Cell Death Ligand-1 Expression Research Articles

GemOX plus immune checkpoint inhibitor in combination with lenvatinib or NGS-guided targeted therapy in patients with biliary tract cancers.

e16133 Background: The combination of gemcitabine-based chemotherapy and immune checkpoint inhibitors has made great progress recently in advanced biliary tract cancer (BTC). Multi-target TKI lenvatinib or next-generation sequencing (NGS)-guided molecular targeted therapy are also promising. The aim of this study was to explore the anti-tumor effects of combined GemOX plus anti-PD-1 sintilimab and TKI either by lenvatinib or by NGS-guided targeted therapy if there is available target for local advanced or metastatic BTCs. Methods: This is a prospective single arm clinical study. Patients with local advanced or metastatic BTC were given intravenous infusion of standard GemOX (85mg/m2 oxaliplatin on day 1 and gemcitabine 1000mg/m2 on a 1-8-day schedule of a 3-week treatment cycle) plus 200mg q3w of sintilimab and lenvatinib or targeted therapy based on NGS (olaparib for BRCA1/2 mutation, dasatinib for IDH1/2 mutation, afatinib for EGFR mutation, lenvatinib for PDGFR and KIT mutation, lenvatinib for FGFR/KIT mutation). The primary end point was objective response rate (ORR), and the secondary end points were progression-free survival (PFS) and overall survival (OS). Tumor response was evaluated according to RECIST v1.1 criteria. Results: From November 2020 to December 2021, 22 patients with locally advanced or metastatic BTCs (6 GBC, 14 iCCA, 1 pCCA and 1 dCCA) were enrolled in the regimen, with an average age of 58.4 years. Partial response (PR) was achieved in 10 cases, stable disease (SD) in 9 cases and progression disease (PD) in 3 cases (13.6 %). The objective response rate (ORR) was 45.5%, and the disease control rate (DCR) was 86.4%. By December 31st, 2021, the median follow-up time was 13.1 months. The most common adverse events were anorexia (68.2%), nausea (68.2%), vomiting (36.36%), hair loss (45.5%) and bone marrow suppression (63.6%). During the treatment, the incidence of adverse reactions was 81.8%, and the incidence of grade 3/4 adverse events was 9.09%. For 14 patients with NGS, 5 patients were treated by targeting IDH2, EGFR, FGFR2, PDGFRA/KIT, BRCA2 and resulted in 1 SD and 4 PR with an ORR of 80% and DCR of 100%. The ORR and DCR were both 100% for 4 patients with programmed cell death ligand-1 (PD-L1) expression. While for the 3 patients with supper-progression markers such as RET, MDM2 and FGF14/STK24, there were 2 SD and 1 PD with an ORR of 0% and DCR of only 33%. Conclusions: In patients with advanced BTCs, the combination of GemOX plus sintilimab and lenvatinib or NGS-guided targeted therapy showed promising ORR and DCR, especially for the patients with positive PD-L1 expression and targetable gene alterations.

Development and Validation of an Immune-Related Prognostic Signature in Cervical Cancer.

BackgroundCervical cancer is the fourth most frequent gynecological malignancy across the world. Immunotherapies have proved to improve prognosis of cervical cancer. However, few studies on immune-related prognostic signature had been reported in cervical cancer.MethodsRaw data and clinical information of cervical cancer samples were downloaded from TCGA and UCSC Xena website. Immunophenoscore of immune infiltration cells in cervical cancer samples was calculated through the ssGSEA method using GSVA package. WGCNA, Cox regression analysis, LASSO analysis, and GSEA analysis were performed to classify cervical cancer prognosis and explore the biological signaling pathway.ResultsThere were eight immune infiltration cells associated with prognosis of cervical cancer. Through WGCNA, 153 genes from 402 immune-related genes were significantly correlated with prognosis of cervical cancer. A 15-gene signature demonstrated powerful predictive ability in prognosis of cervical cancer. GSEA analysis showed multiple signaling pathways containing Programmed cell death ligand-1 (PD-L1) expression and PD-1 checkpoint pathway differences between high-risk and low-risk groups. Furthermore, the 15-gene signature was associated with multiple immune cells and immune infiltration in tumor microenvironment.ConclusionThe 15-gene signature is an effective potential prognostic classifier in the immunotherapies and surveillance of cervical cancer.

An open-label, phase 2 study of personalized approach with perioperative immunotherapy for bladder preservation in muscle-invasive urothelial bladder carcinoma (MIBC).

