there is a dearth of investigations on the effectiveness of ABCP therapy as the primary outcome of EGFR-TKI use. A single-center retrospective analysis was performed on 24 cases of stage IV EGFR-positive non-squamous NSCLC patients who received one or more lines of EGFR-TKItherapy and subsequently initiated ABCP therapy within the timeframe of April 1, 2019, to April 30, 2023. This study assessed overall survival and progression-free survival associated with ABCP therapy, further analyzing the overall survival data based on EGFR subgroups. The mean age of the cohort was 65 ± 9 years with 14 females (58%). The performance status (PS) was recorded as 0 in 13 out of 24 patients (54%) and 1 in 11 out of 24 patients (46%). Thirteen (54%) patients had a history of smoking. Adenocarcinoma histology was prevalent in all cases. The EGFR mutations included Ex19del in 14 patients (58%) and L858R in 10 (42%) patients. At ABCP therapy initiation, liver metastases were evident in three cases (13%) and brain metastases in eight (33%). Programmed death ligand 1 (22C3) expression levels varied, with <1%, 1-49%, and ≥50% observed in five, 11, and five cases, respectively, while data were missing for three cases. The median follow-up duration was 14.1 months, with median overall survival estimated at 23.6 months (95% CI: 14.5 months - not reached) and median progression-free survival at 5.6 months (95% CI: 4.9-11.5 months). The EGFR L858R mutation showed a favorable trend in overall survival compared with the EGFR Ex19del mutation (not evaluated vs. 23.6 months). ABCP therapy for EGFR-positive non-squamous NSCLC is a promising option, similar to immune checkpoint inhibitor-free platinum-based combination therapy. Therefore, prospective trials are necessary to confirm the efficacy of these treatments.

Results of a phase I/IIa trial of SV-BR-1-GM inoculation with low-dose cyclophosphamide and interferon alpha (Bria-IMT) in metastatic breast cancer

ABSTRACT This Phase I/IIa open-label, single-arm clinical trial addressing advanced, refractory, metastatic breast cancer was conducted at six medical centers in the United States. We repeated inoculations with irradiated SV-BR-1-GM, a breast cancer cell line with antigen-presenting activity engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), with pre-dose low-dose cyclophosphamide and post-dose local interferon alpha. Twenty-six patients were enrolled; 23 (88.5%) were inoculated, receiving a total of 79 inoculations. There were six Grade 4 and one Grade 5 adverse events noted (judged unrelated to SV-BR-1-GM). Disease control (stable disease [SD]) occurred in 8 of 16 evaluable patients; 4 showed objective regression of metastases, including 1 patient with near-complete regressions in 20 of 20 pulmonary lesions. All patients with regressions had human leukocyte antigen (HLA) matches with SV-BR-1-GM; non-responders were equally divided between matching and nonmatching (p = .01, Chi-squared), and having ≥2 HLA matches with SV-BR-1-GM (n = 6) correlated with clinical benefit. Delayed-type hypersensitivity (DTH) testing to candida antigen and SV-BR-1-GM generated positive responses (≥5 mm) in 11 (42.3%) and 13 (50%) patients, respectively. Quantifying peripheral circulating tumor cells (CTCs) and cancer-associated macrophage-like cells (CAMLs) showed that a drop in CAMLs was significantly correlated with an improvement in progression-free survival (PFS; 4.1 months vs. 1.8 months, p = .0058). Eight of 10 patients significantly upregulated programmed cell death ligand 1 (PD-L1) on CTCs/CAMLs with treatment (p = .0012). These observations support the safety of the Bria-IMT regimen, demonstrate clinical regressions, imply a role for HLA matching, and identify a possible value for monitoring CAMLs in peripheral blood.

Molecular Diagnostic Yield and Safety Profile of Ultrasound-Guided Lung Biopsies: A Cross-Sectional Study.

