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Heterogeneity in immune checkpoint blockade (ICB) resistance mechanisms limits efficacy in lung cancer patients. Emerging studies reveal genomic and non-genomic tumor-centric alterations can drive resistance. Tumor cell extrinsic factors (host and microenvironmental influences) also impact ICB response. Technological and conceptual advances in dissecting resistance are revealing novel therapeutic opportunities. Several key factors, such as development of compounded biomarker signatures, will require our focus over the coming years to fully realize ICB clinical efficacy. Immune checkpoint blockade (ICB) therapy works by inhibiting suppressive checkpoints that become upregulated after T cell activation, like PD-1/PD-L1 and CTLA-4. While the initial FDA approvals of ICB have revolutionized cancer therapies and fueled a burgeoning immuno-oncology field, more recent clinical development of new agents has been slow. Here, focusing on lung cancer, we review the latest research uncovering tumor cell intrinsic and extrinsic ICB resistance mechanisms as major hurdles to treatment efficacy and clinical progress. These include genomic and non-genomic tumor cell alterations, along with host and microenvironmental factors like the microbiome, metabolite accumulation, and hypoxia. Together, these factors can cooperate to promote immunosuppression and ICB resistance. Opportunities to prevent resistance are constantly evolving in this rapidly expanding field, with the goal of moving toward personalized immunotherapeutic regimens. [ABSTRACT FROM AUTHOR]

Negative immunoregulatory signal (PD-L1, CXCR4, et al.) and weak immunogenicity elicited immune system failing to detect and destroy cancerous cells. CXCR4 blockade promoted T cell tumor infiltration and increased tumor sensitivity to anti-PD-L1 therapy. Here, pH-responsive reassembled nanomaterials were constructed with anti-PD-L1 peptide and CXCR4 antagonists grafting (APAB), synergized with photothermal therapy for melanoma and breast tumor interference. The self-assembled APAB nanoparticles accumulated in the tumor and rapidly transformed into nanofibers in response to the acidic tumor microenvironment, leading to the exposure of grafted therapeutic agents. APAB enabling to reassemble around tumor cells and remained stable for over 96 h due to the aggregation induced retention (AIR) effect, led to long-term efficiently combined PD-L1 and CXCR4 blockade. Photothermal efficiency (ICG) induced immunogenic cell death (ICD) of tumor cells so as to effectively improve the immunogenicity. The combined therapy (ICG@APAB) could effectively inhibit the growth of primary tumor (∼83.52%) and distant tumor (∼76.24%) in melanoma-bearing mice, and significantly (p < 0.05) prolong the survival time over 42 days. The inhibition assay on tumor metastasis in 4 T1 model mice exhibited ICG@APAB almostly suppressed the occurrence of lung metastases and the expression levels of CD31, MMP-9 and VEGF in tumor decreased by 82.26%, 90.45% and 41.54%, respectively. The in vivo reassembly strategy will offer novel perspectives benefical future immunotherapies and push development of combined therapeutics into clinical settings. [Display omitted] [ABSTRACT FROM AUTHOR]

The Scottish Medical Consortium recently approved first-line pembrolizumab monotherapy or in combination with chemotherapy for head and neck squamous cell carcinoma in the palliative setting, contrasting with the decision made by the National Institute for Health and Care Excellence, who approved monotherapy alone in England and Wales. The aim of this study was to provide real-world performance data for first-line pembrolizumab-containing treatments for head and neck squamous cell carcinoma in the palliative setting in Scotland. We analysed the electronic records of patients who started pembrolizumab-containing treatment between 1 March 2020 and 30 September 2021. Outcomes included overall survival, progression-free survival (PFS), the duration of response and the disease control rate. Data were compared with the KEYNOTE-048 study and clinical factors were evaluated for association with survival. Our cohort included 91 patients (median follow-up 10.8 months). Patient characteristics were similar to those in the KEYNOTE-048 study, although our cohort had a higher proportion of patients with newly diagnosed, non-metastatic disease. For patients receiving monotherapy (n = 76), 12- and 24-month overall survival were 45% and 27%, respectively. For patients receiving pembrolizumab–chemotherapy (n = 15), 12-month overall survival was 60% (24-month overall survival had not yet been reached). Experiencing one or more immune-related adverse event (irAE; versus no irAEs), of any grade, was associated with favourable overall survival and PFS for patients receiving monotherapy in both univariable Log-rank analysis (median overall survival 17.4 months versus 8.6 months, respectively, P = 0.0033; median PFS 10.9 months versus 3.0 months, respectively, P < 0.0001) and multivariable analysis (Cox proportional hazards regression: overall survival hazard ratio 0.31, P = 0.0009; PFS hazard ratio 0.17, P < 0.0001). Our real-world data support the KEYNOTE-048 study findings and the value of combination treatment options. Additionally, our data show that irAEs of any grade, as reported in routine clinical records, are associated with better outcomes in this patient group, adding to the growing body of evidence showing that irAEs are generally a positive marker of programmed death-ligand 1 (PD-L1) inhibitor response. • Pembrolizumab efficacy and toxicity were similar between our real-world and KEYNOTE-048 data. • Locally advanced, treatment-naïve patients had comparable outcomes to other groups. • irAEs were associated with better outcomes when receiving pembrolizumab. [ABSTRACT FROM AUTHOR]

Cabozantinib is a widely used multikinase-inhibitor for the treatment of metastatic renal cell carcinoma (mRCC). This study analyzed the efficacy of cabozantinib in real world, including heavily pretreated patients. Antitumor activity was observed in various treatment lines; moreover, we observed that an alternative treatment schedule improves PFS when compared to continuous dosing. No new safety signals emerged from our analysis. Background: The multikinase-inhibitor Cabozantinib is a widely used treatment strategy in metastatic renal cell carcinoma (mRCC), either in combination with the programmed cell death protein-1 (PD-1) inhibitor nivolumab or as monotherapy. Cabozantinib is given continuously at a dose of 60 mg once daily when used as a single agent and at 40 mg when combined with nivolumab. Treatment-related adverse events (TRAE's) were shown to occur frequently. Objective: We aimed to assess the safety and efficacy of cabozantinib in patients with mRCC. Patients were treated in various lines. Furthermore, we analyzed the impact of an alternative treatment schedule in patients not able to maintain continuous dosing. Patients: This is a single center retrospective study from the Medical University of Vienna. Outcome Measurements and Statistical Analysis: Overall response rates (ORR), progression free survival (PFS) and overall survival (OS) were evaluated for the entire cohort, by treatment line and by treatment schedule. Results: Between January 2014 until April 2021, 71 patients received cabozantinib. Sixty-seven patients were eligible for full evaluation. By IMDC cr iter ia, 32.4%, 59.2%, and 8.5% were classified as favorable, intermediate and poor risk respectively. Cabozantinib was offered as a 2nd-line or 3rd-line treatment in 38.0% and 32.4% of patients, respectively. An alternative treatment schedule was offered in 39.1% of patients. Objective responses were found in 43.3% (CR 6%) of patients and the median PFS was 10.8 months (95% CI: 5.5-16.2). When compared to continuous dosing, an alternative treatment schedule was associated with longer PFS (12.2 months (95% CI: 0-25.5) vs. 6.1 months (95% CI: 0.37-11.8) (P = .014, HR 0.46 (95% CI: 0.24-0.86), respectively) and a lower frequency and severity of TRAE's. Conclusions: Safety and efficacy of cabozantinib in real world is comparable to what has been observed in the pivotal trials, irrespective of the treatment line. An alternative schedule may further improve efficacy and safety. [ABSTRACT FROM AUTHOR]

Programmed cell death protein 1 (PD-1) axis blockade has become the mainstay in the treatment of recurrent and/or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Programmed death-ligand 1 (PD-L1) is the only approved biomarker for patient selection; however, response rate is limited even among high expressors. Our primary objective was to investigate the association of immune cell-related biomarkers in the tumor and tumor microenvironment with PD-1 checkpoint inhibitors' outcomes in patients with R/M HNSCC. NCT03652142 was a prospective study in nivolumab-treated platinum-refractory R/M HNSCC, aiming to evaluate biomarkers of response to treatment. Tumor biopsies and blood samples were collected from 60 patients at baseline, post-treatment, and at progression. Immune cells in the tumor and stromal compartments were quantified by immunofluorescence using a five-protein panel (CD3, CD8, CD20, FoxP3, cytokeratin). Tertiary lymphoid structures (TLSs), PD-L1 expression, and peripheral blood immune cell composition were also evaluated for associations with outcome. Our findings were validated by gene set enrichment analysis (GSEA) messenger RNA in situ expression data from the same patients, for B-cell- and TLS-associated genes. High pre-treatment density of stromal B cells was associated with prolonged progression-free survival (PFS) (P = 0.011). This result was validated by GSEA, as stromal enrichment with B-cell-associated genes showed association with response to nivolumab. PD-L1 positivity combined with high B-cell counts in stroma defined a subgroup with significantly longer PFS and overall survival (P = 0.013 and P = 0.0028, respectively). Increased B cells in pre-treatment HNSCC biopsy samples correlate with prolonged benefit from PD-1-based immunotherapy and could further enhance the predictive value of PD-L1 expression. • PD-1/PD-L1 axis inhibitors have become the standard of care for R/M HNSCC. • Low response rates dictate the need to identify resistance mechanisms and develop biomarkers for patient selection. • The associations of immune cell density with treatment outcomes were investigated in nivolumab-treated R/M HNSCC cases. • Increased B-cell infiltration led to prolonged PFS and improved PD-L1-based patient selection. • The synchronous assessment of B-cell infiltration and PD-L1 expression could guide therapeutic decisions in R/M HNSCC. [ABSTRACT FROM AUTHOR]

[Display omitted] No direct comparison has been performed between different programmed cell death-1 (PD-1) inhibitors for first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). The feasibility of using PD-L1-expression-guided immunotherapy remains unknown. In this open-label, phase 2 study (NCT04252365), patients with advanced NSCLC without EGFR or ALK alterations were randomized (1:1) to receive sintilimab or pembrolizumab monotherapy (PD-L1 expression ≥ 50%), or sintilimab or pembrolizumab plus platinum-based chemotherapy (PD-L1 expression < 50%). The sample size was calculated by optimal two-stage design. The primary endpoint was the objective response rate (ORR). The study included 71 patients (sintilimab arms, n = 35; pembrolizumab arms, n = 36) and met its primary endpoint, with a confirmed ORR of 51.4% (18/35) in the sintilimab arms. The confirmed ORR (95% confidence interval) was 46.2% (19.2%, 74.9%) and 42.9% (17.7%, 71.1%) for patients treated with sintilimab and pembrolizumab monotherapy; and 54.5% (32.2%, 75.6%) and 45.4% (24.4%, 67.8%) for those treated with sintilimab- and pembrolizumab-based combination therapies. The median progression-free survival was 6.9 versus 8.1 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 7.6 versus 11.0 months in monotherapy and 7.4 versus 7.1 months in combination therapies. The median overall survival was 14.9 versus 21.3 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 14.9 versus 22.6 months in monotherapy and 14.7 versus 17.3 months in combination therapies. Treatment-related adverse events were consistent with safety outcomes of monotherapy and combination therapy in previous phase III studies. However, the incidence of rash was higher with sintilimab than pembrolizumab monotherapy. This is the first prospective phase 2 study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC. Sintilimab was efficacious and well-tolerated irrespective of PD-L1 expression level in patients with advanced NSCLC and had similar efficacy and safety to pembrolizumab. [ABSTRACT FROM AUTHOR]