TPS590 Background: Radical cystectomy (RC) without neoadjuvant chemotherapy is standard-of-care for cisplatin (cis)-ineligible pts (and those refusing cisplatin) with MIBC. Checkpoint inhibitors (CPIs) are being actively explored in the perioperative setting. CPIs documented a 42% pathologic complete response-rate (ypT0N0) in our previous trial (PURE-01, NCT02736266). In this trial, programmed cell-death ligand-1 (PD-L1) expression was associated with ypT0N0 response ( Necchi A, et al. Eur Urol. 2019), and a cohort of PD-L1+ pts who refused RC are still alive at long-term follow-up ( Bandini, Ann Oncol 2020). Initial data from trials aimed at delivering a systemic therapy while sparing any local therapy on the bladder tumor in highly-selected pts are promising ( Galsky, 2021, Geynisman, 2021). Sasanlimab (SASI) is a humanized, hinge region–stabilized (21) IgG4 mAb directed against human PD-1. Sasanlimab is currently being tested subcutaneously (SQ) in a phase III study in non-MIBC. Our hypothesis is that SASI can be offered in PD-L1+ pts as an exclusive therapeutic option instead of any additional treatment, after a clinical complete response (cCR) with an induction phase. Methods: This is a Phase 2, open-label, non-randomized, single-cohort study in pts with MIBC who are ineligible or unwilling to receive cisplatin-based neoadjuvant chemotherapy. The study will include pts with a PD-L1 CPS≥10% in tumor biopsy.Other key inclusion criteria: UC histology, an ECOG PS 0−1. Cis-ineligibility is defined as one of the following: glomerular filtration rate ≥30 but < 60 mL/min, or CTCAE v5 ≥grade 2 hearing loss or peripheral neuropathy. Key exclusion criteria: clinical evidence of ≥N1 or metastatic disease or UC in upper urinary tract; prior systemic therapy, radiation therapy, or prior RC. Pts will undergo a transurethral resection of the bladder (TURBT), a CT scan, and a 18FDG-PET/CT scan. SASI will be administered SQ at the recommended dose of 300mg for a total of 3 cycles every 4 weeks prior to redo-TURBT. Pts who will achieve a cCR (i.e., no evidence of residual viable tumor at re-TURBT sample, urinary cytology and imaging tests) will receive additional SASI treatment for a total period of 12 months, every 4 weeks. Pts with non-CR will be excluded from the study and start treatment according to guidelines or investigator preference. Primary endpoint: event-free survival (EFS). Secondary endpoint: proportion of cCR. According to Simon's 2-stage MinMax design, a total of 55 pts will be included, and we anticipate the need for enrolling 110 pts for the neoadjuvant phase of the study. This assumption will correspond to the need for screening approximatively 220 pts onto this trial. Exploratory analyses will include: artificial intelligence through multiparametric bladder MRI/PET, and ctDNA analyses pre-post neoadjuvant period. Clinical trial information: 2021-001649-10.

Programmed Cell Death Ligand 1 Expression in Cytological and Surgical Non-Small Cell Lung Cancer Specimens in Association with EGFR Mutation and Overall Survival: A Single-Institution Experience.

The aim of this study was to evaluate programmed cell death ligand-1 (PD-L1) expression and the relationship between driver mutations and survival analysis in advanced-stage non-small cell lung carcinoma (NSCLC). A total of 122 advanced-stage NSCLC patients were included in this retrospective study. The patients were diagnosed based on cytological examination and histopathological analysis of biopsy or resection material that had undergone at least 1 molecular analysis. The expression of PD-L1 in tumors and tumor-infiltrating lymphocytes (TIL) was scored and compared with age, sex, organ, biopsy method, tumor subtype, driver mutation status, and overall survival data. There was no statistically significant difference between PD-L1-positivity and age, gender, location, pattern, or pathological diagnosis of the type of sample. When the threshold value for PD-L1 IHC evaluation was accepted as ≥1% and ≥50%, the rate of positivity was 19.7% and 7.4%, respectively. Since there is a wide range of positivity rates reported in the literature, we could not reach a conclusion as to whether the PD-L1-positivity rate we observed was high or low. There is a need for comparative studies where the technique, clones, threshold values, and phases are homogenized. There is an inverse correlation between the EGFR-mutant population and PD-L1 positivity. In terms of overall survival, no relationship was found between PD-L1 positivity, the presence of TIL, and EGFR mutation status.

Abstract PO-058: Anti-cancer activity of NTAX-44 (bioprocessed arsenic trioxide) on pancreatic cancer cell line