The recent advances in precision oncology for lung cancer treatment has focused attention on the importance of obtaining appropriate specimens for tissue diagnosis as well as comprehensive molecular profiling. CT scan-guided biopsies and bronchoscopy are currently the main procedures employed for tissue sampling. However, growing evidence suggests that ultrasound-guided biopsies may represent an effective as well as safe approach in this diagnostic area. This study explores the safety and the diagnostic yield for cancer molecular profiling in ultrasound-guided percutaneous lung lesion biopsies (US-PLLB). One hundred consecutive patients with suspected lung cancer, between January 2021 and May 2024, who had ultrasound-guided lung biopsies have been retrospectively analyzed. Molecular profiling was conducted with next-generation sequencing Genexus using Oncomine precision assay or polymerase chain reaction according to specimen quality. Qualitative immunohistochemical assay of programmed death ligand 1 (PD-L1) expression was evaluated by the Dako PD-L1 immunohistochemistry 22C3 pharmDx assay. The co-primary endpoints were the molecular diagnostic yield and the safety profile of US-guided lung biopsies. From January 2021 to May 2024, 100 US-guided lung biopsies were carried out and 95 were considered for inclusion in the study. US-PLLB provided informative tissue for a histological evaluation in 93 of 95 patients with an overall diagnostic accuracy of 96.84% [Sensitivity: 92.63%; Specificity: 96.84%; PPV: 100%; NPV: 100%]. Sixty-Six patients were diagnosed with NSCLC (69.47%) and were considered for molecular diagnostic yield evaluation and PD-L1 testing. Four patients had malignant lymphoid lesions. US-PLLB was not adequate to achieve a final diagnosis in three patients (3.16%). Complete molecular profiling and PD-L1 evaluation were achieved in all patients with adenocarcinoma (molecular diagnostic yield: 100%). PD-L1 evaluation was achieved in 28 of 29 patients (96.55%) with either SCC or NOS lung cancer. The overall complication rate was 9.47% (n = 9). Six patients (6.31%) developed pneumothorax, while three patients (3.16%) suffered mild haemoptysis without desaturation. According to our findings, US-guided lung biopsy is a safe, minimally invasive procedure in patients with suspected lung malignancies, providing an excellent diagnostic yield for both comprehensive molecular profiling and PD-L1 testing. In addition, our results suggest that US-guided biopsy may also be an effective diagnostic approach in patients with suspected lung lymphoma.

Astrocytes and the tumor microenvironment inflammatory state dictate the killing of glioblastoma cells by Smac mimetic compounds

Smac mimetic compounds (SMCs) are small molecule drugs that sensitize cancer cells to TNF-α-induced cell death and have multiple immunostimulatory effects through alterations in NF-κB signaling. The combination of SMCs with immunotherapies has been reported to result in durable cures of up to 40% in syngeneic, orthotopic murine glioblastoma (GBM) models. Herein, we find that SMC resistance is not due to a cell-intrinsic mechanism of resistance. We thus evaluated the contribution of GBM and brain stromal components to identify parameters leading to SMC efficacy and resistance. The common physiological features of GBM tumors, such as hypoxia, hyaluronic acid, and glucose deprivation were found not to play a significant role in SMC efficacy. SMCs induced the death of microglia and macrophages, which are the major immune infiltrates in the tumor microenvironment. This death of microglia and macrophages then enhances the ability of SMCs to induce GBM cell death. Conversely, astrocytes promoted GBM cell growth and abrogated the ability of SMCs to induce death of GBM cells. The astrocyte-mediated resistance can be overcome in the presence of exogenous TNF-α. Overall, our results highlight that SMCs can induce death of microglia and macrophages, which then provides a source of death ligands for GBM cells, and that the targeting of astrocytes is a potential mechanism for overcoming SMC resistance for the treatment of GBM.

Efficacy of chemotherapy containing bevacizumab in patients with metastatic colorectal cancer according to programmed cell death ligand 1.

Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, inhibits angiogenesis and reduces tumor growth. Serum VEGF-C, lactate dehydrogenase, and inflammatory markers have been reported as predictive markers related to bevacizumab treatment. Programmed cell death ligand 1 (PD-L1) could act upon VEGF receptor 2 to induce cancer cell angiogenesis and metastasis. To investigate the efficacy of bevacizumab-containing chemotherapy in patients with metastatic colorectal cancer (CRC) according to the expression of PD-L1. This analysis included CRC patients who received bevacizumab plus FOLFOX or FOLFIRI as first-line therapy between June 24, 2014 and February 28, 2022, at Samsung Medical Center (Seoul, South Korea). Analysis of patient data included evaluation of PD-L1 expression by the combined positive score (CPS). We analyzed the efficacy of bevacizumab according to PD-L1 expression status in patients with CRC. A total of 124 patients was included in this analysis. Almost all patients were treated with bevacizumab plus FOLFIRI or FOLFOX as the first-line chemotherapy. While 77% of patients received FOLFOX, 23% received FOLFIRI as backbone first-line chemotherapy. The numbers of patients with a PD-L1 CPS of 1 or more, 5 or more, or 10 or more were 105 (85%), 64 (52%), and 32 (26%), respectively. The results showed no significant difference in progression-free survival (PFS) and overall survival (OS) with bevacizumab treatment between patients with PD-L1 CPS less than 1 and those with PD-L1 CPS of 1 or more (PD-L1 < 1% vs PD-L1 ≥ 1%; PFS: P = 0.93, OS: P = 0.33), between patients with PD-L1 CPS less than 5 and of 5 or more (PD-L1 < 5% vs PD-L1 ≥ 5%; PFS: P = 0.409, OS: P = 0.746), and between patients with PD-L1 CPS less than 10 and of 10 or more (PD-L1 < 10% vs PD-L1 ≥ 10%; PFS: P = 0.529, OS: P = 0.568). Chemotherapy containing bevacizumab can be considered as first-line therapy in metastatic CRC irrespective of PD-L1 expression.