Evidence recently showed that pleiotropic cytokine interferon-gamma (IFN-γ) in the tumor microenvironment (TME) plays a positive role in hepatocellular carcinoma (HCC) progression through the regulation of liver cancer stem cells (LCSCs) in HCC. The present study explored the role and potential mechanism of mitochondrial programmed cell death-ligand 1 (PD-L1) and its regulation of ferroptosis in modulating the cancer stemness of LCSCs. It was shown that mimicking TME IFN-γ exposure increased the LCSCs ratio and cancer stemness phenotypes in HCC cells. IFN-γ exposure inhibited sorafenib (Sora)-induced ferroptosis by enhancing glutathione peroxidase 4 (GPX4) expression as well reactive oxygen species (ROS) and lipid peroxidation (LPO) generation in LCSCs. Furthermore, IFN-γ exposure upregulated PD-L1 expression and its mitochondrial translocation, inducing dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and correlating with glycolytic metabolism reprogramming in LCSCs. The genetic intervention of PD-L1 promoted ferroptosis-dependent anti-tumor effects of Sora, reduced glycolytic metabolism reprogramming, and inhibited cancer stemness of HCC in vitro and in vivo. Our results revealed a novel mechanism that IFN-γ exposure-induced mitochondrial translocation of PD-L1 enhanced glycolytic reprogramming to mediate the GPX4-dependent ferroptosis resistance and cancer stemness in LCSCs. This study provided new insights into the role of mitochondrial PD-L1-Drp1-GPX4 signal axis in regulating IFN-γ exposure-associated cancer stemness in LCSCs and verified that PD-L1-targeted intervention in combination with Sora might achieve promising synergistic anti-HCC effects. Interventing mitochondrial PD-L1 suppressed IFN-γ-induced cancer stemness in hepatocellular carcinoma by sensitizing sorafenib-induced ferroptosis (Created with BioRender.com). [Display omitted] • IFN-γ promoted ferroptosis resistance of LCSCs to sorafenib via mediating cancer stemness. • IFN-γ exposure upregulated PD-L1 and its mitochondrial translocation to reprogram glycolytic metabolism. • Mitochondrial PD-L1-Drp1 signal axis modulated GPX4-dependent ferroptosis in sorafenib-treated LCSCs. • Targeting intervention of PD-L1 promoted anti-HCC effects via enhancing ferroptosis susceptibility to sorafenib. [ABSTRACT FROM AUTHOR]

The aim of this network meta-analysis was to elucidate the efficacy and safety of various immune checkpoint inhibitors (ICIs) used in combination with chemotherapy for the treatment of non-small cell lung cancer (NSCLC). Data from randomised controlled trials comparing perioperative ICI–chemotherapy and chemotherapy alone were acquired from the EMBASE, Web of Science, Cochrane Library databases, PubMed, and meeting abstracts from inception until August 2023. The endpoints for this analysis were pathological complete response, event-free survival and treatment-related adverse events of any grade or adverse events of grade 3 or higher. In total, six randomised controlled trials with 2538 NSCLC patients were selected for this network meta-analysis. Compared with other ICIs, toripalimab + chemotherapy demonstrated increased pathological complete response rates and prolonged event-free survival in NSCLC. In patients with negative/low PD-L1 expression or squamous cell pathology, toripalimab + chemotherapy was the most effective regimen. In contrast, nivolumab + chemotherapy was preferable for patients with high PD-L1 expression or non-squamous cell pathology. Among the analysed regimens, toripalimab + chemotherapy presented the highest risk of adverse events of any grade, whereas nivolumab + chemotherapy showed the highest risk of grade 3–4 adverse events. Conversely, durvalumab + chemotherapy exhibited the lowest risk of grade 3–4 adverse events. Among the evaluated perioperative immunochemotherapy regimens, toripalimab + chemotherapy indicated a significantly increased survival benefit for most resectable NSCLC patients. However, for high PD-L1 expression and non-squamous NSCLC patients, nivolumab + chemotherapy provided the most potent outcomes. Perioperative durvalumab + chemotherapy is a relatively safe treatment. The findings of this investigation are expected to assist clinicians in making informed decisions among promising treatment options. • Perioperative toripalimab + chemotherapy is the most effective regimen for resectable NSCLC. • For PD-L1 > 50% NSCLC patients, nivolumab + chemotherapy provided the most potent outcomes. • For non-squamous NSCLC patients, nivolumab + chemotherapy was the most effective regimen. • Durvalumab + chemotherapy is a relatively safe treatment option. [ABSTRACT FROM AUTHOR]

We profiled the genomes of over 12,0 0 0 advanced prostate cancer samples and probed a large clinicogenomic database with ~10 0 0 patients to clarify the impact MYCamp in PCa. Results suggest that MYCamp advanced PCa has limited targeted therapies and is an aggressive subset of advanced prostate cancer found disproportionately more common in men with African ancestry. Background: MYC is a commonly amplified, potentially targetable gene in prostate cancer (PCa). We sought to define the molecular, immunologic, and clinicodemographic landscape of MYC amplification (MYCamp) in advanced PCa to establish a rationale for personalized treatment combinations. Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on PCa tumor samples. MYCamp = copy number =6 (CN). Patients treated between January 2011 and December 2020 were selected from a nationwide deidentified (280 clinics) EHR-derived clinicogenomic database (CGDB). Results: Of 12,528 hormone-sensitive and castrate-resistant (CRPC) samples, MYCamp was detected in 10.6% (median CN = 8). MYCamp was more frequent in men with African versus European ancestry (12.9% vs. 10.2% P = .002), in metastatic vs. primary tissue (15.7% vs. 6.2% P < .001), and enriched in metastatic liver lesions (20.2%), but inversely associated with high microsatellite-instability (0.8% vs. 2.4%, P < .001). MYC CN =15 was associated with PD-L1 expression (26.1% vs. 9.8%, P = .025). Amplification of AR, RAD21,LYN, CCND1,ZNF703,FGF3/4/19, and FGFR1 was enriched in MYCamp vs. MYCwt (all P < .001). In liquid samples with tumor fraction [TF] > 0, MYCamp was detected in 2.0% (28/1,402), and 4.5% (20/445) with TF > 20%. In the CGDB, (67 MYCamp and 658 MYCwt), patients received similar treatments; most received hormone therapies (35.8% MYCamp vs. 31.5% MYCwt) or chemotherapy (37.3% MYCamp vs. 27.7% MYCwt) as first therapy after CGP report. Conclusion: MYCamp defines a biologically distinct subset of PCa patients and is characterized with multiple proxies of advanced disease. These data suggest that MYCamp may be prognostic; independent cohorts are needed to validate these findings. [ABSTRACT FROM AUTHOR]

To determine the associations of intravoxel incoherent motion (IVIM) parameters with expression of programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), and evaluate the performance of the combined model established based on IVIM and clinicopathological parameters in predicting PD-L1and PD-1 status of cervical cancer (CC) patients. Seventy-eight consecutive CC patients were enrolled prospectively and underwent magnetic resonance imaging (MRI) including IVIM. IVIM quantitative parameters were measured, compared, and correlated with PD-L1 and PD-1 expression. Independent factors related to PD-L1 and PD-1 positivity were identified and were used to establish the combined model. The combined model's diagnostic performance was evaluated using the receiver operating characteristic (ROC) analysis. The Shapley additive explanation (SHAP) algorithm was used to explain the contribution of each parameter in the combined model. The real diffusion coefficient (D) value was significantly lower in the PD-L1-positive group than in the PD-L1-negative group (0.64 ± 0.12 versus 0.72 ± 0.11, p= 0.021). The PD-1-positive and PD-1-negative groups showed similar trends (0.63 ± 0.13 versus 0.73 ± 0.09, p= 0.003). Parametrial invasion, lymph node status, pathological grade, FIGO (International Federation of Gynecology and Obstetrics) staging, and D values were independently associated with PD-L1 and PD-1expression. A combined model incorporating these parameters showed good discrimination with the sensitivity, specificity of 90.9%, 82.6% for PD-L1, and 93.5%, 72% for PD-1. According to the SHAP value, FIGO staging and pathological grade were the most influential features of the prediction model. IVIM parameters were found to correlate with PD-L1 and PD-1 expression. The combined model, incorporating parametrial invasion, lymph node status, pathological grade, FIGO staging, and D values, showed good discrimination in predicting PD-L1 and PD-1 status, providing the basis for CC immunotherapy. • D value is negatively correlated with PD-L1 and PD-1 expression. • The combined model has the best discrimination providing a basis for immunotherapy. • According to SHAP analysis, FIGO staging and pathological grade are major features. [ABSTRACT FROM AUTHOR]

• PD-1 expression on CD4+ cells increase at pancreatitis and can be used as prognostic factors. • PD-L1 expression on CD14+ cells increase at pancreatitis and can be used as prognostic factors. • Intermediate monocyte ratios increase at pancreatitis and can be used as prognostic factors. • CD14+ HLA-DR+ cells and classical monocyte could also be used to predict organ failure. This study aimed to assess the significance of immunophenotyping and serum cytokines in predicting the clinical progression of acute biliary pancreatitis (ABP). Cytokine levels, T-helper, cytotoxic T, natural killer (NK) cells, monocytes, HLA-DR, and PD-1, as well as PDL-1 immune checkpoints, were measured in ABP patients at the time of diagnosis and compared with results from healthy volunteers. The study also compared leukocyte counts, hematocrit, immunophenotyping results, cytokine statuses, and PD-1, PDL-1 expression between healthy volunteers and ABP subgroups categorized by pancreatitis severity. The study included 65 ABP patients and 20 healthy volunteers. Significant differences were observed between groups in hematocrit, leukocyte counts, total monocytes, lymphocytes, CD3+ total T cells, CD4+ Th cells, PD-1 expression on CD4+ and CD8+ T lymphocytes, HLA-DR expression on CD14+ monocytes, NK cells, PD-L1 expression on CD14+ monocytes, classical and intermediate monocytes, as well as levels of IL-6, IL-8, IL-10, IL-18, and IL-33 cytokines. Moderate correlations were found with lymphocyte counts, PD-1+CD4+ cells, PD-L1+CD14+ cells, and strong correlations with HLA-DR+CD14+ cells. Hematocrit, CD3+ total T cells, NK cells, CD4+PD-1 + T cells, and CD8+PD-1 + T cells showed independent associations with the severity of ABP. Lymphocyte counts, CD14+HLA-DR+ cells, CD14+PD-L1+ cells, CD4+PD-1 + T cells, classical, and intermediate monocytes exhibited the highest Area Under the Curve rates in determining organ failure. Hematocrit, lymphocyte counts, CD14+HLA-DR+ cells, CD14+PD-L1+ cells, and intermediate monocytes emerged as parameters most closely associated with the severity and these parameters could be useful in predicting the severity of ABP. [ABSTRACT FROM AUTHOR]

To compare the clinical efficacy and safety of first-line treatments for advanced unresectable oesophageal squamous cell cancer. A systematic review and network meta-analysis was carried out by retrieving and retaining relevant literature from databases. The studies were randomised controlled trials comparing first-line treatments for advanced unresectable oesophageal squamous cell cancer. A Bayesian network meta-analysis was used to assess clinical outcomes. Nine studies including 4499 patients receiving first-line treatments were analysed. For all populations, toripalimab plus chemotherapy tended to provide the best overall survival (hazard ratio 0.58, 95% confidence intervals 0.43–0.78) and sintilimab plus chemotherapy provided the best progression-free survival (0.56, 0.46–0.68). Nivolumab plus chemotherapy presented the best objective response rate (odds ratio 2.45, 1.78–3.42) and camrelizumab plus chemotherapy (0.47, 0.29–0.74) appeared to be the safest. Sintilimab plus chemotherapy (0.55, 0.40–0.75) and nivolumab (0.54, 0.37–0.80) plus chemotherapy had the best overall survival in programmed death ligand 1 (PD-L1) tumour proportion score <1% and ≥1% subgroups. Toripalimab plus chemotherapy (0.61, 0.40–0.93) and pembrolizumab (0.57, 0.43–0.75) were the best in overall survival in combined positive score <10 and ≥10 subgroups, respectively. Toripalimab plus chemotherapy showed the best overall survival in the Asian group; pembrolizumab presented better overall survival in the Asian population than the non-Asian group. Most immunotherapy combined with chemotherapy showed superior clinical benefits and sintilimab plus chemotherapy, toripalimab plus chemotherapy and tislelizumab plus chemotherapy had better comprehensive clinical efficacy. PD-L1 expression detection and ethnicity differences are still of great significance and most suitable regimens varied from each subgroup. • Current first-line treatments, including immunotherapy, chemotherapy and monoclonal antibody, were compared in this study. • Immunotherapy, such as sintilimab, toripalimab and tislelizumab, combining with chemotherapy has showed their superiority. • Efficacy still differs in PD-L1 expression level and region subgroups. • Epidermal growth factor receptor targeted monoclonal antibody and chemotherapy didn't show their advantages. [ABSTRACT FROM AUTHOR]

