PD-L1 High Expression Research Articles

High expression levels of TLR9 and PD-L1 indicates a poor prognosis in patients with angioimmunoblastic T-cell lymphoma: a retrospective study of 88 cases in a single center.

Background: The role of TLR9 expressed by tumor cells in evading immune surveillance was confirmed. PD-L1 expression in tumor cells plays a key role in tumor immune escape, which is associated with poor prognosis. However, the clinical relevance of TLR9 and PD-L1 expression in angioimmunoblastic T-cell lymphoma (AITL) has not been evaluated.Materials and methods: In this study, we identified differentially expressed genes in AITL samples by bioinformatic analysis, and we first examined TLR9 and PD-L1 expression by immunohistochemical staining in patients with AITL and compared these data with clinical features and survival time.Results: It was found that the expression of PD-L1 and multiple TLRs was higher in AITL than normal T-cell samples, and TLR9 and PD-L1 expression displayed complex interactions by bioinformatic analysis. The rates of TLR9 and PD-L1 high expression were 69% and 50%, respectively. High expression of either TLR9 or PD-L1 indicated a poor survival rate for patients with AITL. Multivariate analysis further confirmed that high expression levels of TLR9 and PD-L1 were unfavorable prognostic factors for AITL. We further found inferior overall survival in AITL with clinical features of ECOG status ≥ 2, advanced-stage, elevated serum LDH levels, elevated serum β2-MG levels, and high IPI score.Conclusion: TLR9 and PD-L1 expression may be a novel predictor of prognosis for patients with AITL and may serve as potential therapeutic strategy.

Clinicopathologic Significance and Immunogenomic Analysis of Programmed Death-Ligand 1 (PD-L1) and Programmed Death 1 (PD-1) Expression in Thymic Epithelial Tumors.

Objectives: Thymic epithelial tumors (TETs) are rare malignant tumors that exhibit heterogeneous histology and clinical behavior. As immune check point inhibitors, drugs targeting anti-programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have shown remarkable results against many cancers; thus, the importance of PD-1/PD-L1 immunohistochemistry as a predictive or prognostic biomarker has grown. However, limited data on PD-L1 and PD-1 expression in TETs have been reported; moreover, these results have been variable. Here, we examined the expression of PD-1/PD-L1 proteins in TETs and analyzed the clinicopathologic significance of this expression.Patients and Methods: A tissue microarray was constructed using 368 samples of TETs, each in triplicate. Immunohistochemistry for PD-L1 (SP263 assay) and PD-1 in TETs and CD8 in thymic carcinoma (TC) was performed; next, correlations with clinicopathologic characteristics were analyzed. PD-L1high was designated as ≥50% of tumor proportion score; PD-1high and CD8high were defined as ≥5% and 1% of tumoral immune cells, respectively.Results: The cohort consisted of 308 patients with thymomas and 60 patients with TC. PD-L1 positivity was identified in 90.6% (328/362, ≥1%) of TETs, PD-1 expression of intra-/peritumoral T cells was identified in 53.6% (194/362) of TETs and CD8 positivity was identified in 11% (7/60, ≥1%) of TC. Of the 362 patients, 141 (39.0%) exhibited high PD-L1 expression (PD-L1high). The PD-L1high thymoma group was correlated with high Masaoka-Koga stage (p < 0.001), type B3 histology (p < 0.001), and myasthenia gravis (p < 0.001). This group exhibited poor overall survival (OS, p = 0.003, log-rank) and worse disease-free survival (DFS, p = 0.042, log-rank). No survival differences were detected between PD-L1high and PD-L1low groups in TC. Additionally, there was no correlation between PD-1 expression and survival in patients with TETs. Multivariate analysis revealed that PD-L1high expression was an independent poor prognostic factor (p = 0.047, HR 2.087, 95% CI, 1.009–4.318) in thymomas.Conclusions: To our knowledge, this is the largest study on TETs published in English literature. This study provides useful information regarding the prognosis of and potential therapeutic options for patients with TETs.

P1.04-50 Real World Efficacy of Pembrolizumab of as a 1st Line Treatment in Metastatic Non-Small Cell Lung Cancer with PD-L1 High Expression

P1.04-50 Real World Efficacy of Pembrolizumab of as a 1st Line Treatment in Metastatic Non-Small Cell Lung Cancer with PD-L1 High Expression

PD-1 high expression predicts lower local disease control in stage IV M0 nasopharyngeal carcinoma