Abstract Purpose: Pancreatic Cancer remains to be highly lethal malignancy mainly because of a high incidence of drug resistance. Because of this, there is a great need for new therapies which can improve overall therapeutic outcomes in pancreatic cancer patients. Arsenic trioxide is an approved drug for the treatment of acute promyelocytic leukemia (APML) and is in the experimental stage for use in different malignancies. Earlier in-vitro studies on human pancreatic cell lines have shown that arsenic trioxide has potent anti-proliferative effects with induction of apoptosis. NTAX-44 is a novel orally administrable Arsenic trioxide that is derived using green chemistry based patented technology. This compound is bioavailable when administered orally, and it has demonstrated good safety and tolerability in bioavailability clinical trials. In the present study, we conducted preclinical studies to evaluate the anti-proliferative effect and inhibition of programmed cell death ligand-1 (PD-L1) expression activity by NTAX-44. Method: The effect of NTAX-44 was assessed on the viability of MIA-Pa-Ca-2 cell lines grown as monolayers by MTS assay. We further checked the expression of PD-L1 in MIA-Pa-Ca-2 cell line treated with NTAX-44 by flow cytometry. PD-L1, an immune checkpoint regulator, has been speculated to play a significant role in suppressing the immune system. It also helps tumor cells evade anti-tumor immunity. The expression of PD-L1 was induced by IFN-gamma stimulation. The anti-metastatic capacity of NTAX-44 was evaluated by in ovo chick embryo yolk sac membrane (YSM) angiogenesis assay. The cytocompatibility testing was done by testing the effect of NTAX-44 on the viability of normal human peripheral blood mononuclear cells (PBMC) by MTS assay. Results: NTAX-44 effectively inhibited the viability of MIA-Pa-Ca (IC50 4.63 +/- 1.16μg/ml for 48 hr and 0.50 +/- 0.63 for 72 hr of treatment); demonstrating the anti-proliferative activity of NTAX-44 against MIA-Pa-Ca-2 cell line. Furthermore, NTAX-44 at 25µg/ml concentration significantly inhibited IFN-gamma-induced PD-L1 expression in the MIA-Pa-Ca-2 cell line. Evaluation of the anti-metastatic potential of NTAX-44 exhibited around 40% inhibition in the number of quaternary blood vessels was observed on the treatment of YSM with NTAX-44 compared to vehicle control. It is noteworthy that the anti-angiogenic activity was comparable to that of Bevacizumab (Avastin®). The cytocompatibility testing revealed that it was well tolerated at a concentration up to 200μg/ml in PBMC cells. Conclusions: The preclinical data presented in this study suggests the potential of NTAX-44 to inhibit proliferation and, PD-L1 expression in MIA-Pa-Ca-2 cells and prevent angiogenesis in YSM. These properties along, with their good tolerability as indicated by cytocompatibility testing, are indicative of the potential role of NTAX-44 as an oral chemotherapeutic agent in the treatment of Pancreatic cancer. Though the preclinical studies performed on NTAX-44 are very promising but further clinical evaluation is warranted. Citation Format: Yogesh Bendale, Padma Shastri, Radha Poojari, Nandinee Khot, Surendra Nagare, Avinash Kadam. Anti-cancer activity of NTAX-44 (bioprocessed arsenic trioxide) on pancreatic cancer cell line [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-058.

Automated tumor proportion scoring for PD-L1 expression based on multistage ensemble strategy in non-small cell lung cancer

IntroductionProgrammed cell death ligand-1 (PD-L1) expression is a promising biomarker for identifying treatment related to non-small cell lung cancer (NSCLC). Automated image analysis served as an aided PD-L1 scoring tool for pathologists to reduce inter- and intrareader variability. We developed a novel automated tumor proportion scoring (TPS) algorithm, and evaluated the concordance of this image analysis algorithm with pathologist scores.MethodsWe included 230 NSCLC samples prepared and stained using the PD-L1(SP263) and PD-L1(22C3) antibodies separately. The scoring algorithm was based on regional segmentation and cellular detection. We used 30 PD-L1(SP263) slides for algorithm training and validation.ResultsOverall, 192 SP263 samples and 117 22C3 samples were amenable to image analysis scoring. Automated image analysis and pathologist scores were highly concordant [intraclass correlation coefficient (ICC) = 0.873 and 0.737]. Concordances at moderate and high cutoff values were better than at low cutoff values significantly. For SP263 and 22C3, the concordances in squamous cell carcinomas were better than adenocarcinomas (SP263 ICC = 0.884 vs 0.783; 22C3 ICC = 0.782 vs 0.500). In addition, our automated immune cell proportion scoring (IPS) scores achieved high positive correlation with the pathologists TPS scores.ConclusionsThe novel automated image analysis scoring algorithm permitted quantitative comparison with existing PD-L1 diagnostic assays and demonstrated effectiveness by combining cellular and regional information for image algorithm training. Meanwhile, the fact that concordances vary in different subtypes of NSCLC samples, which should be considered in algorithm development.

PD-1 antibody (Camrelizumab) for metastatic EBV positive gastric cancer: A prospective single-arm, open-label, phase 2 trial.

e16014 Background: Programmed cell death 1 (PD-1) inhibitors have been approved as third line therapy for patients with metastatic gastric cancer (mGC). Epstein–Barr virus (EBV)-positive is a potential predictor to response of PD-1 inhibitors. The aim of this study was to assess the efficacy and safety of camrelizumab as salvage treatment in metastatic EBV positive GC patients and explored the potential biomarkers associated with response (NCT03755440). Methods: In this prospective single-arm, phase II study, stage IV EBV positive GC patients received 200 mg camrelizumab by intravenous infusion every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR), which were based on RECIST V.1.1. Secondary endpoints were progression free survival (PFS), overall survival (OS), disease control rate (DCR), durationn of response (DoR), and toxicity. Exploratory analysis included association between response and tumor mutational burden (TMB) and cell death ligand-1 (PD-L1) expression. Results: According to Simon’s optimum two-stage design with α = 0.05 and β = 0.20. P0 = 15% (null hypothesis), the presence of at least 1 success in the 6 patients enrolled in the first stage allowed the trial to proceed to the second stage in which 13 more patients were needed to be enrolled for the minimum total of 20 patients (5% lost to follow-up calculated). Six eligible patients were enrolled at the first stage. All the patients were HER2 negative and pMMR. None of the patients had an objective response. The DCR was 66.7%. The median PFS was 2.2 months (95% CI: 1.5 months-not reached (NR)) and median OS was 6.8 months (95% CI: 1.7 months-NR). The most common treatment-related adverse event (TRAE) was reactive cutaneous capillary endothelial proliferation. No grade 3 or worse TRAEs were found. Only one patient had PD-L1 combined positive score (CPS) ≥1 but got disease progression. Three patients were TMB > 10Mb and two of them got stable disease while one got disease progression. Conclusions: EBV positive is not a good predictor for response to PD-1 inhibitors. Potential biomarkers are needed to identify EBVaGC patients who might respond to PD-1 inhibitors. Clinical trial information: NCT03755440.