Peptide immune checkpoint inhibitors in cancer immunotherapy have attracted great attention recently, but oral delivery of these peptides remains a huge challenge due to the harsh gastrointestinal environment, large molecular size, high hydrophilic, and poor transmembrane permeability. Here, for the first time, a fish oil-based microemulsion was developed for oral delivery of programmed death-1/programmed cell death-ligand 1 (PD-1/PD-L1) blocking model peptide, OPBP-1. The delivery system was characterized, in vitro and in vivo studies were conducted to evaluate its overall implication. As a result, this nutraceutical microemulsion was easily formed without the need of co-surfactants, and it appeared light yellow, transparent, good flowability with a particle size of 152 ± 0.73 nm, with a sustained drug release manner of 56.45 ± 0.36% over 24 h and a great stability within the harsh intestinal environment. It enhanced intestinal drug uptake and transportation over human intestinal epithelial Caco-2 cells, and drastically elevated the oral peptide bioavailability of 4.1-fold higher than that of OPBP-1 solution. Meanwhile, the mechanism of these dietary droplets permeated over the intestinal enterocytic membrane was found via clathrin and caveolae-mediated endocytic pathways. From the in vivo studies, the microemulsion facilitated the infiltration of CD8+ T lymphocytes in tumors, with increased interferon-γ (IFN-γ) secretion. Thus, it manifested a promising immune anti-tumor effect and significantly inhibited the growth of murine colonic carcinoma (CT26). Furthermore, it was found that the fish oil could induce ferroptosis in tumor cells and exhibited synergistic effect with OPBP-1 for cancer immunotherapy. In conclusion, this fish oil-based formulation demonstrated great potential for oral delivery of peptides with its natural property in reactive oxygen species (ROS)-related ferroptosis of tumor cells, which provides a great platform for functional green oral delivery system in cancer immunotherapy. [Display omitted] • The fish oil-based microemulsion was easily formed without the need of any co-surfactant. • The fish oil-based microemulsion significantly enhanced oral absorption of peptide drugs. • This microemulsion permeated through the intestinal epithelial cells via clathrin and caveolae-mediated endocytic pathway. • Fish oil could promote the tumor cell ferroptosis. • Fish oil could synergize with IFN-γ produced by CD8+ T cells to elicit synergistic effects for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The PD-1/PD-L1 checkpoint pathway is important for regulating immune responses and can be targeted by immunomodulatory drugs to treat a variety of immune disorders. However, the precise protein-protein interactions required for the initiation of PD-1/PD-L1 signaling are currently unknown. Previously, we designed a series of first-generation PD-1 targeting peptides based on the native interface region of programmed death ligand 1 (PD-L1) that effectively reduced PD-1/PD-L1 binding. In this work, we further characterized the previously identified lead peptide, MN1.1, to identify key PD-1 binding residues and design an optimized peptide, MN1.4. We show MN1.4 is significantly more stable than MN1.1 in serum and retains the ability to block PD-1/PD-L1 complex formation. We further characterized the immunomodulatory effects of MN1.4 treatment by measuring markers of T cell activation in a co-culture model with ovarian cancer cells and peripheral blood mononuclear cells. We found MN1.4 treatment reduced cytokine secretion and suppressed T cell responses in a similar manner as recombinant PD-L1. Therefore, the PD-L1 interface region used to design MN1.4 appeared sufficient to initiate PD-1 signaling and likely represents the minimum necessary region of PD-L1 required for PD-1 recognition. We propose a peptide agonist for PD-1, such as MN1.4, could have several applications for treating autoimmune disorders caused by PD-1 deficiencies such as type 1 diabetes, inflammatory arthritis, or autoimmune side effects arising from monoclonal antibodybased cancer immunotherapies. [ABSTRACT FROM AUTHOR]

The development of Immune checkpoint blockade(ICB) therapy and BRAF- and MEK-targeted therapies has reshaped the survival outcomes of the patients with advanced melanoma. PD-1/PD-L1 blockade was an approved strategy in melanoma treatment. Here we design a PD-L1 xCD3 nanobody as a novel bispecific T cell engager (BiTE) in treating PD-L1 overexpression melanoma. BiTE PD-L1 × CD3 Nb was predicted to bind near a large acidic surface on CD3-ε similar to UCHT1-scFv antibody based on alpha-fold and molecular docking. BiTE PD-L1 × CD3 Nb and anti-CD3 Nb retained the ability to activate T cells to produce TNF-α and IFN-γ in a dose-dependent manner. The IC 50 value of BiTE PD-L1 × CD3 Nb was 4.208 μ g/mL. BiTE PD-L1 × CD3 Nb showed obvious cytotoxic activity on both A375WT and A375PD-L1 related to PD-L1 expression level. • A bispecific PD-L1xCD3 nanobody was designed as a novel Bispecific T-cells engager(BiTE). • BiTE PD-L1 × CD3 Nb was predicted to bind near a large acidic surface on CD3-ε similar to UCHT1-scFv antibody based on Alpha-fold and molecular docking. • A specific PD-L1 overexpression A375 cell line was constructed as a humanized melanoma model. • BiTE PD-L1 × CD3 Nb could disrupt PD-1/PD-L1 engagement and activate T cells to produce cytokines. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockades have made huge breakthrough among some cancer types including lung cancer. However, only a small proportion of patients will benefit from immune checkpoint blockades; other patients have no or minor response to immunotherapy. The underlying mechanisms and efficient biomarkers to predict immunotherapy resistances remain unclear and lacking. In this study, BATF2 knockout mice, human xenograft mice, were used for in vivo studies. Relevant RNA and protein levels were analyzed by RT– quantitative PCR and Western blotting. As a result, we found that the expression of BATF2 is negatively correlated with expression of programmed death-ligand 1 in the plasma of patients. Mechanically, we showed that BATF2 inhibits programmed death-ligand 1 expression in cancer cells by inhibiting the PI3K–AKT pathway where ZEB2 plays an important role in this process. Based on bioinformatics analysis, we found that the function of BATF2 in promoting antitumor immune response in patients with non–small cell lung cancer, which is mediated by BATF2, enhances CD8+ T-cell infiltration as well as activation. The expression of BATF2 from circulating tumor cells and tissues can be serve as an efficient biomarker to predict diagnosis, prognosis, and immunotherapy efficacy. [ABSTRACT FROM AUTHOR]

• Cryoablation synergized with PD-1 blockade can elicit a robust antitumor immune response. • Anti-PD-L1/cryoablation therapy selectively derived the improvement of depolarized mitochondria in PD-1+CD8+T cells. • Mitochondrial dynamics in CD8+TILs were involved in modulating the local immune response. Immune checkpoint blockade (ICB) has shown improvement in overall survival for lung cancer in clinical trials. However, monotherapies have limited efficacy in improving outcomes and benefit only a subset of patients. Combination therapies targeting multiple pathways can augment an immune response to improve survival further. Here, we demonstrate that combinatorial anti-PD-L1/cryoablation therapy generated a synergistic antitumor activity in the established lung cancer model. Importantly, it was observed that this favorable antitumor immune response comes predominantly from the PD-1+CD8+ T cells generated after the combination therapy, referred as improvement of IFN-γ production and mitochondrial metabolism, which resembled highly functional effectors CD8+ T cells. Notably, the cellular levels of mitochondrial reactive oxygen and mitochondria mass excessively coincided with alteration of IFN-γ secretion in PD-1+CD8+T cell subset. So far, anti-PD-L1/cryoablation therapy selectively derived the improvement of depolarized mitochondria in PD-1+CD8+T cell subset, subsequently rebuild the anti-tumor function of the exhausted CD8+ T cells. Collectively, there is considerable interest in anti-PD-L1 plus cryoablation combination therapy for patients with lung cancer, and defining the underlying mechanisms of the observed synergy. [ABSTRACT FROM AUTHOR]

The incidence of head and neck cancer (HNC) which is the seventh most common cancer worldwide, continues to rise due to tobacco-derived carcinogens, excessive alcohol consumption, and common infection with oncogenic strains of human papillomavirus (HPV) [1,2]. The steady increase in the number of HPV-related oropharyngeal cancers makes the landscape of HNC more heterogeneous. Radiation therapy (RT) remains the mainstay of treatment as a sole modality, in combination with chemotherapy (chemoradiotherapy, CRT) or adjuvant after surgery. However, reliable predictive markers of response to conventional RT or CRT have not been found, despite established knowledge about the predictors of checkpoint inhibitors in metastatic disease. In view of the unsatisfactory results of clinical trials using concurrent RT/CRT with immunotherapy, increasing attention is being paid to the local effects of RT on the tumor microenvironment and systemic immune response. We hypothesized that the baseline expression of programmed death 1 ligand (PD-L1) and intratumoral infiltration with CD8+ lymphocytes (TILsCD8+) score in the non-metastatic oral cavity (OC) and oro-/hypopharynx (PX) cancers may correlate with RT response. It was a retrospective single-center analysis involving OC and PX patients who underwent radical RT (66Gy prescribed to the primary tumor, given in 30 fx/6 weeks) with or without concurrent chemotherapy (Cisplatin 100 mg/m2 i.v. every three weeks or 40 mg/m2 i.v weekly). We performed analysis of TILsCD8+ and PD-L1 expression status in the archival biospecimens of the treatment-naïve primary tumor. Tissue microarrays (TMA) were prepared using the Manual Tissue Arrayer MTA-1 (Beecher Instruments, Inc., USA). The TMA sections were first stained with hematoxylin and eosin to verify the invasive neoplastic content within each core. Next, consecutive sections were stained with IVD-grade antibodies, anti-PD-L1 (SP263) and anti-CD8 (SP57). PD-L1 expression was assessed in tumor cells, as TPS. For statistical analysis, the patients were divided into three groups: consistently negative (all cores with no positive cells), heterogeneous, and consistently PD-L1 high (const-high, all cores with >30% positive cells). Next, for each patient, the mean number of TILsCD8 per 1.76 mm2 of invasive tumor was calculated and recorded semi-quantitatively. Scores of <5, 6–50, 51–199, and ≥200 lymphocytes per core were rated as immunoscores (IMs) of 0, 1, 2, and 3, respectively. For statistical analyses, patients were divided into two groups: TILsCD8-negative (IM = 0) and TILsCD8-positive (IM ≥ 1). [Display omitted] The study group was compromised of 61 patients (OC, n=33; PX, n=28). The cumulative 5-year overall survival (5YOS) rate was 57.58% and 64.29%, respectively. Patients were treated between 2012 and 2018, postoperatively (PORT; n=26) or qualified for definitive CRT (n=35). HPV-positive cancers accounted for 3% of OC and 54% of PX. In the OC and PX groups, more patients were PD-L1 negative, 57% and 67%, respectively (Table 1). The univariate analysis showed no influence of PD-L1 expression values on long-term survival. However, the survival curves of patients with PX and PD-L1 expression ≥1% vs. <1% visibly separate (p=0.18) (Figure 1). Most of the examined patients with OC showed a positive TILsCD8 score, with longer 5YOS compared to patients with score 0, however the difference did not reach statistical significance (OC - 48.3% vs 25%; p=0.65). [Display omitted] In our analysis, no association of PD-L1 expression and TILsCD8+ score, and patient outcome can be found. In univariate analysis we did not find any predictive factors for RT response. The main limitation of our study was very small group sizes. [ABSTRACT FROM AUTHOR]