BackgroundTumor-infiltrating lymphocytes (TILs) play a critical role in tumor immune surveillance and immune suppression. Understanding tumor infiltrating T cell subset density, location and PD-1/PD-L1 expression might provide insight for the prediction of tumor therapeutic response and clinical outcome. The purpose of this study was to evaluate the expression and localization of CD8, FoxP3, PD-1, and PD-L1 in primary tumor tissues and their effects on prognosis of stage IV M0 locally advanced nasopharyngeal carcinoma (NPC) patients.MethodsSixty NPC patients with stage IV M0 locally advanced disease were treated with definitive chemoradiation. Tumor biopsies from primary lesion were analyzed for the expression and localization of CD8, FoxP3, PD-1, and PD-L1 by immunohistochemistry. Their associations with local disease control and survival of NPC were analyzed.ResultsThe average follow-up time was 43 months (range from 14 to 61 months). High expression of CD8+, FoxP3+, PD-1+ and PD-L1+ was observed in 60, 86.7, 56.7, and 91.7% of patients, respectively. There was no correlation between clinicopathological features and the expression of these immune markers. High PD-1 expression was found to be associated with lower local disease control (5-year LRFS 23.2% vs 96.8%, p < 0.001) and unfavorable clinical outcome (5-year OS 47.4% vs 73.3%, p = 0.014). In multivariate analysis, PD-1 expression was also an adverse prognostic factor for 5-year OS (HR: 3.68, P = 0.023) and LRFS (HR: 16.89, 1.27–11.84, P = 0.007). Those with PD-1 distribution in both stroma and tumor region had the poorest prognosis. However, PD-1 expression has no significant correlation with 5-year RRFS (p = 0.980) and DMFS (p = 0.865). Patients with both PD-1 and PD-L1 high expression had significant poor local disease control (5-year LRFS 96.0% vs 43.0%, p < 0.001) and overall survival (5-year OS 80.8% vs 45.1%, p < 0.001) compared with the others. Other immune markers were not found having corrections with disease control and survival.ConclusionsPD-1 high expression, especially with PD-L1 co-expression, is associated with high local recurrence and unfavorable clinical outcome for stage IV M0 NPC patients, and might be a potential target for immunotherapy.

PD-L1 expression on circulating tumor cells and prognosis of breast cancer patients.

e14028 Background: Nowadays programmed cell death (ligand) 1 (PD1/PD-L1) inhibitors in the clinic show benefit for appropriate patient. There are clinical trials for specific breast cancer patients. We all know that the prognosis of breast cancer is associated with CTC. However, PD-L1 expression on circulating tumor cells (CTC) is lack of research. It is crucial for the prediction and supervision of molecular-targeted therapy, while the predictive biomarker response to PD(-L)1 checkpoint inhibitors is lacking. So we tried to explore the relationship between overexpression of PD-L1 on CTCs and prognosis and clinicopathological features of breast cancer patients. Methods: We analyzed CTC and PD-L1 mRNA expression on CTC in 20 primary breast cancer patients, through mRNA probe hybridization. The relationship between clinicopathological features and PD-L1 expression on CTC was analyzed by chi square test. Kaplan-Meier and univariate Cox proportional hazards model analyses were used to compare the survival of patients with high PD-L1 expression and patients with low PD-L1 expression. Results: The median follow-up time was 40 months (range, 36-43 months). Of the 20 patients, 15 had more than 1 CTC in 7.5ml peripheral blood. Among the 15 patients, each one has at least 1 CTC showing PD-L1. The expression of PD-L1 on CTC was divided into low expression, medium expression and high expression, then we gave 1 score for low expression, 2 score for medium expression and 3 score for high expression. PD-L1 high expression was total score≥3, while PD-L1 low expression was total score ＜ 3. We found PD-L1 expression on CTC is related to the tumor size(P = 0.012) lymph node status (P = 0.001) and PR status (P = 0.037). There was significant difference between T2 and T3 in large tumor group(P = 0.003), while in node status group statistical difference can be found in N1 vs N3(P = 0.000) and N2 vs N3(P = 0.015). Our data indicated that patients with high PD-L1 expression on CTC had poor overall survival(P = 0.004) compared to low PD-L1 expression on CTC (Table). Univariate Cox proportional hazards model analysis showed that high PD-L1 expression on CTC was an independent prognostic factor. Conclusions: PD-L1 on CTC is indeed associated with some poor clinicopathological features. High expression of PD-L1 on CTC is an independent prognostic factor for shorter survival. [Table: see text]

Molecular correlates of PD-L1 expression in patients with non-small cell lung cancer.