Prognostic Value of Programmed Cell Death-Ligand 1 Expression in Tumor-Infiltrating Lymphocytes and Viral Load in Peripheral Blood Mononuclear Cells for Epstein-Barr Virus-Positive Nasopharyngeal Carcinoma.

Epstein-Barr virus (EBV) infection has a role in the development and progression of nasopharyngeal carcinoma (NPC); however, it is unclear whether EBV load correlates with tumor prognosis or the need for immunotherapy. This study evaluated whether the EBV DNA concentration in peripheral blood mononuclear cells (PBMC) or programmed cell death-ligand1 (PD-L1) expression in tumor-infiltrating lymphocytes (TIL) could predict the clinical outcomes of patients with NPC. Clinicopathological parameters of 198 patients with NPC were analyzed retrospectively from June 2012 to May 2018. Patients' EBV loads were determined by droplet digital PCR. TIL PD-L1 was analyzed by immunohistochemistry. A log value of 1.98 log IU/mL for PBMC EBV DNA and a percentage of PD-L1 expression of 15% in TILs marked distinguishing cutoffs in NPC prognosis. The 5-year progression-free survival (PFS) rates in patients with high vs low log (PBMC EBV DNA) were 68.2% and 93.1%, respectively (P = 0.002). The 5-year PFS rates in patients with high vs low TIL PD-L1 expression were 66.3% and 33.7%, respectively (P = 0.03). The 5-year PFS rates of the high-risk group (high log [PBMC EBV DNA] and low TIL PD-L1), low-risk group (low log [PBMC EBV DNA] and high TIL PD-L1), and those in between (intermediate group) were 0%, 91.9%, and 71.4%, respectively (P < 0.001). Concentrations of PBMC EBV DNA and TIL PD-L1 expression can be used as prognostic markers in NPC. The combination of both an increased EBV DNA concentration and suppressed TIL PD-L1 expression is associated with metastasis or relapse.

Evaluation of an online training tool for scoring programmed cell death ligand-1 (PD-L1) diagnostic tests for lung cancer

BackgroundNumerous studies indicate that higher tumour programmed cell death ligand-1 (PD-L1) expression is associated with greater response to anti-programmed cell death-1 (PD-1)/PD-L1 immunotherapy in non-small cell lung cancer (NSCLC). In the era of precision medicine, there is a need to provide reliable, standardised training for pathologists to improve their accuracy of interpretation and scoring, as the results are used directly to inform clinical decisions. Here we present findings regarding reader reproducibility of PD-L1 tumour cell (TC) staining scoring for NSCLC using a PD-L1 e-trainer tool as part of a PD-L1 immunohistochemistry reader training course.MethodsThe PD-L1 training course was developed based on the use of VENTANA PD-L1 (SP263) and Dako PD-L1 IHC PharmDx 22C3 stained NSCLC samples in combination with a PD-L1 e-trainer tool. Five-hundred formalin-fixed, paraffin-embedded archival samples were obtained from commercial sources and stained for PD-L1. Slides were scored by two expert pathologists, then scanned to produce digital images and re-scored. Thirty-three cases were selected and sorted into three sets: a training set and two self-assessment tests (pre-test and ‘competence’ test). Participants (all selected board-certified pathologists) received face-to-face training including use of an e-trainer tool. Statistical analyses were performed using the competence test set. Overall percentage agreement (OPA) was assessed between the participant pathologists’ registered scores and the reference scores assigned by expert pathologists at clinically relevant PD-L1 cut-offs (≥1%, ≥25% and ≥ 50%).ResultsSeven sessions were held and 69 participant pathologists completed the training. Inter-reader concordance indicated high OPA (85–95%) for PD-L1 TC scoring at clinically relevant cut-offs, with Fleiss’ Kappa > 0.5.ConclusionsUse of this web-based training tool incorporated into classroom-style training was associated with an overall moderately good level of inter-reader reproducibility at key cut-offs for TC PD-L1 expression testing in NSCLC. Overall, the online training tool offers a means of standardised training for practising pathologists in a clinical setting.

A Safety Study of Oral Venetoclax in Combination With Intravenous Pembrolizumab in Adult Participants With Previously Untreated Non-Small Cell Lung Cancer (NSCLC) With High Programmed Cell Death Ligand-1 (PD-L1) Expression

A Safety Study of Oral Venetoclax in Combination With Intravenous Pembrolizumab in Adult Participants With Previously Untreated Non-Small Cell Lung Cancer (NSCLC) With High Programmed Cell Death Ligand-1 (PD-L1) Expression

SUPREME-HN: a retrospective biomarker study assessing the prognostic value of PD-L1 expression in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck

BackgroundProgrammed cell death ligand-1 (PD-L1) expression on tumor cells (TCs) is associated with improved survival in patients with head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy, although its role as a prognostic factor is controversial. This study investigates whether tumoral expression of PD-L1 is a prognostic marker in patients with recurrent and/or metastatic (R/M) HNSCC treated with standard chemotherapy.MethodsThis retrospective, multicenter, noninterventional study assessed PD-L1 expression on archival R/M HNSCC tissue samples using the VENTANA PD-L1 (SP263) Assay. PD-L1 high was defined as PD-L1 staining of ≥ 25% TC, with exploratory scoring at TC ≥ 10% and TC ≥ 50%. The primary objective of this study was to estimate the prognostic value of PD-L1 status in terms of overall survival (OS) in patients with R/M HNSCC.Results412 patients (median age, 62.0 years; 79.9% male; 88.2% Caucasian) were included from 19 sites in seven countries. 132 patients (32.0%) had TC ≥ 25% PD-L1 expression; 199 patients (48.3%) and 85 patients (20.6%) had TC ≥ 10% and ≥ 50%, respectively. OS did not differ significantly across PD-L1 expression (at TC ≥ 25% cutoff median OS: 8.2 months vs TC < 25%, 10.1 months, P = 0.55) or the ≥ 10% and ≥ 50% cutoffs (at TC ≥ 10%, median OS: 9.6 months vs TC < 10%, 9.4 months, P = 0.32, and at TC ≥ 50%, median OS 7.9 vs TC < 50%, 10.0 months, P = 0.39, respectively).ConclusionsPD-L1 expression, assessed using the VENTANA PD-L1 (SP263) Assay, was not prognostic of OS in patients with R/M HNSCC treated with standard of care chemotherapies.Trial registration ClinicalTrials.gov, NCT02543476. Registered September 4, 2015.

Perforation of small intestinal metastasis of lung adenocarcinoma treated with pembrolizumab: a case report

BackgroundPembrolizumab is an immune checkpoint inhibitor and is an anti-human programmed cell death-1 (PD-1) monoclonal antibody. Pembrolizumab is used for non-small cell lung carcinoma with high programmed cell death ligand-1 (PD-L1) expression. It has been found that better overall survival can be obtained using pembrolizumab compared to the existing chemotherapy. We report a case of perforation of small intestinal metastasis after pembrolizumab treatment.Case presentationA 62-year-old man was treated by pembrolizumab for PD-L1 highly expressed lung adenocarcinoma, with multiple metastasis (small intestinal, lymph nodes, and bone). The treatment was stopped owing to drug-induced pneumonitis. One month after drug withdrawal, the patient visited the emergency department of our hospital with the complaint of severe stomachache. He had a rigid abdomen and generalized tenderness, and computed tomography scans showed free air within the abdomen. We diagnosed bowel perforation and performed emergency surgery. Surgical findings revealed multiple small intestine metastasis and mesenteric lymph node metastasis. Perforation was found in the metastatic site in the jejunum located around 40 cm anal to Treitz’s ligament. This perforated part was resected, and functional end-to-end anastomosis was performed using linear staplers. The post-operative course was uneventful. Pathological examination revealed lung adenocarcinoma metastasis at the perforation site, and the effectiveness of pembrolizumab was grade 1b (Japanese Classification of the Colorectal Carcinoma, seventh edition).ConclusionsThis is the first report of perforation of small intestinal metastasis of lung adenocarcinoma after pembrolizumab treatment. Because pembrolizumab causes some side effects, particularly autoimmune side effects, careful attention during treatment is warranted.

Abstract 3993: Programmed cell death ligand-1 (PD-L1) and CD8 expression profiling identifies an immunologic subtype of pancreatic ductal adenocarcinomas with favorable survival

Abstract Unselected cases of pancreatic adenocarcinoma (PDAC) have not shown clinical benefit from single agent immune checkpoint therapy, but a subset of PDAC are known to upregulate pathways involved in acquired immune suppression. Further delineation of immunologic subtypes of PDAC is key to smarter trial designs and progress toward improved immunotherapy strategies. To accomplish this, we first employed clinical survival and RNA expression data from 155 patients in The Cancer Genome Atlas (TCGA) to investigate the relationship between immune modulating checkpoints and immune subset marker, CD8A, and their impact on survival in PDAC patients. Among the markers explored, overexpression of PD-L1 (HR=2.55, p=0.001) and IDO1 (HR=2.24, p&amp;lt;0.01) were individually associated with poor survival. PD-L1 expression was not significantly associated with stage or tumor mutational burden of the PDACs. While CD8A expression alone was not correlated with survival, stratifying the analysis based on PD-L1 and CD8 expression identified a subtype characterized by low PD-L1 and high CD8A with favorable survival (p=0.004). Similarly, the combination of low IDO1 and high CD8A expression was associated with favorable survival (p=0.038). We further extended these observations using an independent PDAC cohort of 33 patients from our institution via immunohistochemistry, again observing that low PD-L1 / high CD8 subtype associates with positive prognosis (p=0.021). Although PDAC is regarded as a poorly immunogenic cancer type, these findings infer that baseline T cell infiltration into PDAC is a feature of long term survival and highlights the importance of developing future immunotherapeutic strategies based on data-supported biomarkers to refine patient selection. Citation Format: Won Jin Ho, Ludmila Danilova, Qingfeng Zhu, Teena Vithayathil, Ana De Jesus-Acosta, Nilo Azad, Daniel Laheru, Elana Fertig, Robert Anders, Elizabeth Jaffee, Mark Yarchoan. Programmed cell death ligand-1 (PD-L1) and CD8 expression profiling identifies an immunologic subtype of pancreatic ductal adenocarcinomas with favorable survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3993.