Background: Although immunotherapy has revolutionized the treatment paradigm of many cancers including HNSCC, only a subset of patients derives meaningful clinical benefit from immune checkpoint inhibitors (ICIs). Currently, PD-L1 protein expression remains the only predictive biomarker for ICI response studied in prospective first line immunotherapy clinical trials in HNSCC. PD-L1 expression level, however, is an imperfect biomarker for ICI response due to several limitations such as the variability in expression level cut-offs defined as positive vs. negative between assays, subjective interobserver variability and clinical sampling bias in acquiring specimens. Research efforts are ongoing to develop other biomarkers that can precisely identify patients who will derive benefits from ICIs. Our objective was to assess the results of comprehensive genomic and immune profiling (CGIP) in patients with HNSCC and describe the immune microenvironment of tumors with different levels of PD-L1 expression. Methods: A retrospective analysis of 409 patients with HNSCC tested by CGIP during standard-of-care was performed to compare the immune microenvironment of tumors with high (N=168), moderate-low (N=183), or negative (N=58) PD-L1 expression. Patient tumors were categorized into PD-L1 expression groups using combined positive score (CPS) thresholds of ≥20 (high), 1 to 19 (moderate-low), and <1 (negative). These CPS scores were selected according to the cut-offs used in the Phase III Keynote-048 study that led to the approval of pembrolizumab in HNSCC. DNA-seq of 523 genes analyzed tumor mutational burden (TMB). RNA expression analysis was performed for 395 immune genes. Gene expression-based signatures for tumor immunogenicity score (TIGS), cellular proliferation (CP) and cancer testis antigen burden (CTAB) were calculated from percentile ranks of normalized gene expression values. Expressions of three emerging biomarkers linked to an immune checkpoint mechanism (LAG3, TIGIT and TIM3) were also determined by RNA-seq. PD-L1 expression was assessed using immunohistochemistry. Wilcoxon rank-sum tests were used to detect significant differences between PD-L1 groups in TMB, gene expression signatures, and gene expressions of TIM-3, TIGIT and LAG-3. Results: Tumors with high PD-L1 demonstrated increased expression of genes associated with tumor immunogenicity compared to moderate-low (median TIGS of 54 vs 41; p<1E-4) and negative (median TIGS of 54 vs 43; p<1E-4) tumors (Fig 1B). PD-L1 high tumors also showed increased expression of other emerging biomarkers involved in immune checkpoint pathways such as LAG-3, TIGIT and TIM-3, compared to moderate-low and negative tumors (Fig 1E-G). We found no significant differences between PD-L1 groups in TMB and the remaining composite gene expression signatures (p>0.05; Fig 1A,C,D). Conclusion: Our findings highlight the complex interplay of diverse immune cells and checkpoint markers in the tumor microenvironment (TME) beyond PD-L1 in HNSCC. Tumors with high PD-L1 expression harbored a greater degree of immune infiltration, demonstrating a higher TIGS score as well as other checkpoint markers of emerging clinical importance such as LAG-3, TIGIT and TIM-3. Interestingly, tumors with PD-L1 moderate-low expression did not exhibit significant differences in TIGS, TIGIT and TIM-3, compared to PD-L1 negative tumors. These results suggest that HNSCC tumors with PD-L1 CPS ≥ 20 have the most robust immunogenic profile. Understanding the different components of TME can aid in implementing innovative therapeutic strategies to enhance the immune responses and potentially overcome resistance to ICIs in HNSCC. [ABSTRACT FROM AUTHOR]

The CD58-CD2 axis regulates T cell-mediated cancer immunity, but little is known about the regulation of CD58. In two recent papers pubished in Cancer Cell , Miao et al. and Ho et al. define a mechanism of CD58 regulation by CMTM6 and show an unexpected yin-yang link between PD-L1 and CD58. The CD58-CD2 axis regulates T cell-mediated cancer immunity, but little is known about the regulation of CD58. In two recent papers published in Cancer Cell , Miao et al. and Ho et al. define a mechanism of CD58 regulation by CMTM6 and show an unexpected yin-yang link between PD-L1 and CD58. [ABSTRACT FROM AUTHOR]

As PD-L1 expression has been proposed as one of the cancer biomarkers for non-small cell lung cancer (NSCLC), the predictive value of tumour proportional score (TPS) in the effect of immunotherapy [programmed death protein-1/ligand 1 (PD-1/L1) inhibitors] for NSCLC is worth exploring further. Here, we aimed to summarise the outcomes of current NSCLC randomised controlled trials (RCTs) and explore the predictive value of TPS in clinical immunotherapy, including immune checkpoint inhibitors (ICIs) with or without chemotherapy. RCTs published by PubMed, Medline, Embase and Scopus before February 2023 comparing immunotherapy (PD-1/L1 with or without other therapy) versus a control group in advanced or metastatic NSCLC were included to assess the prognosis according to the patients' TPS with 1% and 50% as the thresholds. The primary endpoints were overall survival and progression-free survival. In total, 28 RCTs containing 17 266 participants with advanced or metastatic NSCLC were included in this meta-analysis. Statistical results showed that compared with TPS <1%, ≥1% or within 1–49%, patients with TPS ≥50% benefited more significantly from the immunotherapy. A subgroup analysis showed that when TPS was <1%, ≥1% or within 1–49%, ICIs + chemotherapy had better efficacy than ICIs alone; PD-1 (such as pembrolizumab) inhibitors had better efficacy than PD-L1 inhibitors (such as atezolizumab). The efficacy of immunotherapy (PD-1/L1 inhibitors) for advanced or metastatic NSCLC is influenced by TPS. • For patients with advanced NSCLC, the efficacy of immunotherapy is related to TPS. • For patients with TPS>50%, immunotherapy has ideal efficacy. • For patients with high PD-L1 expression, immunotherapy can be recommended first. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade (ICB) is considered as a promising approach for cancer treatment. However, the potency of ICB therapy in yolk sac tumors (YSTs) has not been confirmed, and the comprehensive analysis of tumor immune microenvironment and the expression of PD-1/PD-L1 and CTLA4 were also not thoroughly evaluated. Immunohistochemistry was performed in formalin-fixed, paraffin-embedded tumor specimens from 23 YSTs patients to detect the density and distribution of tumor-infiltrating T cells, tertiary lymphoid structures (TLSs), as well as the expression of PD-1/PD-L1 and CTLA4. Overall, more than half (61 %) of all patients exhibited an immune-desert phenotype based on CD3+ T cells. PD-1 expression was identified in five tumor samples (21.7 %), and PD-L1 expression exhibited a different positive rate in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) (39.1 % and 17.4 %). Noteworthily, the rate of positive CTLA4 expression in both TCs and TILs was markedly higher (69.6 % and 56.5 %) than those of PD-1 and PD-L1 expression. Furthermore, TLSs were observed in 21.74 % of all tissues, and samples with TLSs exhibited significantly higher densities of TILs and higher expression of immune checkpoint molecules, particularly PD-1/PD-L1. In addition, tumors located in testes also exhibited a higher density of TILs and higher expression of immune checkpoint molecules. Generally a high frequency of CTLA4 expression was found, PD-1/PD-L1 expression, the immune-inflamed phenotype, and TLSs were low frequency in YSTs, however, YSTs in testes showed a higher density of TILs and higher expression of immune checkpoint molecules. [ABSTRACT FROM AUTHOR]

To present an integrated 2-[18F]-fluoro-2-deoxy- d- glucose (18F-FDG) positron-emission tomography (PET)/computed tomography (CT) radiomic characterisation of programmed death-ligand 1 (PD-L1) status in non-small-cell lung cancer (NSCLC). In this retrospective study, 18F-FDG PET/CT images and clinical data of 394 eligible patients were divided into training (n= 275) and test sets (n= 119). Next, the corresponding nodule of interest was segmented manually on the axial CT images by radiologists. After which, the spatial position matching method was used to match the image positions of CT and PET, and radiomic features of the CT and PET images were extracted. Radiomic models were built using five different machine-learning classifiers and the performance of the radiomic models were further evaluated. Finally, a radiomic signature was established to predict the PD-L1 status in patients with NSCLC using the features in the best performing radiomic model. The radiomic model based on the PET intranodular region determined using the logistic regression classifier preformed best, yielding an area under the receiver operating characteristics curve (AUC) of 0.813 (95% CI: 0.812, 0.821) on the test set. The clinical features did not improve the test set AUC (0.806, 95% CI: 0.801, 0.810). The final radiomic signature for PD-L1 status was consisted of three PET radiomic features. This study showed that an 18F-FDG PET/CT-based radiomic signature could be used as a non-invasive biomarker to discriminate PD-L1-positive from PD-L1-negative in patients with NSCLC. • Need non-invasive PD-L1 status predictor for NSCLC to guide anti-PD-L1 treatment. • PET metabolic parameters have limitations in measuring PD-L1 status. • This study aims to create a PET/CT radiomic signature to predict PD-L1 status. [ABSTRACT FROM AUTHOR]

To develop a deep-learning model using contrast-enhanced chest computed tomography (CT) images to predict programmed death-ligand 1 (PD-L1) expression in patients with non-small-cell lung cancer (NSCLC). Preoperative enhanced chest CT images and immunohistochemistry results for PD-L1 expression (<1% and ≥1% were defined as negative and positive, respectively) were collected retrospectively from 125 NSCLC patients to train and validate a deep-learning radiomics model (DLRM) for the prediction of PD-L1 expression in tumours. The DLRM was developed by combining the deep-learning signature (DLS) obtained from a convolutional neural network and clinicopathological factors. The indexes of the area under the curve (AUC), integrated discrimination improvement (IDI), and decision curve analysis (DCA) were used to evaluate the efficiency of the DLRM. DLS and tumour stage were identified as independent predictors of PD-L1 expression by the DLRM. The AUCs of the DLRM were 0.804 (95% confidence interval: 0.697–0.911) and 0.804 (95% confidence interval: 0.679–0.929) in the training and validation cohorts, respectively. IDI analysis showed the DLRM had better diagnostic accuracy than DLS (0.0028 [ p< 0.05]) in the validation cohort. Additionally, DCA revealed that the DLRM had more net benefit than the DLS for clinical utility. The proposed DLRM using enhanced chest CT images could function as a non-invasive diagnostic tool to differentiate PD-L1 expression in NSCLC patients. • Immunotherapy brings new hope for lung cancer patients. • The early detection of PD-L1 is very important for making immunotherapy regimen. • The novel noninvasive DLRM model can differentiate PD-L1 expression <1% and ≥1%. [ABSTRACT FROM AUTHOR]

The cuproptosis cell death pathway brings fresh opportunities for tumor therapy. However, efficient and targeted cuproptosis induction in tumors is still a challenge. Unfortunately, the well-known cuproptosis initiator, disulfiram and copper complex (DSF/Cu2+), also increases PD-L1 level in tumors, which may diminish the final therapeutic outcome. In this study, DSF/Cu2+-loading MXene nanosheets are coated with PD-1 overexpressing T cell membrane to generate CuX-P system. CuX-P could recognize and stick to PD-L1 on tumor cells like a patch, which promotes the endocytosis of both CuX-P and PD-L1 by tumor cells. Following internalization and release of DSF/Cu2+ in the cytoplasm, PD-L1 expression is upregulated. However, due to the presence of CuX-P in the tumor microenvironment, the then supplemented PD-L1 on tumor surface again binds CuX-P for internalization. This feedback loop keeps blocking and consuming the PD-L1 on tumor surface and promotes the enrichment of CuX-P in tumors to induce cuproptosis. After CuX-P treatment with laser irradiation, strong anti-tumor immune responses are stimulated in a mouse model with triple-negative breast cancer. Thus, this study develops a tumor-targeted biomimetic system that offers simultaneous cuproptosis killing, photothermal therapy (PTT) and immunotherapy in mice. A 2D nano-patch that could stick to tumor cell membrane to block PD-L1 and induce cuproptosis in tumors, which in turn stimulate anti-tumor immune responses to inhibit tumor recurrence. [Display omitted] [ABSTRACT FROM AUTHOR]