9018 Background: PD-L1 expression is the only FDA-approved predictive biomarker for patients with NSCLC treated with immune checkpoint inhibitors. The impact of tumor molecular profiling on tumor PD-L1 expression is not known. We hypothesized that somatic mutations and copy number alterations may be associated with distinct patterns of PD-L1 expression in patients with NSCLC. Methods: We examined patients with NSCLC in whom PD-L1 testing and targeted next-generation sequencing (MSK-IMPACT) were performed on the same tissue sample. PD-L1 expression was determined by IHC using the E1L3N antibody clone and categorized as PD-L1 high (≥ 50%), intermediate (1-49%), or negative ( &lt; 1%) expression. The association of PD-L1 with individual genes, pathways, tumor mutation burden, whole genome duplication (WGD), and aneuploidy (fraction of genome altered (FGA)) were evaluated. P-values &lt; 0.05 and q-values &lt; 0.15 were considered significant for individual genes. Results: 1023 patients with NSCLC had PD-L1 testing and MSK-IMPACT performed on the same tissue sample, 18% (n = 180) had high, 21% (n = 218) had intermediate, and 61% (n = 625) had negative PD-L1 expression. High PD-L1 expression was significantly enriched in metastatic vs primary lesions (p &lt; 0.001). There was a minor correlation between PD-L1 and TMB (spearman rho = 0.195) and PD-L1 and FGA (spearman rho = 0.11). Similar rates of WGD were found among patients with high, intermediate, and negative PD-L1 expression (p = 0.38). Mutations in KRAS and TERT were significantly enriched in PD-L1 high compared to other groups (p = 0.001, q = 0.14; p &lt; 0.001, q = 0.003). By contrast, mutations in EGFR and STK11 were associated with PD-L1 negativity (p &lt; 0.001, q = 0.001; p = 0.001, q = 0.14). Pathway analysis showed DNA repair (p &lt; 0.001), TP53 (p &lt; 0.001), and SWI/SNF (p = 0.04) pathways significantly associated with PD-L1 high compared to PD-L1 negative expression. Conclusions: The genetic features of NSCLC are associated with distinct patterns of PD-L1 expression. This data may provide insight to how the molecular phenotype can interact with the immunologic phenotype of tumors.

Paradoxical pro-tumor functions of dendritic cells on colorectal cancer

Abstract The immune system’s ability to eradicate cancer requires coordination between innate and adaptive immune cells. No other cell type bridges innate and adaptive immunity better than the dendritic cell (DC). For this reason, DCs, specifically the Batf3-dependent DC subset, are thought to be key to anti-tumor immunity. Although the anti-tumor functions of Batf3-dependent DCs have been well described in skin cancer, whether these DCs have similar anti-tumor functions in other cancers is unknown. Here we investigated the roles of Batf3-dependent DCs in colon cancer and paradoxically found that these DCs actually promote colon tumorigenesis. Thus, in a spontaneous colorectal cancer mouse model, loss of Batf3-dependent DCs resulted in decreased colon tumor number. Although Batf3-dependent DCs are best known for expanding IFNγ-producing T cells, in colon tumors, we surprisingly found that Batf3-dependent DCs were required to expand tumor-infiltrating γδT cells producing IL-17. IL-17 is known to promote colon tumorigenesis and our findings pinpoint IL-17-producing γδT cells as a key source of IL-17 for tumor growth, and surprisingly describe a requirement for Batf3-dependent DCs to expand an IL-17-producing T cell population. In addition, we identified tumor-infiltrating Batf3-dependent DCs uniquely upregulate high levels of PD-L1as a second mode of action to promote colon cancer. PD-L1 upregulation and high PD-L1 expression on Batf3-dependent DCs was specific within the tumor microenvironment. Collectively, these paradoxical pro-tumorigenic functions of Batf3-dependent DCs suggest that these DCs are not universally anti-tumor and that targeted therapies that modulate Batf3-dependent DCs could benefit colon cancer patients.

WNT signaling modulates PD-L1 expression in the stem cell compartment of triple-negative breast cancer

Triple-negative breast cancers (TNBCs) are characterized by a poor prognosis and lack of targeted treatments, and thus, new therapeutic strategies are urgently needed. Inhibitors against programmed death-1 (PD-1)/PD-1 ligand (PD-L1) have shown significant efficacy in various solid cancers, but their activity against TNBCs remains limited. Here, we report that human TNBCs molecularly stratified for high levels of PD-L1 (PD-L1High) showed significantly enriched expression of immune and cancer stemness pathways compared with those with low PD-L1 expression (PD-L1Low). In addition, the PD-L1High cases were significantly associated with a high stemness score (SSHigh) signature. TNBC cell lines gated for aldehyde dehydrogenase (ALDH) and CD44 stemness markers exhibited increased levels of PD-L1 versus their ALDH-negative and CD44Low counterparts, and PD-L1High cells generated significantly more mammospheres than PD-L1Low cells. Murine mammary SCA-1-positive tumor cells with PD-L1High expression generated tumors in vivo with higher efficacy than PD-L1Low cells. Furthermore, treatment of TNBC cells with selective WNT inhibitors or activators downregulated or upregulated PD-L1 expression, respectively, implying a functional cross-talk between WNT activity and PD-L1 expression. Remarkably, human TNBC samples contained tumor elements co-expressing PD-L1 with ALDH1A1 and/or CD44v6. Additionally, both PD-L1-/SCA1-positive and ALDH1A1-positive tumor elements were found in close contact with CD3-, and PD-1-positive T cells in murine and human tumor samples. Overall, our study suggests that PD-L1-positive tumor elements with a stemness phenotype may participate in the complex dynamics of TNBC-related immune evasion, which might be targeted through WNT signaling inhibition.

