Positive PD-L1 Expression Research Articles

CLINICOPATHOLOGICAL CHARACTERISTICS OF INVASIVE BREAST CARCINOMA ON PDL-1 IMMUNOHISTOCHEMICAL EXPRESSION IN H. ADAM MALIK HOSPITAL MEDAN

Abstract
 Background: Immune biologic markers that can predict clinical response to anti-PD-1/PD-L1 therapy are needed to identify and validate tumor immunotherapy studies. High PD-L1 expression is associated with increased clinical response in patients with various types of cancer treated with inhibitors of the PD-1/PD-L1 pathway. The researcher wanted to see the clinicopathological characteristics of invasive breast carcinoma according to the immunohistochemical expression of PD-L1.
 Methods: This study is a descriptive study with a cross-sectional, retrospective approach by looking at secondary data from the medical records of the Department of Surgery, Oncology Division, Haji Adam Malik Hospital from January 1, 2019, to December 31, 2021.
 Results: Immunohistochemical expression of PD-L1 was positive in 76.6% of invasive breast carcinomas and negative in 23.3% of invasive breast carcinomas. Immunohistochemical expression of PD-L1 was positive in non-specific IBCs that predominated in every molecular subgroup of breast carcinoma.
 Discussion: Tumours can show positive or negative PD-L1 expression through several biological processes with different functional significance, namely the genetic mechanism of constitutive or oncogene-induced PD-L1 expression, PD-L1 expression induced in T cells, and absence of PD-L1 expression. Due to the absence of T cells and genetic events that block the expression of PD-L1 despite T cell infiltration.

Adjuvant immunotherapy in renal cell carcinoma: A systematic review and meta-analysis of randomized clinical trials.

671 Background: There has been interest in adjuvant immune checkpoint inhibition (ICI) following surgical resection in patients with high-risk renal cell carcinoma (RCC) given high recurrence rates and approvals of ICI in metastatic RCC. The primary objective of this analysis was to synthesize available data regarding the disease-free survival (DFS) benefit of adjuvant ICIs for patients with RCC. Methods: This systematic review was performed according to the PRISMA guidelines. The protocol was registered in PROSPERO (CRD42022361599). We searched PubMed, EMBASE, and relevant conference proceedings to identify phase III randomized controlled trials (RCTs) comparing adjuvant ICI versus placebo/observation. The primary outcome of interest was DFS. Results: Among the four included studies, one demonstrated a significant DFS benefit. There was considerable clinical and statistical heterogeneity (I2=64%) due to differences in inclusion criteria and interventions. While pooled results across the four studies did not demonstrate a significant benefit in DFS overall (HR 0.85, 95% CI 0.69-1.04), there was significant benefit among patients with positive PD-L1 expression (HR 0.72, 95% CI 0.55-0.94) or sarcomatoid features (HR 0.59, 95% CI 0.38-0.91). Conclusions: The evidence base to date regarding ICI as adjuvant therapy in RCC is mixed – conclusions are limited by considerable heterogeneity between studies. However, pooled analyses suggest that patients with positive PDL1 expression or sarcomatoid features are most likely to benefit from adjuvant immunotherapy.

PD-L1 immunohistochemistry assay optimization to provide more comprehensive pathological information in classic Hodgkin lymphoma

Overexpression of PD-L1 can be a predictive marker for anti-PD-1 therapeutic efficacy in classic Hodgkin lymphoma (CHL); however, harmonization of different IHC assays remains to be accomplished, and interpretations of PD-L1 immunostaining results remain controversial in CHL. In this study, we sought to optimize the PD-L1 immunohistochemistry (IHC) assay in CHL. All tests were performed on a tumour tissue microarray established from 54 CHL cases. Three IHC antibodies (405.9A11, SP142, 22C3) for detecting PD-L1 expression were compared semi quantitatively with the RNAscope assay (No. 310035, ACD), and the difference in the expression in background immune cells (ICs) between assays and the associations of expression levels with densities of TILs/TAMs were also analysed. 405.9A11 demonstrated best specificity in HRS cells and best sensitivity in ICs. Positive expression of PD-L1 was more frequent in ICs (85.2%) than in HRS cells (48.1%). Different subgroups of background ICs, including tumour-associated macrophages (TAMs), were assessed and scored for CD4, CD8, FOXP3, and CD163 expression. PD-L1 expression on ICs was the factor most associated with the density of TAMs. 405.9A11 provided the most convincing PD-L1 expression results. Pathologists should report PD-L1 expression in a combined manner, including both the status of HRS cells and the percentage of PD-L1-positive ICs.

Positive Correlation between PMS2 Deficiency and PD-L1 Expression in Pancreatic Cancer