IMpower010 (NCT02486718) demonstrated significantly improved disease-free survival (DFS) with adjuvant atezolizumab versus best supportive care (BSC) following platinum-based chemotherapy in the programmed death-ligand 1 (PD-L1)-positive and all stage II-IIIA non-small-cell lung cancer (NSCLC) populations, at the DFS interim analysis. Results of the first interim analysis of overall survival (OS) are reported here. The design, participants, and primary-endpoint DFS outcomes have been reported for this phase III, open-label, 1 : 1 randomised study of atezolizumab (1200 mg q3w; 16 cycles) versus BSC after adjuvant platinum-based chemotherapy (1-4 cycles) in adults with completely resected stage IB (≥4 cm)-IIIA NSCLC (per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system, 7th edition). Key secondary endpoints included OS in the stage IB-IIIA intent-to-treat (ITT) population and safety in randomised treated patients. The first pre-specified interim analysis of OS was conducted after 251 deaths in the ITT population. Exploratory analyses included OS by baseline PD-L1 expression level (SP263 assay). At a median of 45.3 months' follow-up on 18 April 2022, 127 of 507 patients (25%) in the atezolizumab arm and 124 of 498 (24.9%) in the BSC arm had died. The median OS in the ITT population was not estimable; the stratified hazard ratio (HR) was 0.995 [95% confidence interval (CI) 0.78-1.28]. The stratified OS HRs (95% CI) were 0.95 (0.74-1.24) in the stage II-IIIA (n = 882), 0.71 (0.49-1.03) in the stage II-IIIA PD-L1 tumour cell (TC) ≥1% (n = 476), and 0.43 (95% CI 0.24-0.78) in the stage II-IIIA PD-L1 TC ≥50% (n = 229) populations. Atezolizumab-related adverse event incidences remained unchanged since the previous analysis [grade 3/4 in 53 (10.7%) and grade 5 in 4 (0.8%) of 495 patients, respectively]. Although OS remains immature for the ITT population, these data indicate a positive trend favouring atezolizumab in PD-L1 subgroup analyses, primarily driven by the PD-L1 TC ≥50% stage II-IIIA subgroup. No new safety signals were observed after 13 months' additional follow-up. Together, these findings support the positive benefit–risk profile of adjuvant atezolizumab in this setting. • Atezolizumab significantly improved DFS versus BSC after resection and adjuvant chemo in PD-L1+ stage II-IIIA NSCLC. • Atezolizumab appears to extend OS versus BSC post resection and adjuvant chemo in PD-L1 TC ≥50% stage II-IIIA NSCLC. • Although OS was immature, a positive trend favouring atezolizumab that was greatest in the PD-L1 TC ≥50% stage II-IIIA group. [ABSTRACT FROM AUTHOR]

Cancer treatment has been revolutionized by immune checkpoint inhibitors, which regulate immune cell function by blocking the interactions between immune checkpoint molecules and their ligands. The interaction between programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) is a target for immune checkpoint inhibitors. Nanobodies, which are recombinant variable domains of heavy-chain-only antibodies, can replace existing immune checkpoint inhibitors, such as anti-PD-1 or anti-PD-L1 conventional antibodies. However, the screening process for high-affinity nanobodies is laborious and time-consuming. Here, we identified high-affinity anti-PD-1 nanobodies using peptide barcoding, which enabled reliable and efficient screening by distinguishing each nanobody with a peptide barcode that was genetically appended to each nanobody. We prepared a peptide-barcoded nanobody (PBNb) library with thousands of variants. Three high-affinity PBNbs were identified from the PBNb library by quantifying the peptide barcodes derived from high-affinity PBNbs. Furthermore, these three PBNbs neutralized the interaction between PD-1 and PD-L1. Our results demonstrate the utility of peptide barcoding and the resulting nanobodies can be used as experimental tools and antitumor agents. [Display omitted] [ABSTRACT FROM AUTHOR]

Immunotherapy has fundamentally altered cancer treatment; however, its effectiveness is clinically hampered by insufficient intratumoral T lymphocyte infiltration and failed T lymphocyte priming. Additionally, inducing cancer-specific immune responses while sparing normal cells remains challenging. Herein, we developed a redox-activatable polymeric nanoswitch (c-N@IM/JQ) that remained 'off' status in circulation but rapidly switched 'on' after entering the tumor. Toll-like receptor (TLR) 7/8 agonist (imidazoquinoline, IMQ) and bromodomain and extraterminal inhibitor (JQ1) are locked in c-N@IM/JQ with a redox-cleavable linker (switch off). Upon systemic administration, c-N@IM/JQ with c-RGD peptide modification preferentially accumulated at tumor sites and responded to the high glutathione levels to release native IMQ for fully mobilizing T lymphocyte army, and JQ1 for removing the programmed death ligand (PD-L)-1 protection on tumor cells (switch on). These strengthened T lymphocyte armies are easily accessible to these de-protected tumor cells, revitalizing the immune response against tumors. To enrich the T lymphocyte infiltration, reverse their dysfunction status, and simultaneously induce tumor specific immune responses, a redox-activatable polymeric nanoswitch (c-N@IM/JQ) that remains at off status in circulation but rapidly switches on after entering the tumor is reported. Upon systemic injection, c-N@IM/JQ mobilizes the T lymphocyte army and removes PD-L1 protection on tumor cells, revitalizing the immune response against tumors. [Display omitted] • Immunotherapy is hampered by inadequate T lymphocyte infiltration and priming. • Cancer-specific immune responses remains challenging. • Redox-activatable polymeric nanoswitch (c-N@IM/JQ) is reported. • c-N@IM/JQ remains at off status in circulation but switched on after entering tumor. • IMQ mobilizes T lymphocyte army and JQ1 removes PD-L1 protection on tumor cells. [ABSTRACT FROM AUTHOR]

Cemiplimab provided significant survival benefit to patients with advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50% and no actionable biomarkers at 1-year follow-up. In this exploratory analysis, we provide outcomes after 35 months' follow-up and the effect of adding chemotherapy to cemiplimab at the time of disease progression. EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3 trial. We enrolled patients (aged ≥18 years) with histologically confirmed squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour expression of 50% or more. We randomly assigned (1:1) patients to intravenous cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease progression, or investigator's choice of chemotherapy. Central randomisation scheme generated by an interactive web response system governed the randomisation process that was stratified by histology and geographical region. Primary endpoints were overall survival and progression free survival, as assessed by a blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1. Patients with disease progression on cemiplimab could continue cemiplimab with the addition of up to four cycles of chemotherapy. We assessed response in these patients by BICR against a new baseline, defined as the last scan before chemotherapy initiation. The primary endpoints were assessed in all randomly assigned participants (ie, intention-to-treat population) and in those with a PD-L1 expression of at least 50%. We assessed adverse events in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov , NCT03088540. Between May 29, 2017, and March 4, 2020, we recruited 712 patients (607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%) to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression of at least 50%. At 35 months' follow-up, among those with a verified PD-L1 expression of at least 50% median overall survival in the cemiplimab group was 26·1 months (95% CI 22·1–31·8; 149 [52%] of 284 died) versus 13·3 months (10·5–16·2; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR] 0·57, 95% CI 0·46–0·71; p<0·0001), median progression-free survival was 8·1 months (95% CI 6·2–8·8; 214 events occurred) in the cemiplimab group versus 5·3 months (4·3–6·1; 236 events occurred) in the chemotherapy group (HR 0·51, 95% CI 0·42–0·62; p<0·0001). Continued cemiplimab plus chemotherapy as second-line therapy (n=64) resulted in a median progression-free survival of 6·6 months (6·1–9·3) and overall survival of 15·1 months (11·3–18·7). The most common grade 3–4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia (three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment-related deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to autoimmune myocarditis, cardiac failure, cardio-respiratory arrest, cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis, respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of continued cemiplimab plus chemotherapy, was generally consistent with that previously observed for these treatments, with no new safety signals At 35 months' follow-up, the survival benefit of cemiplimab for patients with advanced non-small-cell lung cancer was at least as pronounced as at 1 year, affirming its use as first-line monotherapy for this population. Adding chemotherapy to cemiplimab at progression might provide a new second-line treatment for patients with advanced non-small-cell lung cancer. Regeneron Pharmaceuticals and Sanofi. [ABSTRACT FROM AUTHOR]

• Antibody response to COVID-19 vaccination is largely impaired during malignancy. • Tumor-induced COVID-19 vaccine bluntness is associated with poor follicular helper T cell and B cell responses. • The tumor-suppressed COVID-19 vaccine effectiveness is restored by PD-1/PD-L1 blockade. • PD-1/PD-L1 blockade preferentially preserves follicular helper T cell response during malignancy. • The PD-1/PD-L1 blockade-recovered COVID-19 vaccine effectiveness is independent of anti-tumor therapeutic outcomes. The COVID-19 vaccinations are crucial in protecting against the global pandemic. However, accumulating studies revealed the severely blunted COVID-19 vaccine effectiveness in cancer patients. The PD-1/PD-L1 immune checkpoint blockade (ICB) therapy leads to durable therapeutic responses in a subset of cancer patients and has been approved to treat a wide spectrum of cancers in the clinic. In this regard, it is pivotal to explore the potential impact of PD-1/PD-L1 ICB therapy on COVID-19 vaccine effectiveness during ongoing malignancy. In this study, using preclinical models, we found that the tumor-suppressed COVID-19 vaccine responses are largely reverted in the setting of PD-1/PD-L1 ICB therapy. We also identified that the PD-1/PD-L1 blockade-directed restoration of COVID-19 vaccine effectiveness is irrelevant to anti-tumor therapeutic outcomes. Mechanistically, the restored COVID-19 vaccine effectiveness is entwined with the PD-1/PD-L1 blockade-driven preponderance of follicular helper T cell and germinal center responses during ongoing malignancy. Thus, our findings indicate that PD-1/PD-L1 blockade will greatly normalize the responses of cancer patients to COVID-19 vaccination, while regardless of its anti-tumor efficacies on these patients. [ABSTRACT FROM AUTHOR]