Immunomodulatory R848-Loaded Anti-PD-L1-Conjugated Reduced Graphene Oxide Quantum Dots for Photothermal Immunotherapy of Glioblastoma.

Glioblastoma multiforme (GBM) is the most severe form of brain cancer and presents unique challenges to developing novel treatments due to its immunosuppressive milieu where receptors like programmed death ligand 1 (PD-L1) are frequently elevated to prevent an effective anti-tumor immune response. To potentially shift the GBM environment from being immunosuppressive to immune-enhancing, we engineered a novel nanovehicle from reduced graphene oxide quantum dot (rGOQD), which are loaded with the immunomodulatory drug resiquimod (R848) and conjugated with an anti-PD-L1 antibody (aPD-L1). The immunomodulatory rGOQD/R8/aPDL1 nanoparticles can actively target the PD-L1 on the surface of ALTS1C1 murine glioblastoma cells and release R848 to enhance the T-cell-driven anti-tumor response. From in vitro experiments, the PD-L1-mediated intracellular uptake and the rGOQD-induced photothermal response after irradiation with near-infrared laser light led to the death of cancer cells and the release of damage-associated molecular patterns (DAMPs). The combinational effect of R848 and released DAMPs synergistically produces antigens to activate dendritic cells, which can prime T lymphocytes to infiltrate the tumor in vivo. As a result, T cells effectively target and attack the PD-L1-suppressed glioma cells and foster a robust photothermal therapy elicited anti-tumor immune response from a syngeneic mouse model of GBM with subcutaneously implanted ALTS1C1 cells.

Pembrolizumab plus cetuximab with neoadjuvant chemotherapy for head and neck squamous cell carcinoma.

Head and neck cancer cells commonly express programmed death ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR), both of which play pivotal roles in the antitumor cellular immune response. Pembrolizumab, a PD-1 inhibitor, and cetuximab, an EGFR inhibitor, are typically effective agents combined with neoadjuvant platinum-based chemotherapy for the treatment of head and neck squamous cell carcinoma (HNSCC). This study aims to evaluate the efficacy and safety of neoadjuvant immunochemotherapy in patients with HNSCC. Patients with HNSCC underwent radical surgery and complete cervical lymph node dissection following neoadjuvant immunochemotherapy at RenJi Hospital from January 2021 to June 2024 were retrospectively analyzed. The primary endpoint was major pathological response (MPR). We further explored the relationship between the efficacy and immune estimators. Twenty-one patients were enrolled in this retrospective study. The MPR was 66.7%, including 11 patients who achieved a pathological complete response (pCR). The overall response rate (ORR) was 90.5%, and the complete response (CR) rate was 28.6%. The oropharynx, as the primary site, was the sensitive tumor type to neoadjuvant immunochemotherapy. The most common adverse event (AEs) was anemia (61.9%). No grade 4 AE or delayed surgery was reported. Laryngeal preservation rates were 90.9% (10/11), and pathological findings confirmed negative surgical margins for all patients. Moreover, pre-treatment peripheral lymphocyte count, monocyte count, and platelet to lymphocyte ratio (PLR) displayed a significant correlation with the treatment response. Pembrolizumab plus cetuximab with chemotherapy for patients with HNSCC is a feasible and safe clinical protocol fulfilling organ preservation and life quality improvement. Pre-treatment peripheral immune estimators could help to screen patients who may respond to the neoadjuvant immunochemotherapy.

Comprehensive Potential of Artificial Intelligence for Predicting PD-L1 Expression and EGFR Mutations in Lung Cancer: A Systematic Review and Meta-Analysis.