The prognostic value of toll-like receptor5 and programmed cell death-ligand1 in patients with peripheral T-cell non-Hodgkin lymphoma

TLR5 is expressed in a variety of tumors. However, the clinical impact of TLR5 in Peripheral T-cell non-Hodgkin lymphomas (PTCLs) remains unclear. We analyzed differentially expressed genes in PTCLs samples from Gene Expression Omnibus database. We examined TLR5 and programed cell death-ligand1 (PD-L1) expression by immunohistochemistry in PTCLs tissues. Gene expression profiling shown PD-L1 and TLR5 expression was higher in PTCLs than in normal samples. The rates of high TLR5 and PD-L1 expression were 12.5% and 45.8%. We found association between TLR5 and PD-L1 expression. Low TLR5 expression or high PD-L1 expression was correlated with shorter overall survival and inferior disease-free survival. Multivariate Cox regression analysis shown low TLR5 expression, high PD-L1 expression, gender, and high IPI score were prognostic factors (p < .05). PTCLs patients with low TLR5 expression and high PD-L1 expression had worse prognosis. TLR5 and PD-L1 may serve as potential therapeutic targets in PTCLs patients.

Evaluation of prognostic effects of MSI, PD-L1 and TIL in resected bladder cancer.

465 Background: The aim of the study was evaluating prognostic significance of tumor infiltrating lymphocytes (TIL), microsatellite instability (MSI) and programmed cell death ligand-1 (PD-L1) expression which are used as predictive biomarkers in immunotherapy. Methods: Clinic and pathologic features of bladder cancer patients who were underwent radical cystectomy were retrospectively analyzed from patients’ records in this single-center study. PD-L1, PD-L1 in TIL, PMS2, MSH2, MSH6 and MLH1 immunohistochemistry staining were carried out to archived resected tumor specimens of the eligible patients. MSI was evaluated according to existing of PMS2, MSH2, MSH6 and MLH1. Results: Fifty-six males (91.8%) and 5 females (8.2%) of total 61 patients were eligible for the study. Median age was 61.72 (35-81). PD-L1 expression in tumor cells and PD-L1 expression in TIL were positive in 14,8% (n = 9) and 16.4% (n = 10) of total 74 patients, respectively. MSI was high in 15 patients (24.6%). Intratumoral TIL rate was &lt; 10% in 49 patients (80.3%) while &gt; 10% in 12 patients. (19.7%) In Chi-square test, there was no statistically significant relationship between PD-L1, PD-L1 in TIL, MSI and TIL rate and patients’ characteristics including sex, stage, pathologic grade and lymph node status. Three-years overall survival (OS) rate was calculated as 43%. Univariate analysis did not reveal any significant difference in 3-years OS in PD-L1 expression in tumor, PD-L1 expression in TIL and TIL rate &gt; 10% . (p = 0.822, p = 0.638, p = 0.318; respectively ). There was a positive trend with MSI high patients and OS (p = 0.089). At also; age and stage showed statistically significant difference in multivariate analysis. (p = 0.023, p = 0.011, respectively). Conclusions: This study revealed that there is no prognostic significance of PD-L1 and TIL. However, there are positive trend between OS and MSI, which is proven as predictive biomarker of immunotherapy, in patients who were followed with same treatment and follow-up approach in single center. These results must be corroborated with large and prospective investigations in order to better understanding biology and behavior of bladder cancer.

Prognostic impact of programmed cell death ligand 1 expression on long-term oncologic outcomes in colorectal cancer.

The present study evaluated the association between programmed cell death ligand-1 (PD-L1) expression and long-term oncologic outcomes in colorectal cancer (CRC). PD-L1 expression was evaluated using immunohistochemistry in 175 patients who underwent surgical resection for CRC between September 1999 and August 2004. Patients were grouped according to PD-L1 expression, with 82 (46.9%) and 93 (53.1%) in the low and high PD-L1 expression groups, respectively. The overall survival (OS) and disease-free survival (DFS) rates were significantly better in the high expression group compared with in the low expression group (OS: 48.2 vs. 32.9%, P=0.047; DFS: 43.3 vs. 32.9%, P=0.021). According to the Tumor-Node-Metastasis stage subgroups, the OS rates in the low and high expression groups, respectively, were 66.7 and 60.0% in stage I (P=0.715), 51.8 and 46.7% in stage II (P=0.789), 19.6 and 51.1% in stage III (P=0.011) and 9.1 and 0% in stage IV (P=0.005). The DFS rates in the low and high expression groups, respectively, were 66.7 and 60.0% in stage I (P=0.715), 51.8 and 46.7% in stage II (P=0.857), 19.6 and 38.3% in stage III (P=0.006) and 9.1 and 0% in stage IV (P=0.700). The systemic recurrence rate was significantly higher in the low expression group compared with in the high expression group (42.7 vs. 12.9%, respectively, P=0.030). Low PD-L1 expression was significantly associated with tumor relapse and poor prognosis in stage III CRC.