Melanomas frequently harbour somatic mutations in BRAF (40%) or NRAS (20%). Impact of NRAS mutations on the therapeutic outcome of immune checkpoint inhibitors (ICI) remains controversial. Potential correlation of the NRAS mutational status and programmed cell death ligand-1 (PD-L1) expression in melanoma is unknown. Advanced, non-resectable melanoma patients with known NRAS mutation status treated with first-line ICI between 06/2014 and 05/2020 in the prospective multicenter skin cancer registry ADOREG were included. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to NRAS status were analysed. A multivariate Cox model was used to analyse factors associated with PFS and OS; survival was analysed using the Kaplan–Meier approach. Among 637 BRAF wild-type patients, 310 (49%) had an NRAS mutation with Q61R (41%) and Q61K (32%). NRAS -mutated (NRAS mut) melanomas were significantly more often located on the lower extremities and trunk (p = 0.001); nodular melanoma was the most common subtype (p < 0.0001). No significant differences were found for PFS and OS for anti-PD1 monotherapy (2-year PFS 39%, [95% confidence interval (CI), 33–47] in NRAS mut patients and 41% [95% CI, 35–48] in NRAS -wild type (NRAS wt) patients; 2-year OS was 54% [95% CI, 48–61] in NRAS mut patients and 57% [95% CI, 50–64] in NRAS wt patients) and anti-PD1 plus anti-CTLA4 therapy between both cohorts (2-year PFS was 54% [95% CI, 44–66] in NRAS mut patients and 53% [95% CI, 41–67] in NRAS wt patients; 2-year OS was 58% [95% CI, 49–70] in NRAS mut patients and 62% [95% CI, 51–75] in NRA Swt patients). The ORR to anti-PD1 was 35% for NRAS wt patients and 26% for NRAS mut patients and 34% compared to 32% for combinational therapy. Data on PD-L1 expression was available in 82 patients (13%). PD-L1 expression (> 5%) was not correlated to NRAS mutational status. In multivariate analysis, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance status ≥ 1, and brain metastases were significantly associated with a higher risk of death in all patients. The PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. Similar ORR was seen in NRAS wt and NRAS mut patients. Tumour PD-L1 expression did not correlate with NRAS mutational status. • PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. • Similar response rates to anti-PD1-based ICI were seen for NRAS mut and NRAS wt patients. • There was no correlation between NRAS mutation status and programmed cell death ligand-1 expression. [ABSTRACT FROM AUTHOR]

In the phase II/III RELATIVITY-047 trial, a novel fixed-dose combination (FDC) of nivolumab plus relatlimab (NIVO + RELA; a programmed death-1 and a lymphocyte-activation gene 3 inhibitor, respectively) significantly improved progression-free survival (PFS) versus NIVO in patients with previously untreated unresectable or metastatic melanoma (median follow-up, 13.2 months) with stable health-related quality of life (HRQoL), although grade three or four treatment-related adverse events (TRAEs) were more frequent with the combination. Updated HRQoL results (median follow-up, 19.3 months) are presented. Patients were randomised to receive intravenous NIVO + RELA (480 mg and 160 mg, respectively) or NIVO (480 mg) every 4 weeks. HRQoL was assessed using the Functional Assessment of Cancer Treatment-Melanoma (FACT-M) and EQ-5D-3L questionnaires at baseline, before dosing at each treatment cycle, and at follow-up (posttreatment) visits. Consistent with the initial analysis, HRQoL remained stable with NIVO + RELA on treatment and was similar to that with NIVO. Mean changes from baseline did not exceed clinically meaningful thresholds. HRQoL results were consistent across instruments and scales/subscales. Despite an increased rate of grade three or four TRAEs with NIVO + RELA versus NIVO, the proportion of patients reporting that they were bothered 'quite a bit' or 'very much' by TRAEs was low and comparable between treatments. Results from the RELATIVITY-047 trial show that the PFS benefit with NIVO + RELA FDC over NIVO was obtained with stable patient-reported HRQoL, supporting NIVO + RELA as a first-line treatment option for patients with advanced melanoma. • Nivolumab plus relatlimab (NIVO + RELA) improves PFS versus nivolumab in melanoma, with added toxicity. • In RELATIVITY-047, quality of life (QoL) was stable/similar with both treatments. • Results were consistent across all QoL instruments and subscales. • QoL results suggest that the two treatments had similar overall tolerability. • These results support NIVO + RELA as a first-line option for melanoma. [ABSTRACT FROM AUTHOR]

Metastasis remains the major reason for the high mortality of patients with hepatocellular carcinoma (HCC). This study was designed to investigate the role of E-twenty-six-specific sequence variant 4 (ETV4) in promoting HCC metastasis and to explore a new combination therapy strategy for ETV4-mediated HCC metastasis. PLC/PRF/5, MHCC97H, Hepa1-6, and H22 cells were used to establish orthotopic HCC models. Clodronate liposomes were used to clear macrophages in C57BL/6 mice. Gr-1 monoclonal antibody was used to clear myeloid-derived suppressor cells (MDSCs) in C57BL/6 mice. Flow cytometry and immunofluorescence were used to detect the changes of key immune cells in the tumour microenvironment. ETV4 expression was positively related to higher tumour–node–metastasis (TNM) stage, poor tumour differentiation, microvascular invasion, and poor prognosis in human HCC. Overexpression of ETV4 in HCC cells transactivated PD-L1 and CCL2 expression, which increased tumour-associated macrophage (TAM) and MDSC infiltration and inhibited CD8+ T-cell accumulation. Knockdown of CCL2 by lentivirus or CCR2 inhibitor CCX872 treatment impaired ETV4-induced TAM and MDSC infiltration and HCC metastasis. Furthermore, FGF19/FGFR4 and HGF/c-MET jointly upregulated ETV4 expression through the ERK1/2 pathway. Additionally, ETV4 upregulated FGFR4 expression, and downregulation of FGFR4 decreased ETV4-enhanced HCC metastasis, which created a FGF19–ETV4–FGFR4 positive feedback loop. Finally, anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib prominently inhibited FGF19–ETV4 signalling-induced HCC metastasis. ETV4 is a prognostic biomarker, and anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib may be effective strategies to inhibit HCC metastasis. Here, we reported that ETV4 increased PD-L1 and chemokine CCL2 expression in HCC cells, which resulted in TAM and MDSC accumulation and CD8+ T-cell inhibition to facilitate HCC metastasis. More importantly, we found that anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib markedly inhibited FGF19–ETV4 signalling-mediated HCC metastasis. This preclinical study will provide a theoretical basis for the development of new combination immunotherapy strategies for patients with HCC. [Display omitted] • ETV4 is upregulated and indicates poor prognosis in human HCC. • ETV4 increases TAM and MDSC infiltration and inhibits CD8+ T-cell accumulation, facilitating HCC metastasis. • FGF19/FGFR4 and HGF/c-MET upregulate ETV4 expression in HCC cells. • Anti-PD-L1 combined with BLU-554 or trametinib inhibit FGF19-ETV4 signalling-mediated HCC metastasis. [ABSTRACT FROM AUTHOR]

T cell-based immunotherapy (TCBI) is an emerging approach to combat tumors. However, the outcome of TCBI is still far from satisfaction clinically, owing to stumbling blocks from insufficient immunogenicity, T cell exhaustion and immune evasion from programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway. Herein, an injectable tumor lysates-constructed hydrogel is reported to address these issues. Chemically modified tumor lysates are, for the first time, designed as the gelator to intratumorally construct hydrogel, achieving a robust antigen reservoir to induce strong immunogenicity. Meanwhile, hydrogel-encapsulated nicotinamide riboside and SB415286 enable strong mitophagy in T cells to prevent their exhaustion as well as powerfully genetical suppression of PD-1 expression to regulate immune evasion. Thus, our injectable hydrogel creates a robust immune niche within tumor, enabling to significantly potentiate TCBI. Our strategy pharmacologically regulates body's own T cells in situ, demonstrating potent immunotherapeutic effects and offering a conceptually new approach for TCBI. [Display omitted] • Tumor lysates are designed as the gelator to intratumorally construct hydrogel. • Hydrogel creates a robust immune niche to potentiate T cell-based immunotherapy. • Hydrogel acts as a powerful antigen reservoir to induce strong immunogenicity. • Hydrogel demonstrates strong mitophagy to prevent T cell exhaustion. • Hydrogel enables potent inhibition of PD-1 expression for regulating immune evasion. [ABSTRACT FROM AUTHOR]

The clinical value of soluble forms of programmed cell death–1 (sPD-1), PD ligand 1 (sPD-L1) and cytotoxic T lymphocyte–associated protein–4 (sCTLA-4) for gastric cancer (GC) patients treated with nivolumab monotherapy has remained unknown. Blood samples collected before nivolumab treatment from 439 GC patients enrolled in the DELIVER (Japan Clinical Cancer Research Organisation GC-08) trial were analysed for sPD-1, sPD-L1 and sCTLA-4. Corresponding baseline clinical data were also retrieved. Higher plasma levels of sPD-1 (hazard ratio [HR] = 1.27, p = 0.020), sPD-L1 (HR = 1.86, p < 0.001) and sCTLA-4 (HR = 1.33, p = 0.008) were significantly associated with shorter overall survival (OS), whereas only higher sPD-L1 levels was significantly associated with shorter progression-free survival (HR = 1.30, p = 0.008). The sPD-L1 concentration was significantly associated with the Glasgow prognostic score (GPS) (p < 0.001), but both sPD-L1 (HR = 1.67, p < 0.001) and GPS (HR = 1.39, p = 0.009 for GPS 0 versus 1; HR = 1.95, p < 0.001 for GPS 0 versus 2) were independently associated with OS. Patients with a GPS of 0 and low sPD-L1 thus showed the longest OS (median, 12.0 months) and those with a GPS of 2 and high sPD-L1 showed the shortest OS (median, 3.1 months), yielding a HR of 3.69 (p < 0.001). Baseline sPD-L1 levels have the potential to predict survival for advanced GC patients treated with nivolumab, with the prognostic accuracy of sPD-L1 being improved by its combination with GPS. • A prognostic impact of soluble forms of programmed cell death ligand 1 (sPD-L1) was demonstrated for nivolumab-treated gastric cancer. • Both sPD-L1 and Glasgow prognostic score were independently associated with overall survival. • The prognostic accuracy of sPD-L1 was improved by its combination with Glasgow prognostic score. [ABSTRACT FROM AUTHOR]

Immunotherapy with immune-checkpoint inhibitors (ICIs) targeting programmed cell death 1 or programmed death-ligand 1 has revolutionised the treatment of advanced non-small cell lung cancer (NSCLC) and has been investigated in early NSCLC, alone or in combination with chemotherapy, anti-CTLA-4 antibodies and radiotherapy. Although more mature data are needed before setting a change of paradigm in early stages, reports of pathological response rates and disease-free survival are promising, especially with neoadjuvant multimodality approaches. Nevertheless, major pathological response rates for neoadjuvant anti-PD-(L)1 monotherapy rarely exceed 40%, and biomarkers for characterising patients who may benefit the most from ICIs are lacking. These biomarkers have a distinct value from the metastatic setting, with highly different tumour biologies. Among the most investigated so far in this context, programmed death-ligand 1 expression and, to a lesser extent, tumour mutational burden seem to correlate better with higher pathological response rates and survival. Epidermal growth factor receptor , Serine/Threonine Kinase 11 and Kelch-like ECH-associated protein 1 mutations rise as essential determinations for the treatment selection in early-stage NSCLC. Emerging and promising approaches comprise evaluation of blood-based ratios, microbiota, and baseline intratumoural TCR clonality. Circulating tumour DNA will be of great help in the near future when selecting best candidates for adjuvant ICIs, monitoring the tumour response to the neoadjuvant treatment in order to improve the rates of complete resections in the early stage. • Immune-checkpoint inhibitors (ICIs)are becoming a standard in early non-small cell lung cancer but do not benefit all patients. • Programmed death-ligand 1 expression and tumour mutational burden are the better-documented biomarkers. • Patients with epidermal growth factor receptor , Serine/Threonine Kinase 11 or Kelch-like ECH-associated protein 1 alterations yield poor benefit from ICIs. • Emerging biomarkers include TCR clonality, microbiota and blood-based ratios. • Circulating tumour DNA is a reliable tool to evaluate disease burden following surgery or ICIs. [ABSTRACT FROM AUTHOR]