The Immune Checkpoint Regulator PDL1 is an Independent Prognostic Biomarker for Biochemical Recurrence in Prostate Cancer Patients Following Adjuvant Hormonal Therapy.

Background: The programmed death 1 (PD1)/programmed death ligand 1 (PDL1) targeted therapies have gained positive outcomes in several tumors, but the evidence of the expression and prognosis value of PD1/PDL1 in high risk prostate cancer was rare.Methods: Immunohistochemical analysis of PDL1/PD1 expression by a validated antibody was performed in a retrospectively collected high risk prostate cancer cohort who received adjuvant hormonal therapy (AHT) after radical prostatectomy (RP). The association between PDL1/PD1 expression and prognosis was determined.Results: In total, 127 patients were enrolled. 49.6% patients were considered PDL1-high expression while the PD1-positive expression proportion was 24.4%. High PDL1 and negative PD1 expression were significantly associated with lower prostate specific antigen (PSA) density (p=0.010 and p=0.033, respectively). Compared with the PDL1-low expression patients, the PDL1-high expression patients had significantly shorter time to PSA nadir (TTN) (P=0.001) and biochemical recurrence (BCR) (P=0.004). In Kaplan-Meier analysis, the PDL1-high expression group (p<0.0001) and the PDL1-high/PD1-negative expression group (p<0.0001) showed markedly lower BCR-free survival in localized disease. Univariate cause-specific Cox proportional hazard regression model concluded total PSA (p=0.047), PDL1-high-expression (p<0.001), PDL1-high/PD1-negative expression (p<0.001) were significant risk factors of shorter progression time to BCR in localized disease. PDL1-high-expression was the independent predictor of time to BCR in multiple Cox regression of all patients (Hazard ratio [HR]: 3.901; 95% Confidence interval [CI]: 1.287-11.824; p=0.016).Conclusions: PDL1 expression is not only highly prevalent in high-risk prostate cancer, but is also an independent biomarker in the prognosis of high-risk prostate cancer received AHT after RP. PDL1/PD1 targeted therapy might be a potentially adjuvant treatment option for high-risk prostate cancer after RP.

467P - Correlation between PD-L1 expression and clinicopathological characterization in NSCLC

Background: Inhibition of the PD-1/PD-L1 pathway may induce anticancer immune responses in non-small cell lung cancer (NSCLC). Here, we analyzed the correlation between PD-L1 expression and clinicopathological characteristics, stromal tumor-infiltrating lymphocyts (sTILs), pulmonary major driver gene alteration in NSCLC. Methods: PD-L1 expression characterizations by immunohistochemistry using the clone 22C3 antibody were performed on 1156 NSCLC (329 archived and 827 recently acquired tumor) and 198 small biopsy. Results: PD-L1 high expression was observed in 9.7%, 6.5%, and 27.4% in recently acquired NSCLC, adenocarcinoma (ADC), and squamous cell carcinoma (SqCC) cohort, respectively, which showed higher than in archive cohorts previously reported in our group (4.9%, 0.5%, and 13.9% in NSCLC, ADC, and SqCC, respectively). In subgroup analysis, PD-L1 high expression was significantly associated with male sex (p = 0.002), larger tumor size (p < 0.001), pleural invasion (p = 0.001), venous and lymphatic invasion (p < 0.001), smoking history (p < 0.001), solid predominant histology (p < 0.001), and advanced pathological stage (p < 0.001) in ADC cohort. It tended to be more common in poorer differentiation (p = 0.011) and absence pleural invasion (p = 0.001) in SqCC. In the small biopsy specimens, PD-L1 high expression was found in 29.3% cases in NSCLC. PD-L1 high expression was significantly associated with high sTILs (p = 0.029). Both PD-L1 high and low expressions were more frequent in EGFR-wild type than in mutated type (p < 0.001). Conclusions: PD-L1 high expression was significantly associated with poor differentiation and ≥50% sTILs. It was more frequently observed in EGFR-wild tumors. The prevalence of PD-L1 expression in recently acquired sample was higher than in archived sample, which suggests that PD-L1 expression should be evaluated as soon as possible after operation, otherwise will be reduced. Legal entity responsible for the study: The author. Funding: Has not received any funding. Disclosure: The author has declared no conflicts of interest.