Abstract 656: PD-L1 expression in primary lesions vs metastatic sites and by demographics in advanced urothelial carcinoma samples

Abstract Background: Determination of programmed cell death ligand-1 (PD-L1) expression levels in tumors may help physicians understand which patients (pts) are most likely to respond to anti-PD-1/PD-L1 therapies in urothelial carcinoma (UC). Understanding the impact of different sample types and demographics on PD-L1 expression is important to determine suitability of tumor biopsies for testing. Methods: As of July 24, 2016, 363 pts screened in the UC cohort of Study CD-ON-MEDI4736-1108 (NCT01693562) had tissue available for analysis and 47 pts had provided paired primary and metastatic samples. FFPE samples were tested in a central laboratory with the VENTANA PD-L1 (SP263) Assay using a BenchMark ULTRA instrument. Pts were classified as having either PD-L1 high (PD-L1 expression ≥25% either on tumour cells [TC] or immune cells [IC]) or PD-L1 low/negative (&amp;lt;25% on TC and IC) tumors. PD-L1 high prevalence was reported in primary vs metastatic sites, and by age, sex and race. Results: PD-L1 status was evaluable for 332/363 (91.5%) pts (175/332 [52.7%] PD-L1 high and 157/332 [47.3%] PD-L1 low/negative) whose UC specimens were tested (intent to diagnose [ITD] population). Overall percentage agreement between paired primary and metastatic samples, based on combined TC/IC scoring ≥25%, was 74.5% (95% CI 59.7 - 86.1%). In the ITD population, using only the samples from which patient PD-L1 expression status was determined, PD-L1 high prevalence in primary and metastatic samples was 57.1% and 50.9% respectively (p=0.343, not significant). The proportion of pts with PD-L1 high status was not enriched in any demographic group (Table). Conclusions: Initial data from UC pts in Study 1108 showed similar PD-L1 high prevalence in primary and metastatic lesions and good concordance between paired primary and metastatic samples. These results build optimism that samples obtained from either location could be used to determine PD-L1 status. Further data are needed to confirm these findings. Patients screened for UC cohort with evaluable PD-L1 result - ITD population (n = 332)ParameterPD-L1 high, n (%)P valueAge, years&amp;lt;65 (n=131)73 (55.7%)0.438≥65 (n=201)102 (50.8%)SexMale (n=236)127 (53.8%)0.610Female (n=96)48 (50.0%)RaceAsian (n=52)23 (44.2%)Asian vs White: 0.406Black or African American (n=10)6 (60.0%)White (n=218)113 (51.8%)Other (n=9)4 (44.4%) Citation Format: M Zajac, A M. Boothman, Y Ben, A Gupta, X Jin, J Antal, A Sharpe, M Scott, M Rebelatto, J Walker. PD-L1 expression in primary lesions vs metastatic sites and by demographics in advanced urothelial carcinoma samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 656. doi:10.1158/1538-7445.AM2017-656

Retrospective review of safety and efficacy of checkpoint inhibition in refractory high-grade gliomas.

2033 Background: Treatment options for refractory high grade gliomas (HGG) are limited. Programmed cell death ligand-1 (PD-L1) expression has been reported in 0-61% of HGGs and therefore might be a suitable target in HGG. The purpose of this study was to describe safety and efficacy of PD-1 inhibition in patients with refractory HGGs. Methods: This IRB approved single center retrospective study at Memorial Sloan Kettering Cancer Center included pathologically confirmed HGG with an age ≥18 years who received a PD-1 inhibitor between 9/2014 and 10/2016 outside of a clinical trial. Results: Twenty five HGGs were identified. All patients received the PD-1 inhibitor pembrolizumab (pembro) as part of compassionate use. Median age was 49 years (range 30-72); 44% were men; 13 had glioblastoma (52%), 7 anaplastic astrocytoma (28%), 2 anaplastic oligodendroglioma (8%), 2 unspecified HGG (8%), and 1 gliosarcoma (4%). Patients received a median of 4 prior lines of therapy (range 1-9). Nineteen (76%) previously failed bevacizumab. Median baseline KPS was 80 (range 50-100). Concurrent treatment included bevacizumab in 17 (68%) or bevacizumab and temozolomide in 2 (8%) patients. Median number of doses administered was 3 (range 1-14). Treatment toxicity and response was assessed in 24 patients. PD-1 inhibitor related adverse events (AEs) included LFT elevations (33%), hypothyroidism (17%), diarrhea (17%), myalgias/arthralgias (13%), and rash (8%). Other common AEs were hyperglycemia, fatigue, thrombocytopenia, lymphopenia, headache, and nausea in the setting of concomitant therapy and additional supportive care (dexamethasone). Grade 3 AEs included seizure (4%), headache (4%), nausea (4%), and vomiting (4%). Best radiographic response was partial response (n = 2), stable disease (n = 5), and progressive disease (n = 17). Median progression free survival (PFS) was 42 days (range 7-282) and median overall survival was 121 days (range 15-415). Three patients (12%) had a PFS &gt; 90 days; of these, 2 received single agent pembro. Conclusions: Patients with HGG had low response rates. However, a small number of patients had prolonged PFS. Pembro was tolerated with few serious AEs, even in patients receiving concomitant therapy.