Ramucirumab plus docetaxel (RD) is a promising treatment for previously treated advanced non-small cell lung cancer (NSCLC). However, its clinical significance after platinum-based chemotherapy plus programmed death-1 (PD-1) blockade remains unclear. What is the clinical significance of RD as a second-line treatment after the failure of chemo-immunotherapy in NSCLC? In this multicentre retrospective study, 288 patients with advanced NSCLC who received RDas second-line therapy after platinum-based chemotherapy plus PD-1 blockade, at 62 Japanese institutions from January 2017 to August 2020, were included. Prognostic analyses were performed using the log-rank test. Prognostic factor analyses were performed using a Cox regression analysis. A total of 288 patients were enrolled: 222 were men (77.1%), 262 were aged <75 years (91.0%), 237 (82.3%) had smoking history and 269 (93.4%) had a performance status (PS) of 0–1. One hundred ninety-nine patients (69.1%) were classified as adenocarcinoma (AC) and 89 (30.9%) as non-AC. The types of PD-1 blockade used in the first-line treatment were anti-PD-1 antibody and anti-programmed death-ligand 1 antibody in 236 (81.9%) and 52 (18.1%) patients, respectively. The objective response rate for RD was 28.8% (95% confidence interval [CI], 23.7–34.4). The disease control rate was 69.8% (95% CI, 64.1–75.0).The median progression free survival and overall survival were 4.1 months (95% CI, 3.5–4.6) and 11.6 months (95% CI, 9.9–13.9), respectively. In a multivariate analysis, non-AC and PS 2–3 were independent prognostic factors for worse progression free survival , while bone metastasis on diagnosis, PS 2–3 and non-AC were identified as independent prognostic factors for poor overall survival. RD is a feasible second-line treatment in patients with advanced NSCLC who had received combined chemo-immunotherapy with PD-1 blockade. UMIN000042333. • The response rate for docetaxel plus ramucirumab (RD) after chemo-immunotherapy was 28.8%. • Progression free survivaland overall survival for RD after chemo-immunotherapy were 4.1 months and 11.6 months, respectively. • The frequency of pneumonitis due to RD after chemo-immunotherapy was 10.8%. • Bone metastasis, poor performance status and non-adenocarcinoma were prognostic factors for poor overall survival. [ABSTRACT FROM AUTHOR]

We analyzed disease-free survival by tumor cell score and combined positive score for PD-L1 expression in CheckMate 274. The results provide insights into the role of adjuvant nivolumab in patients with muscle-invasive urothelial carcinoma who have low PD-L1 expression according to tumor cell score. The CheckMate 274 trial demonstrated improved disease-free survival (DFS) with adjuvant nivolumab versus placebo in patients with muscle-invasive urothelial carcinoma at high risk of recurrence after radical surgery in both the intent-to-treat population and the subset with tumor programmed death ligand 1 (PD-L1) expression ≥1%. To analyze DFS by combined positive score (CPS), which is based on PD-L1 expression in both tumor and immune cells. We randomized a total of 709 patients 1:1 to nivolumab 240 mg or placebo every 2 wk intravenously for ≤1 yr of adjuvant treatment. Nivolumab 240 mg. Primary endpoints were DFS in the intent-to-treat population and patients with tumor PD-L1 expression ≥1% using the tumor cell (TC) score. CPS was determined retrospectively from previously stained slides. Tumor samples with both quantifiable CPS and TC were analyzed. Of 629 patients evaluable for CPS and TC, 557 (89%) had CPS ≥1, 72 (11%) had CPS <1, 249 (40%) had TC ≥1%, and 380 (60%) had TC <1%. Among patients with TC <1%, 81% (n = 309) had CPS ≥1. DFS was improved with nivolumab versus placebo for patients with TC ≥1% (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.35–0.71), those with CPS ≥1 (HR 0.62, 95% CI 0.49–0.78), and patients with both TC <1% and CPS ≥1 (HR 0.73, 95% CI 0.54–0.99). More patients had CPS ≥1 than TC ≥1%, and most patients who had TC <1% had CPS ≥1. In addition, patients with CPS ≥1 experienced improved DFS with nivolumab. These results may, in part, explain the mechanisms underlying a benefit with adjuvant nivolumab even in patients who had both TC <1% and CPS ≥1. We studied survival time without cancer recurrence (disease-free survival; DFS) for patients treated with nivolumab versus placebo after surgery to remove the bladder or components of the urinary tract for bladder cancer in the CheckMate 274 trial. We assessed the impact of levels of the protein PD-L1 expressed either on tumor cells (tumor cell score; TC) or on both tumor cells and immune cells surrounding the tumor (combined positive score; CPS). DFS was impoved with nivolumab versus placebo for patients with TC ≥1%, CPS ≥1, and for patients with both TC <1% and CPS ≥1. This analysis may help physicians understand which patients would benefit most from treatment with nivolumab. [ABSTRACT FROM AUTHOR]

Data on the role of the microbiota in cancer have accumulated in recent years, with particular interest in intratumoral bacteria. Previous results have shown that the composition of intratumoral microbiome is different depending on the type of primary tumour and that bacteria from the primary tumour could migrate to metastatic sites. Seventy-nine patients with breast, lung, or colorectal cancer and available biopsy samples from lymph node, lung, or liver site, treated in the SHIVA01 trial were analysed. We performed bacterial 16S rRNA gene sequencing on these samples to characterise the intratumoral microbiome. We assessed the association between microbiome composition, clinicopathological characteristics, and outcomes. Microbial richness (Chao1 index), evenness (Shannon index) and beta-diversity (Bray Curtis distance) were associated with biopsy site (p = 0.0001, p = 0.03 and p < 0.0001, respectively) but not with primary tumour type (p = 0.52, p = 0.54 and p = 0.82, respectively). Furthermore, microbial richness was inversely associated with tumour-infiltrating lymphocytes (TILs, p = 0.02), and PD-L1 expression on immune cells (p = 0.03), or assessed by Tumor Proportion Score (TPS, p = 0.02) or Combined Positive Score (CPS, p = 0.04). Beta-diversity was also associated with these parameters (p < 0.05). Patients with lower intratumoral microbiome richness had shorter overall survival (p = 0.03) and progression-free survival (p = 0.02) in multivariate analysis. Biopsy site, rather than primary tumour type, was strongly associated with microbiome diversity. Immune histopathological parameters such as PD-L1 expression and TILs were significantly associated with alpha and beta-diversity supporting the cancer-microbiome-immune axis hypothesis. • The composition of microbiota in metastases is tissue-rather than tumor-driven. • PD-L1 and tumor-infiltrating lymphocytes are associated with microbiome diversity. • This ancillary study supports the cancer-microbiome-immune axis hypothesis. [ABSTRACT FROM AUTHOR]

• We report prespecified exploratory analyses of an mNSCLC cohort in China (NEPTUNE). 85 chars. • First-line durvalumab + tremelimumab showed a trend of improved OS vs chemotherapy. 85 chars. • This trend was observed in all patients and those with low tumor PD-L1 expression. 84 chars. • 24-month OS and 12-month PFS rates indicated benefit in the survival curve tails. 83 chars. • Durvalumab + tremelimumab was well tolerated with no new safety signals. 74 chars. The phase 3 NEPTUNE study (NCT02542293) evaluated first-line durvalumab plus tremelimumab (DT) versus chemotherapy for metastatic NSCLC. Prespecified exploratory analyses were conducted in an extended cohort enrolled in China. Patients were randomized (1:1) to DT or standard chemotherapy, stratified by PD-L1 tumor cell (TC) expression (≥25 % vs < 25 %), histology, and smoking history. The primary analysis for this cohort was overall survival (OS) in patients with PD-L1 TC < 1 %. Secondary analyses included OS and progression-free survival (PFS) in the ITT population and PD-L1 subgroups, and safety. No alpha was allocated to these cohort analyses (data cut-off, 21-September-2020). 78 and 82 patients were randomized to DT and chemotherapy, respectively; 26 and 29 had PD-L1 TC < 1 % (median follow-up, 31.2 and 29.7 months [censored patients]). Among patients with PD-L1 TC < 1 %, OS favored DT versus chemotherapy (HR 0.60; 95 % CI, 0.32–1.11), with medians of 15.0 months (95 % CI, 10.5–27.4) and 11.7 months (95 % CI, 8.6–20.5), respectively; 24-month rates were 36.0 % (95 % CI, 18.2–54.2) and 17.9 % (95 % CI, 6.5–33.7). In the ITT population, OS was prolonged with DT versus chemotherapy (HR 0.70; 95 % CI, 0.48–1.02); medians were 20.0 and 14.1 months and 24-month rates were 44.2 % and 30.4 %. PFS was similar in the PD-L1 TC < 1 % (HR 1.13; 95 % CI, 0.59–2.14) and ITT (HR 0.95; 95 % CI, 0.66–1.36) populations; 12-month rates were 15.6 % versus 11.3 % and 23.9 % versus 16.6 %. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 31.2 % with DT and 52.6 % with chemotherapy; 3.9 % versus 10.3 % discontinued due to TRAEs. In exploratory analyses, first-line DT showed a trend towards improved OS versus chemotherapy among Chinese patients in the PD-L1 TC < 1 % population and ITT population, with 24-month OS and 12-month PFS rates indicating benefit in survival curve tails. DT was well tolerated with no new safety signals. [ABSTRACT FROM AUTHOR]

• Programmed death-ligand 1 (PD-L1) is prognostic in alveolar echinococcosis (AE). • PD-L1 is overexpressed in the surgical specimens of patients with AE recurrence. • Patients with AE with PD-L1 liver expression <1% showed a better disease-free survival. Alveolar echinococcosis (AE) recurrence is one of the major stakes in patients undergoing surgery, the main curative treatment. Preliminary data demonstrated an effect of programmed death-ligand1 (PD-L1) inhibitors on AE proliferation in animals. The current study aimed to analyze the prognostic value of PD-L1 expression in tissue samples of patients with AE undergoing surgery. A cross-sectional study of patients operated for AE between 2002 and 2017 was performed. Patients with recurrence were matched 1: 2 with patients without recurrence. The matching criteria were PNM staging (P = hepatic localization of the parasite, N = extra-hepatic involvement of neighboring organs, and M = absence or presence of metastasis), resection status, preoperative albendazole treatment, and lesion size. PD-L1 immunohistochemistry staining was performed in surgical liver specimens. The expression of PD-L1 was assessed in immune cells. Disease-free survival was calculated using the Kaplan-Meier method. Among 68 consecutive patients, eight patients with recurrence were matched to 16 patients without recurrence. PD-L1 was overexpressed in patients with recurrence (recurrence: PD-L1 <1%: one, PD-L1 ≥1%: seven; no recurrence: PD-L1 <1%: nine, PD-L1 ≥1%: seven, P = 0.040). Moreover, patients with lower PD-L1 expression (<1%) showed better median disease-free survival (120 months, 95% confidence interval 104-135 vs 74, 95% confidence interval 44-104, P = 0.050). These findings highlight the proof of concept of PD-L1 in AE, but further data on its prognostic importance and the role of immune checkpoint blockade as a promising therapeutical strategy are needed. [ABSTRACT FROM AUTHOR]