P2.01-88 C-Reactive Protein (CRP) as a Predictive Marker for Survival in Patients with Advanced NSCLC Treated with First Line Pembrolizumab Monotherapy

Pembrolizumab have shown longer activity in patients with advanced non-small cell lung cancer (NSCLC) especially when PD-L1 expression was high. But even with high PD-L1 expression, more than half of them failed to response. We focused on C-reactive protein (CRP), inflammatory protein measured routinely in clinical practice, to find out its role as predictive biomarker for pembrolizumab. We analyzed advanced NSCLC patients with PD-L1 high expression (EGFR mutation (-), EML-4-ALK fusion (-)) who were treated with pembrolizumab as first-line therapy in our clinical practice. Patients received pembrolizumab (200mg/body, q3W) until progressive disease or unacceptable toxicity. During treatment period we measured serum biochemistry and blood cell count regularly. We evaluated the association the factors such as serum marker including inflammatory protein, age, performance status, histology, smoking status, prior radiation therapy and presence or absence of immune-related adverse events after treatment with the effect such as antitumor response, progression-free survival (PFS) and overall survival (OS). A total of 31 patients treated with pembrolizumab from March 2017 to February 2018 were analyzed for this research. Their characteristics were: median age 72 (range 37-84),male/female 24/7, adenocarcinoma/squamous cell carcinoma/pleomorphic carcinoma/neuroendocrine carcinoma/NOS 17/5/3/1/5, clinical stage IIIB/IV/recurrence 3/21/7, median CRP level at pretreatment 1.15mg/dL (0.07-15.27). Among the candidate biomarker, there were no association except for CRP. Serum CRP level at pretreatment was not predictive, but change of serum CRP level at 6 weeks after anti-PD-1 therapy initiation was most predictive in the analysis. Depressed CRP group showed longer PFS and OS than elevated group (PFS: p=0.08, HR 0.29, OS: p=0.08, HR 0.28, log-rank test). Our analysis suggests that serum CRP elevation at 6 weeks of treatment predict for longer survival when pembrolizumab was given as first-line treatment. This finding might be related to inflammation status of patients and efficacy of anti-PD-1 inhibitor.

P3.04-15 IDO and Tim3 Gene Expression is Correlated in NSCLC Patients with Low PDL1 Gene Expression

Tumor cells evade immunosurveillance by expression of immune checkpoint proteins PD-L1, IDO, and TIM3, even when tumor-infiltrating lymphocytes (TILs) are present. Combination of checkpoint inhibitors Pembrolizumab(PD-1i) and Epacadostat (IDOi) failed to show synergy in melanoma. Yet there are several candidate targets for checkpoint inhibition and rational selection of which combinations to explore is lacking. In particular, which checkpoints to target when PD-L1 is not expressed is largely unexplored. The purpose of this study was to assess the expression of 12 immune checkpoint genes in lung cancer patients with high and low expression of PD-L1. Retrospective review of deep whole transcriptomic sequencing (RNA-Seq) (∼200x106 reads per tumor) on 1467 unselected clinical cases from NantHealth. 112 NSCLC cases were categorized as PD-L1-low and PD-L1-high by median splitting. Expression and co-expression of 12 checkpoint markers (CTLA4,IDO,FOXP3,LAG3,TIGIT,VEGFA,VEGFC,VEGFB,PDL2,PDL1,OX40, and TIM3) were analyzed for tissue-specific enrichment and within PD-L1-defined categories. Immune-cell infiltration was estimated using RNA deconvolution based on known immune cell marker genes (Bindea et al 2013). CTLA, TIGIT and FOXP3 showed high correlations across all 112 samples as well within the PD-L1 low and high expression groups and differential expression across the two groups, with higher expression of the markers among the PD-L1 high expression group versus the low group. Within the PD-L1 high expression group, the expression of markers LAG3, TIM3, OX40, FOXP3, CTLA4 and TIGIT was both higher and more highly correlated than in the PD-L1 low group. Within the PD-L1-low category, IDO1 and TIM3 have relatively high expression and are highly correlated with each other (R=0.72, p=3.85x10ˆ-10). PD-L1 is a primary driver of immune suppression, however when PD-L1 is low there may be some differential role for IDO or TIM3. Combination IDOi and Tim3i should be considered in PD-L1 low patients.