To evaluate the methodological quality and the predictive performance of artificial intelligence (AI) for predicting programmed death ligand 1 (PD-L1) expression and epidermal growth factor receptors (EGFR) mutations in lung cancer (LC) based on systematic review and meta-analysis. AI studies based on PET/CT, CT, PET, and immunohistochemistry (IHC)-whole-slide image (WSI) were included to predict PD-L1 expression or EGFR mutations in LC. The modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was used to evaluate the methodological quality. A comprehensive meta-analysis was conducted to analyze the overall area under the curve (AUC). The Cochrane diagnostic test and I2 statistics were used to assess the heterogeneity of the meta-analysis. A total of 45 AI studies were included, of which 10 were used to predict PD-L1 expression and 35 were used to predict EGFR mutations. Based on the analysis using the QUADAS-2 tool, 37 studies achieved a high-quality score of 7. In the meta-analysis of PD-L1 expression levels, the overall AUCs for PET/CT, CT, and IHC-WSI were 0.80 (95% confidence interval [CI], 0.77-0.84), 0.74 (95% CI, 0.69-0.77), and 0.95 (95% CI, 0.93-0.97), respectively. For EGFR mutation status, the overall AUCs for PET/CT, CT, and PET were 0.85 (95% CI, 0.81-0.88), 0.83 (95% CI, 0.80-0.86), and 0.75 (95% CI, 0.71-0.79), respectively. The Cochrane Diagnostic Test revealed an I2 value exceeding 50%, indicating substantial heterogeneity in the PD-L1 and EGFR meta-analyses. When AI was combined with clinicopathological features, the enhancement in predicting PD-L1 expression was not substantial, whereas the prediction of EGFR mutations showed improvement compared to the CT and PET models, albeit not significantly so compared to the PET/CT models. The overall performance of AI in predicting PD-L1 expression and EGFR mutations in LC has promising clinical implications.

Exploratory study of PD-1 inhibitors for recurrent meningioma.

26 Background: Meningiomas are the most common primary intracranial tumor. Some patients still have poorly controlled conditions after multiple surgeries and radiotherapies. More effective treatment methods are urgently needed. Previous studies have suggested that meningioma may shape an inhibitory tumor immune microenvironment and achieve immune escape by expressing programmed cell death ligand 1 (PD-L1) and other factors. Immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors have shown promising efficacy in cases, but large-sample studies are needed to confirm these findings. Methods: Recurrent meningioma patients were included and treated with PD-1 inhibitors until tumor progression or intolerance occurred. The efficacy evaluation of enrolled patients used the Response Assessment in Neuro-Oncology (RANO) criteria. The primary endpoint was progression-free survival at 6 months (PFS-6), and secondary endpoints were progression-free survival at 12 months (PFS-12) and overall survival (OS). Adverse events were also recorded. Regular imaging follow-ups were conducted, and clinical characteristics were collected for survival analysis. Peripheral blood lymphocyte subsets and cytokines were detected before and after treatment, and tumor paraffin sections were used for immunohistochemical detection of relevant molecular markers. Results: A total of 35 recurrent meningioma patients (10 grade I, 14 grade II, 11 grade III) were included. Among all grades of patients, the median PFS was 9 months, PFS-6 was 63.6%, and PFS-12 was 47.6%. In grade I patients, the median PFS was 14 months, PFS-6 was 83%, and PFS-12 was 67%. In grade II/III patients, the median PFS was 9 months, PFS-6 was 58.9%, and PFS-12 was 42%. Among all grades of meningioma patients, PFS was significantly correlated with Ki-67 index (P = 0.021) and tumor progression times (P = 0.019). In grade II/III meningioma patients, PFS was only correlated with tumor progression times (P = 0.012). Twenty-five patients had stable disease, and seven patients had disease progression, with no patient achieving partial or complete remission. There was no significant correlation between tumor mutation burden (TMB) and PFS. Further immunohistochemical analysis of tumor tissues in three recurrent high-grade patients revealed varying degrees of increase in local CD3+, CD4+, CD8+ and PD-1+ T lymphocytes after treatment compared to baseline. Conclusions: Our study suggests that PD-1 inhibitors may prolong PFS in recurrent meningioma patients (especially high-grade) with good drug safety, warranting further exploration. Recurrent meningiomas have an immunosuppressive tumor microenvironment, and PD-1 inhibitors may improve the immune status of tumor microenvironments. Clinical trial information: NCT04728568 .