Abstract P6-07-05: PD-L1 expression and decreased tumor-infiltrating lymphocytes are associated with poor prognosis in patients with triple negative breast cancer

Abstract Background: Tumor microenvironment has been considered to have an active role in determining the aggressiveness of tumor cells. Recently, programmed cell death ligand-1 (PD-L1) expression or tumor-infiltrating lymphocytes (TILs) are known to be an important prognostic factor of breast cancer. However, the correlation of expression of PD-L1 and TILs still remains unclear. Triple-negative breast cancer (TNBC) is a heterogeneous tumor that encompasses many different subclasses. Further identification of these subclasses is necessary in order to predict prognosis and choose appropriate treatments. Our goal was to correlate PD-L1 expression with clinicopathological features including TILs by using a large cohort of TNBCs. Patients and Methods: This study included 248 patients with primary TNBC who underwent resection without neoadjuvant chemotherapy at our three hospitals between January 2004 and December 2014. The tumor subtypes were routinely determined immunohistochemically by using resected specimens. IHC scoring for PD-L1 expression was defined in reference to that for HER2 expression. PD-L1 positivity was defined as both IHC 2+ and IHC 3+. Cases were defined as high if stromal TILs ≥50% according to recommendations by the International TILs Working Group. Results: Of the 248 TNBCs, PD-L1 were expressed as positive in 103 (41.5%) tumors, and TILs were highly present in 118 (47.6%) tumors. PD-L1 expression was significantly correlated with higher levels of TILs (P &amp;lt; 0.0001). There was no significant difference when the prognosis of the patients who had PD-L1-positive tumors was compared with that of the patients who had PD-L1-negative tumors (P = 0.56 in recurrence free survival [RFS] and P = 0.13 in overall survival [OS]). Meanwhile, the patients with high-TILs tumors had longer OS, compared to the patients with low-TILs tumors (P = 0.55 in RFS and P = 0.016 in OS). The analysis in the cross effect between PD-L1 expression and TILs using cox proportional hazards model demonstrated that the PD-L1 expression and TILs are not independent factors(P = 0.0018 in RFS and P = 0.015 in OS). The PD-L1-positive group with low-TILs had significantly shorter survival than the PD-L1-positive group with high-TILs (hazard ratio [HR] = 4.7, 95% confidence interval [CI] 1.6–12.7, P = 0.0067 in RFS; HR = 8.4, 95%CI 2.3-30.3, P = 0.0019 in OS). Conclusions: Our data indicated that PD-L1 expression was related to higher levels of TILs, and PD-L1-positive tumors with low-TILs were associated with poor prognosis in patients with TNBCs. It is proposed that these biomarkers may be of use for predicting their prognosis and essential in the subclassification of TNBCs. Citation Format: Mori H, Kubo M, Yamaguti R, Nishimura R, Osako T, Arima N, Okumura Y, Okido M, Yamada M, Kai M, Kishimoto J, Oda Y, Nakamura M. PD-L1 expression and decreased tumor-infiltrating lymphocytes are associated with poor prognosis in patients with triple negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-05.

Abstract P4-09-15: BRCAness and PD-L1 expression of basal-like and not basal-like triple negative breast cancer

Abstract Background: Triple Negative Breast Cancer (TNBC) subtype occurs in approximately 20% of all patients with breast cancer and is associated with rapid growth, early metastasis and poor prognosis compared with other subtypes. TNBCs are a heterogeneous disease entity and further subclassification is needed, but still ongoing. In this study, we assessed BRCAness, defined as shared characteristics between sporadic and BRCA1-mutated tumors, in a cohort of basal-like and non-basal-like TNBCs. Patients and Methods: DNA was isolated from formalin-fixed paraffin-embedded tumor tissues and BRCAness status was analyzed in 262 patients with primary TNBCs resected at our three hospitals between 2004 and 2014. Classification of BRCAness was performed by using Multiple Ligation-dependent Probe Amplification (MLPA) with the probemix P376 BRCA1ness by MRC (Amsterdam, Holland). The tumor subtypes were routinely determined immunohistochemically by using resected specimens. Basal-like phenotype was defined as being positive for Epidermal Growth Factor Receptor (EGFR) and/or Cytokeratin 5/6 (CK5/6). Moreover, TNBCs were stained and analyzed for programmed cell death ligand-1 (PD-L1) expression as a target of new immune therapies. Results: Of 262 TNBCs, 232 tumors (88.5%) was a basal-like phenotype. The results of MLPA assay showed that 159 (68.5%) of 232 tumors had a BRCAness profile. Patients with basal-like BRCAness tumors were younger than patients with basal-like non-BRCAness tumors (p&amp;lt;0.0001). There was no significant difference between the two groups regarding pathological stage. The basal-like BRCAness group had shorter relapse-free survival (RFS) and overall survival (OS) than the basal-like non-BRCAness group (p=0.028 and p=0.13, respectively), and anthracycline-based regimens provided greater benefit to the basal-like BRCAness group significantly (p=0.01 in RFS and p=0.007 in OS). PD-L1 was expressed in 71 (44.7%) of 159 basal-like TNBCs with BRCAness. Conclusion: We reported the majority of basal-like TNBCs showed a BRCAness profile and PD-L1 expressed in approximately 50% of BRCAness tumors. It is known that about 30% of BRCAness tumors are BRCA1-mutated tumors. Those biomarkers are essential for subclassification of TNBCs and may offer not only platinum-based chemotherapy but also novel therapies, such as immune-targeted therapies of PD-1/PD-L1 inhibitors and PARP inhibitors, to patients with basal-like TNBCs with BRCAness. Citation Format: Mori H, Kubo M, Yamada M, Kai M, Osako T, Nishimura R, Arima N, Okido M, Kuroki S, Oda Y, Nakamura M. BRCAness and PD-L1 expression of basal-like and not basal-like triple negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-15.