Cytology cell blocks are suitable for immunohistochemical testing for PD-L1 in lung cancer

BackgroundPD-L1 immunohistochemistry (IHC) testing is usually carried out on tissue blocks from core needle biopsy or surgical resections. In this study, we assessed the feasibility of using cytology cell blocks for PD-L1 IHC assay. MethodsA total of 1419 consecutive cases of non-small-cell lung cancer (NSCLC), including 371 cytology cell blocks, 809 small biopsies, and 239 surgical specimens, were included in the study. The cytology cell blocks were prepared with formalin only, methanol/alcohol only or both. PD-L1 expression was examined by staining with Dako PD-L1 IHC 22C3 pharmDx kit. A Tumor Proportion Score (TPS) was categorized as <1%, 1%–49% and ≥50% tumor cells. A total of 100 viable tumor cells were required for adequacy. ResultsOf the cytology cell blocks, 92% of the specimens had an adequate number of tumor cells, not significantly different from small biopsies. The rate of TPS ≥50% differed between sample types and was observed in 42% of cytology cell blocks versus 36% of small biopsies (P = 0.04), and 29% of surgical resections (P = 0.001). The fixative methods did not affect the immunostaining, with overall PD-L1 high expression (TPS ≥50%) rates of 42% in formalin-fixed specimens versus 40% in specimens with combined fixation by methanol/alcohol and formalin (NS). The PD-L1 high expression rate was not associated with EGFR, ALK or KRAS molecular alterations. Higher stage (IV) was associated with higher PD-L1 TPS (P= 0.001). ConclusionOur results show that when the TPS ≥50% is used as the end point, PD-L1 IHC performs well with cytology cell blocks. Cell blocks should be considered as a valuable resource for PD-L1 testing in advanced NSCLC. The clinical significance of higher PD-L1 IHC scores in cytology specimens needs to be evaluated prospectively.

Immuno-oncology biomarker study in a large cohort of LC-SCRUM-Japan: Assessment of PD-L1 expression and tumor mutation burden in non-small cell lung cancer patients treated with immune checkpoint inhibitors.

9070Background: PD-L1 high expression and high tumor mutation burden (TMB) are reported to be correlated with high sensitivity to immune checkpoint inhibitor (ICI) in non-small cell lung cancer (NS...

Expression of PD-1/PD-L1 in gliomas and its relationship with survival prognosis: A meta-analysis

Objective To evaluate the expression of PD-1/PD-L1 in gliomas and its relationship with the tumor grade and prognosis. Methods Related studies were searched from PubMed, Embase, The Cochrane Library databases from inception to November 1st, 2016. Researchers screened literature, extracted data and evaluated the risk of bias of eligible studies dependently. The meta-analysis was conducted by Revman 5.3 software. Results A total of 17 studies and 1 179 gliomas were included. Meta-analysis showed that the expression rates of PD-L1 in tumor cells and tumor-infiltrating lymphocytes were 51% (RD=0.51, 95%CI: 0.41-0.61, P<0.001) and 51% (RD=0.51, 95%CI: 0.30-0.71, P<0.001), respectively. In terms of the relationship of PD-1/PD-L1 expression to WHO grade of gliomas, the meta-analysis showed that the higher grade was associated with higher positive rate of PD-L1 expression, but the difference between adjacent grades was not statistical significant (Ⅱ vs. Ⅲ: RR=0.94, 95%CI: 0.72-1.23, P=0.66; Ⅲ vs. Ⅳ: RR=0.77, 95%CI: 0.56-1.05, P=0.10; Ⅱ vs. Ⅳ: RR=0.72, 95%CI: 0.53-1.97, P=0.03). Survival analysis showed that the prognostic risk of PD-L1 high expression group was higher than that in low expression group (HR=1.51, 95%CI: 1.21-1.79, P<0.001) and the difference was statistically significant. Conclusion PD-1/PD-L1 seems to have a high expression rate in gliomas and is associated with tumor grade, which might be an important factor in the prognosis of gliomas. Key words: Glioma; Programmed cell death 1 receptor; Programmed cell death 1 ligand 1; Prognosis; Meta-analysis

CLEC1B Expression and PD-L1 Expression Predict Clinical Outcome in Hepatocellular Carcinoma with Tumor Hemorrhage

Spontaneous tumor hemorrhage (TH) is frequently observed in solid tumors including human hepatocellular carcinoma (HCC). TH implies fast-growing and worse tumor immunological microenvironment; however, the underlying mechanism remains largely unknown. CLEC1B is a signature gene highly associated with tumor progression. PD-L1 expression is a key biomarker predictive of immune checkpoint therapies, which showed astonishing effect on various types of tumor. We assume that, in HCC, TH may closely associate with the expression of these two molecules. In this study, 136 patients with HCC were enrolled. qRT-PCR showed that CLEC1B expression is significantly lower in HCC tumor tissue. Immunohistochemistry of HCC tissue microarrays demonstrated that PD-L1high and CLEC1Blow expressions were significantly correlated with TH and clinicopathological features indicating worse HCC progression. According to univariate/multivariate analysis, a combination of PD-L1high and CLEC1Blow expression was an independent prognostic factor indicating the poor outcome. The prognostic value of PD-L1high and CLEC1Blow was validated by Cox proportional-hazard analyses. Collectively, tumor with TH is closely associated with CLEC1Blow & PD-L1high expression, which may imply high response of PD-L1/PD-1 immune checkpoint therapies. CLEC1B may be a potential therapeutic target for PD-L1/PD-1 immunotherapy. PD-L1high and CLEC1Blow can be a valuable prognosis factor implying worse clinical outcomes.