Molecular characteristics of squamous cell anal carcinoma (SCAC) are poorly explored. Immune checkpoint inhibitors showed limited activity in phase I/II trials, but predictive and prognostic biomarkers are lacking. In the phase II randomised trial CARACAS (NCT03944252), avelumab alone (Arm A) or with cetuximab (Arm B) was tested in pre-treated advanced SCAC , with overall response rate being the primary end-point. On pre-treatment tumour tissue samples, we assessed Human papillomavirus status, programmed-death ligand 1 (PD-L1) expression, mismatch repair proteins expression, tumour mutational burden (TMB) and comprehensive genomic profiling by FoundationOne CDx. Tumour-infiltrating lymphocytes were characterised on haematoxylin-eosine-stained samples. Primary objective was to describe response to immunotherapy in the CARACAS trial population according to molecular and histological characteristics. Secondary objectives were to assess progression-free survival (PFS) and overall survival (OS) according to molecular biomarkers. High PD-L1 (>40 with combined positive score) was significantly more frequent in patients with disease control (p = 0.0109). High TMB (>10 mutations per megabase) was related to better OS (hazard ratio (HR) = 0.09; 95%confidence interval (CI) 0.01–0.68; p = 0.019) and PFS (HR = 0.44; 95%CI = 0.15–1.27; p = 0.129). High expression of PD-L1 conferred longer OS (HR = 0.46; 95%CI = 0.19–1.08; p = 0.075) and PFS (HR = 0.42; 95%CI = 0.20–0.92; p = 0.03). Neither OS (HR = 1.30; 95%CI = 0.72–2.36; p = 0.39) or PFS (HR = 1.31; 95%CI = 0.74–2.31; p = 0.357) was affected by high (>1.2) Tumour-infiltrating lymphocytes count. High TMB and PD-L1identified patients were with significantly better OS (HR = 0.33; 95%CI = 0.13–0.81; p = 0.015) and PFS (HR = 0.48; 95%CI = 0.23–1.00; p = 0.015). To our knowledge, TranslaCARACAS is the first study to document prognostic role of TMB and PD-L1 in advanced SCAC patients treated with immune checkpoint inhibitors. • In advanced squamous cell anal carcinoma no standard therapies in lines after the first are established. • CARACAS was the first randomised trial in advanced squamous cell anal carcinoma in advanced lines. • High PD-L1 conferred longer PFS; high tumour mutational burden was related to better overall survival. • This study documented prognostic value of tumour mutational burden and PD-L1 in advanced squamous cell anal carcinoma treated with immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

This study aimed to assess the cost-effectiveness of pembrolizumab monotherapy in the first-line treatment of advanced non–small cell lung cancer (NSCLC) in adults whose tumors expressed programmed death-ligand 1 (PD-L1) with a tumor proportion score (TPS) ≥ 50% in the Irish healthcare setting. Effectiveness inputs were derived from the 5-year analysis of KEYNOTE-024 phase III clinical trial. The intervention was pembrolizumab monotherapy; the comparator was a weighted average of the 5 chemotherapy regimens from the trial. The population included those with previously untreated advanced PD-L1 TPS ≥ 50% NSCLC. A de novo partitioned survival model was developed. Survival modeling was done using Bayesian model averaging on fitted parametric functions. Costs included drug acquisition, treatment initiation, administration and monitoring, adverse events, subsequent treatments, and terminal care. Costs and health state utilities were sourced from the literature and Irish sources. The model had a 20-year time horizon. The perspective taken was the Health Service Executive. A 4% discount rate was applied. Outcomes were expressed as an incremental cost-effectiveness ratio (ICER), measured in terms of incremental costs per quality-adjusted life-year (QALY). Probabilistic sensitivity analysis and 1-way sensitivity analyses were conducted. The model estimated a base case ICER of €54 237 per QALY. The probabilistic sensitivity analysis estimated an average ICER of €54 568 per QALY and a 11% probability of cost-effectiveness at the Irish cost-effectiveness threshold of €45 000 per QALY. At the current list price, first-line pembrolizumab monotherapy is not considered cost-effective for the treatment of advanced PD-L1 TPS ≥ 50% NSCLC in the Irish healthcare setting. [ABSTRACT FROM AUTHOR]

Halo nevus, also called Sutton's nevus, is a nevus cell nevus surrounded by vitiligo thought to be caused by a T-cell mediated immune response to the nevus antigen. The immune microenvironment is mysterious, however, as vitiligo often does not improve even when the nevus cells are removed. To analyze the clinical course and immune microenvironment of patients with halo nevus who had undergone nevus excision. We collected 54 halo nevus patients and performed multivariate analysis and immunohistochemical analysis, including multiplexed immune cell phenotyping and spatial single-cell analyses using the PhenoCycler® assay. Multivariate analysis revealed that only the presence or absence of vitiligo vulgaris at the time of consultation was associated with improvement in the surrounding vitiligo following excision. Expression of programmed death-ligand 1 in nevus cells was significantly higher in non-improved cases compared with improved cases. The PhenoCycler® assay revealed that CD107a-positive and CD21-positive cells were more prevalent in improved cases than in non-improved cases. In the improved cases, active cell-cell interactions, centered on CD21-positive cells, were observed, whereas in the non-improved cases, cell-cell interactions were sparse. Instead, a dense infiltration of CD8-positive cells and CD3 and CD4-positive cells was observed in non-improved cases. Elucidation of the immune microenvironment of halo nevus is also relevant to melanoma-associated vitiligo and will contribute to our understanding of tumor immunity. • We collected 54 halo nevus patients and performed multivariate analysis and immunohistochemical analysis. • The presence or absence of vitiligo vulgaris was associated with improvement in the surrounding vitiligo. • Expression of PD-L1 in nevus cells was significantly higher in non-improved cases compared with improved case. • Multiplexed immune cell phenotyping and spatial single-cell analyses of representative 2 cases were performe. [ABSTRACT FROM AUTHOR]

Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis. The phase III KESTREL study evaluated the efficacy of durvalumab [programmed death-ligand 1 (PD-L1) antibody] with or without tremelimumab [cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody], versus the EXTREME regimen in patients with R/M HNSCC. Patients with HNSCC who had not received prior systemic treatment for R/M disease were randomized (2 : 1 : 1) to receive durvalumab 1500 mg every 4 weeks (Q4W) plus tremelimumab 75 mg Q4W (up to four doses), durvalumab monotherapy 1500 mg Q4W, or the EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) until disease progression. Durvalumab efficacy, with or without tremelimumab, versus the EXTREME regimen in patients with PD-L1-high tumors and in all randomized patients was assessed. Safety was also assessed. Durvalumab and durvalumab plus tremelimumab were not superior to EXTREME for overall survival (OS) in patients with PD-L1-high expression [median, 10.9 and 11.2 versus 10.9 months, respectively; hazard ratio (HR) = 0.96; 95% confidence interval (CI) 0.69-1.32; P = 0.787 and HR = 1.05; 95% CI 0.80-1.39, respectively]. Durvalumab and durvalumab plus tremelimumab prolonged duration of response versus EXTREME (49.3% and 48.1% versus 9.8% of patients remaining in response at 12 months), correlating with long-term OS for responding patients; however, median progression-free survival was longer with EXTREME (2.8 and 2.8 versus 5.4 months). Exploratory analyses suggested that subsequent immunotherapy use by 24.3% of patients in the EXTREME regimen arm contributed to the similar OS outcomes between arms. Grade 3/4 treatment-related adverse events (TRAEs) for durvalumab, durvalumab plus tremelimumab, and EXTREME were 8.9%, 19.1%, and 53.1%, respectively. In patients with PD-L1-high expression, OS was comparable between durvalumab and the EXTREME regimen. Durvalumab alone, and with tremelimumab, demonstrated durable responses and reduced TRAEs versus the EXTREME regimen in R/M HNSCC. • KESTREL assessed first-line durvalumab with or without tremelimumab versus the EXTREME regimen in patients with R/M HNSCC. • Durvalumab ± tremelimumab was not superior to the EXTREME regimen for OS in patients with PD-L1-high expression. • Durvalumab ± tremelimumab produced durable responses and fewer TRAEs versus EXTREME in patients with R/M HNSCC. • Subsequent immunotherapy use may have contributed to longer-than-expected OS in the EXTREME regimen arm. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is a lethal bile-duct cancer that is difficult to treat by current standard procedures. This drawback has prompted us to develop adoptive T-cell therapy for CCA, which requires an appropriate target antigen for binding of chimeric antigen receptor (CAR) T cells. Mucin 1 (MUC1), an overexpressed protein in CCA cells, is a potential target antigen for the CAR T-cell development. However, MUC1 overexpression also is associated with the upregulation of programmed death-ligand 1 (PD-L1), an immune checkpoint protein that prohibits anti-tumor functions of T cells, probably causing poor overall survival of patients with CCA. To overcome this problem, we developed anti-MUC1-CAR T cells containing PD-1-CD28 switch receptor (SR), namely αM.CAR/SR T cells, to target MUC1 and switch on the inhibitory signal of PD-1/PD-L1 interaction to activate CD28 signaling. Our lentiviral construct contains the sequences that encode anti-MUC1-single chain variable fragment, CD137 and CD3ζ, linked with P2A, PD-1 and CD28. Initially, the upregulations of MUC1 and PD-L1 proteins were confirmed in CCA cell lines. αM.CAR and SR were co-expressed in 53.53 ± 13.89% of transduced T cells, mainly CD8+ T cells (85.7 ± 0.75%, P <0.0001) with the effector memory phenotype (59.22 ± 16.31%, P < 0.01). αM.CAR/SR T cells produced high levels of intracellular tumor necrosis factor-α and interferon-γ in response to the activation by CCA cells expressing MUC1, including KKU-055 (27.18 ± 4.38% and 27.33 ± 5.55%, respectively, P < 0.05) and KKU-213A (47.37 ± 12.67% and 54.55 ± 8.66%, respectively, P < 0.01). Remarkably, the cytotoxic function of αM.CAR/SR T cells against KKU-213A cells expressing PD-L1 was significantly enhanced compared with the αM.CAR T cells (70.69 ± 14.38% versus 47.15 ± 8.413%, respectively; P = 0.0301), correlated with increased granzyme B production (60.6 ± 9.89% versus 43.2 ± 8.95%, respectively; P = 0.0402). Moreover, the significantly enhanced disruption of KKU-213A spheroids by αM.CAR/SR T cells (P = 0.0027), compared with αM.CAR T cells, was also observed. Taken together, the cytotoxic function of αM.CAR/SR T cells was enhanced over the αM.CAR T cells, which are potential to be further tested for CCA treatment. Cholangiocarcinoma (CCA) is a bile duct cancer with high incidence and mortality lacking of effective treatments. The tissues of patients with CCA show high mucin-1 antigen and immune checkpoint ligand-1 (PD-L1) expression that affect antitumor functions of the immune cells. To overcome this challenge, we developed anti-mucin-1/CAR T cells expressing PD-1-CD28 switch receptor (αM.CAR/SR T cells) that can switch the inhibitory signal of PD-1/PD-L1 to activate the cells. The αM.CAR/SR T cells showed high proliferation, cytokine production, cytotoxicity and modest LAG-3, TIM-3 exhaustion markers. Thus, the αM.CAR/SR T cells are potential to be further developed as adoptive T-cell therapy for CCA. [Display omitted] [ABSTRACT FROM AUTHOR]

Bispecific T-cell Engager (BiTE) antibodies can redirect T-cells to tumor cells, and turn on the targeted lysis of tumor cells. However, BiTE has been challenging in solid tumors due to short plasma half-life, "off-target" effect, and immunosuppression via PD-1/PD-L1 axis. This study designed a safe, long-acting, and highly effective P rotease- A ctivated P STAGylated B iTE, named PAPB , which includes a shielding polypeptide domain (PSTAG), a protease-activated linker, and a BiTE core. The BiTE core consists of two scFvs targeting PD-L1 and CD3. BiTE core bound PD-L1 and CD3 in a dose-dependent manner, and PAPB can release BiTE core in response to MMP2 in the tumor microenvironment to exert antitumor activity. The plasma half-life of PAPB in mice was significantly prolonged from 2.46 h to 6.34 h of the BiTE core. In mice bearing melanoma (A375) xenografts, PAPB significantly increased infiltration of T lymphocytes in tumor tissue, and inhibited tumor proliferation without activating T-cells in the peripheral blood. Overall, the engineering protein PAPB could be a promising drug candidate for solid tumor immunotherapy. [Display omitted] • Protease-activated PSTAGylation could be a universal strategy for improving the druggability of BiTE. • Anti-PD-L1 × CD3 BiTE redirect T-cell to lyse PD-L1 positive tumor cells. • PSTAGylation extends the half-life of BiTE without activity compromise. • PAPB increased infiltrating T cells in PD-L1 positive tumor. • PSTAG polypeptide serves as a shielding domain to reduce the off-target effect of BiTE. [ABSTRACT FROM AUTHOR]