Association of tumor infiltrating CD8 positive T cells and PDL-1 expression with survival after conversion surgery for unresectable gastric cancer.

62 Background: Conversion surgery after chemotherapy responds to unresectable gastric cancer has long-term prognosis, however, chemotherapy after surgery should also be considered to improve treatment outcome. The effectiveness of immune checkpoint inhibitors for gastric cancer has been proved. In this study, we investigated the association between PDL-1 expression and CD8+ T cell infiltration in the primary tumor and prognosis of patients who underwent conversion surgery after S-1-based multidrug chemotherapy in unresectable gastric cancer. Methods: We evaluated PDL-1 expression and CD8 T cell infiltration by immunohistochemical staining and examined the relationship with prognosis in 90 patients with Stage IV gastric cancer who underwent gastrectomy in our department from 2007 to 2015. Results: 90 cases included 47 cases of palliative resection, 26 cases of CY1P 0cases and 17 cases of conversion surgery. Among Conversion Surgery cases, 11 (65%) patients underwent R0 surgery, and the 5-year survival rate was 66%. The 5-year survival rate of non-curative resected cases was 16%. In immunohistochemical examination, PDL-1 high expression was a poor prognostic factor in palliative surgery and CY1P0 cases. Meanwhile, in the case of Conversion Surgery, the 5-year survival rate was 58%, 32%, 61%, and 30% in the order of PDL-1 high expression group, low expression group, CD8 T cell high infiltration, and low infiltration group, respectively. Prognosis of PDL-1 high expression group and CD8 T cell infiltration group was good. There was no association between curative resection and neither of CD8 T cell infiltration or PDL-1 expression. Conclusions: We found that the prognosis was relatively good in patients where local immune response was enhanced, regardless of R0 excision. Our results suggested that infiltration of CD8 T cells in the primary tumor may be a prognostic predictor, and it is expected to use an immune check point inhibitor after conversion surgery for unresectable gastric cancer.

The PD-1/PD-L1 axis and human papilloma virus in patients with head and neck cancer after adjuvant chemoradiotherapy: A multicentre study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).

We examined the prognostic role of PD-1+ and CD8+ tumor infiltrating lymphocytes (TILs), and PD-L1+ cells in patients with squamous cell carcinoma of the head and neck (SCCHN) treated with surgery and postoperative chemoradiotherapy (CRT). FFPE samples from 161 patients were immunohistochemically stained for PD-1, CD8 and PD-L1. The immune marker expression was correlated with clinicopathologic characteristics, and overall survival (OS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of HPV16 DNA/p16 status. The median follow-up was 48 months (range: 4-100). The 2-year-OS was 84.1% for the entire cohort. High PD-1 and PD-L1 expression were more common in patients with positive HPV16 DNA (p < 0.001 and p = 0.008, respectively) and high infiltration by CD8+ TILs (p < 0.001 for both markers). High PD-L1 expression correlated with superior OS (p = 0.025), LPFS (p = 0.047) and DMFS (p = 0.048) in multivariable analysis, whereas no significance could be demonstrated for PD-1. Patients with CD8high /PD-L1high expression had favorable outcome (p < 0.001 for all endpoints) compared to other groups. We validated the superior OS data on CD8high /PD-L1high using the Cancer Genome Atlas TCGA dataset (n = 518; p = 0.032). High PD-L1 expression was a favorable prognostic marker in HPV16-negative but not HPV16-positive patients. In conclusion, HPV-positive tumors showed higher expression of immune markers. PD-L1 expression constitutes an independent prognostic marker in SCCHN patients post-adjuvant CRT. In conjunction with CD8 status, these data provide an important insight on the immune contexture of SCCHN and are directly relevant for future treatment stratification with PD-1/PD-L1 immune checkpoint inhibitors to complement CRT.

Nivolumab Induces Remission in High- PD-L1 Expressing Aggressive B-Non Hodgkin Lymphoma: A Single Center Experience

Patients with relapsed or refractory aggressive B-cell Non-Hodgkin lymphoma (B-NHL) have a poor outcome. Nivolumab (NV) targeting the PD-1 receptor has shown promising results in several malignancies like melanoma, renal and lung carcinoma and Hodgkin lymphoma. Data for aggressive B-NHL are just emerging. PD-L1 expression does not necessarily correlate with response. Among lymphoma subtypes, the expression of PD-L1 seems to vary. So far there are no valid data on PD-L1 expression in aggressive lymphoma under NV treatment.We retrospectively analyzed seven patients who had aggressive B-NHL with a refractory or relapsed disease after at least 3 regimens and were thereupon treated with NV 3mg/kg once a fortnight. Treatment was initiated after signed informed consent for off-label use. The histologic specimens were analyzed for PD-L1 expression by immunohistochemistry (IHC).The median age at NV treatment start was 51 years (27-71). The histopathological diagnoses were primary mediastinal B-cell lymphoma (PMBL; n=2), composite lymphoma with diffuse large B-cell (DLBCL) and Hodgkin lymphoma components (n=2), follicular lymphoma transformed into a DLCBL (n=2) and one mediastinal grey zone lymphoma (MGZL). A median of 5 (3-7) prior therapy regimens were given including hematopoietic stem cell transplantation (HSCT) for 3 patients: autologous (n=2) and allogeneic HSCT (n=1), respectively. The lymphoma status was refractory in 2 patients and relapsed in 5 patients. PD-L1 expression was detected in 5 cases, 3 of them showing a positive staining of 10%, 30%, and 50%, respectively, and 2 cases even of 100% of the lymphoma cells. NV was mostly well tolerated (1 pneumonitis completely resolved after systemic steroid therapy, 1 unrelated death caused by septic shock) with a median of 3 (1-17) cycles administered. Response assessment (clinical examination, ultrasound, CT or PET-CT scans) were performed after a median of 3 cycles (2-7), showing regressive and refractory disease in 3 patients, respectively, while 1 patient died prior to response assessment. Among the three responders (2xCR, 1xPR) MGZL and PBML their tumors had high PD-L1 expression of 30% (n=1) and 100% (n=2), respectively. Two responders (one after autologous, one after allogeneic HSCT) are still under treatment. After 14 weeks, one responding patient showed signs of progression of a previously known cerebral lesion (or pseudo progression under immunotherapy). The third responder proceeded to allogeneic HSCT without relevant complications. The PD-L1 expression among the non-responders were 0% (n=2) with progressive disease being the cause of death and 10% (n=1) for the other who is currently receiving alternative therapy.In conclusion, NV induces remission in heavily pretreated, PD-L1 high expression aggressive B-NHL. The significance of these data are limited due to the small number of patients. Therefore, future results of current phase II trials (NCT02038933) will reveal the role of PD-1 blockade in aggressive B-NHL. DisclosuresViardot:Roche: Honoraria; Takeda: Other: travel support; Pfizer: Honoraria; BMS: Consultancy; Janssen: Consultancy; Amgen: Consultancy.

900TiP - KEYNOTE-100: Phase 2 trial of pembrolizumab in patients with advanced recurrent ovarian cancer

Ovarian cancer is the most lethal gynecologic cancer, with approximately 80% of patients experiencing disease recurrence following standard front-line therapy. Currently, no curative therapy is available for recurrent ovarian cancer (ROC), which is an area with high unmet medical need. Pembrolizumab is a programmed death 1 (PD-1) inhibitor designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumor regression and, ultimately, immune rejection. Prior study of pembrolizumab in advanced epithelial ovarian cancer showed promising clinical activity. Here, we further evaluate the efficacy and safety of pembrolizumab in patients (pts) with advanced ROC in the open-label, single-arm, 2-cohort KEYNOTE-100 study (NCT02674061). Trial design: Pts who are ≥18 years old with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and confirmed disease recurrence following front-line platinum-based therapy can be enrolled. Cohort A will include approximately 250 pts who received ≤2 prior therapies for ROC and had a platinum-free interval (PFI) or treatment-free interval (TFI) of ≥3 to 12 mo based on the last regimen received. Cohort B will include approximately 75 pts who received 3-5 prior therapies for ROC and had a PFI or TFI of ≥3 mo based on the last regimen received. Pts must also have measurable disease and ECOG performance status of 0-1 at baseline and must provide a tumor sample for PD-L1 analysis. Pts will be treated with pembrolizumab 200 mg every 3 wk for 35 cycles or until disease progression, death, unacceptable toxicity, or withdrawal of consent. Pts will have regular imaging and safety assessments during the study. The primary study objectives are to evaluate objective response rate per RECIST v1.1 (primary end point) in cohort A and cohort B all-comer populations and in tumor PD-L1 high-expression populations. Duration of response, progression-free survival, overall survival, and safety will also be evaluated. Clinical trial identification: NCT02674061 Legal entity responsible for the study: Merck & Co., Inc.