Background: Pancreatic cancer is one of the most lethal types of cancer, and immunotherapy has become a promising remedy with advancements in tumor immunology. However, predicting the clinical response to immunotherapy in pancreatic cancer remains a dilemma for clinicians. Methods: GEPIA database was used to analyze the differential expression of MMR and PD-L1 genes in 33 common cancer types including pancreatic cancer. The expression levels of MMR and PD-L1 genes were downloaded from the GEPIA and GEO databases to analyze the correlation between MMR genes and PD-L1, and the clinicopathological and survival information were downloaded from the TCGA databases to analyze the relationship between the expression of MMR, PD-L1 and clinicopathological characteristics, prognosis. Meanwhile, the tumor tissue samples of 41 patients with pancreatic cancer were collected, and the protein expression levels of MMR and PD-L1 were detected by immunohistochemical assay. Furthermore, we analyzed the correlation between MMR and PD-L1, and the correlation between the expression of MMR, PD-L1 and clinicopathological characteristics, prognosis of pancreatic cancer patients. Results: Bioinformatics analysis showed that MLH1, MLH3, MSH2, MSH3, and PMS2 were highly expressed in most cancer types including pancreatic cancer (P P = 0.012), clinical stage (I vs II: P = 0.016), MSH2 expression was related to clinical stage (P P = 0.039), and MSH3 expression was related to T stage (P P P = 0.044) were significantly associated with prognosis. GEPIA data also showed that MSH2 expression was related to prognosis (P = 0.008). The correlation analysis revealed that the expressions MSH2, MLH1, PMS2 had strong correlations with PD-L1 both in GEPIA and GEO databases. Real-world data indicated that of the 41 pancreatic cancer patients, 5 cases had MLH1 deletion, 5 cases had MSH2 deletion, 4 cases had PMS2 deletion, and 12 cases had PD-L1 positive expression. Notably, PMS2 deletion was associated with PD-L1 positive expression (P = 0.035). In addition, MLH1 was related to clinical stage (P = 0.033), age (P = 0.048), and MSH2 was related to clinical stage (P = 0.033). However, MLH1 (P = 0.697), MSH2 (P = 0.956), PMS2 (P = 0.341), and PD-L1 (P = 0.734) appeared to have no impact on overall survival among patients with pancreatic cancer. Conclusion: Both bioinformatics and real-world data showed that there were correlation between PMS2 deletion and PD-L1 expression, and correlation between MLH1, MSH2 and clinical stage.

Prognostic Significance of Immune-checkpoint Molecule PD-L1 in Classical Hodgkin Lymphoma: A Clinicopathologic Study of 120 Cases.

Classic Hodgkin lymphoma (cHL) is a common B-cell malignancy. Despite the good prognosis, in some patients the standard chemotherapy and radiotherapy-based approach does not lead to long-term remission, and these patients eventually relapse. Moreover, the primary refractory disease is of major concern regarding prognosis. We performed a retrospective analysis to evaluate PD-L1 expression in 120 patients with classic Hodgkin lymphoma (cHL). The median follow-up of the entire group of patients was 90 months. After initial therapy, complete remission was achieved in 113 (94.2%) patients. During the follow-up, cHL relapse/refractory disease was reported in 23 (19.2%) cases. A total of five patients died during the follow-up period, all from cHL progression. When determining PD-L1 expression on Hodgkin-Reed-Sternberg (HRS) cells, 37 cases (30.8%) were evaluated as negative, and 83 cases (69.2%) as positive. In the negative PD-L1 group of patients, no cHL relapse/refractory disease was observed during the follow-up period. However, out of 83 patients with positive PD-L1 expression on HRS cells, 23 (28%) showed relapse/refractory cHL. A significantly higher relapse rate was observed in PD-L1-positive patients diagnosed with cHL.

PD-L1 expression-related PI3K pathway correlates with immunotherapy efficacy in gastric cancer.

The programed death ligand-1 combined positive score (PD-L1 CPS), the only FDA-approved biomarker for immune checkpoint inhibitor therapy in gastric cancer (GC) patients, is an important but imperfect predictive biomarker. The molecular characteristics of tumors that influence the PD-L1 CPS are largely unknown and would be helpful for screening patients who would benefit from immunotherapy. PD-L1 immunohistochemistry (IHC) and targeted next-generation sequencing techniques were used to compare genomic alterations in 492 GC patients in two groups (PD-L1 CPS ⩾ 1, positive; CPS < 1, negative). Screened PD-L1 expression-related factors were analyzed for immunotherapy efficacy in three distinct GC cohorts from public databases. Positive PD-L1 expression occurred in 40% of GC patients and was associated with a higher proportion of phosphatidylinositol 3-kinase (PI3K), SWItch/Sucrose NonFermentable (SWI/SNF), lysine demethylase (KDM), and DNA (cytosine-5)-methyltransferase (DNMT) (all p < 0.01), pathway alterations. Compared to wild-type GC patients, those with PI3K pathway alterations had a higher response rate (p = 0.002) and durable clinical benefit rate with immunotherapy (p = 0.023, p = 0.038) as well as longer progression-free survival (p = 0.084, p = 0.0076) and overall survival (p = 0.2, p = 0.037) with immunotherapy. This study revealed PD-L1 expression-related factors in the tumor genome in a GC cohort. Alterations in the PI3K pathway associated with PD-L1 positivity were shown to be associated with better immunotherapy efficacy in three distinct GC cohorts from public databases. Our results provide a potential avenue for patient selection and rational immune combination development for GC patients.

Expression of PD-L1 in Lung Carcinoma and Its Correlation with Histopathological Grade, Stage, and Survival of Patients.

Objective PD-L1, a 40 kDa type 1 transmembrane protein, suppresses the adaptive arm of the immune system. The interaction of PD-1 with the ligand PD-L1 inhibits cytokine production and plays a role in the progression of lung cancer. The present study was performed to observe the expression of PD-L1 in lung carcinoma patients and its correlation with histopathological grade, stage, and survival of patients. Materials and Methods This prospective study included all new cases of lung carcinoma diagnosed on histopathological or cytopathological examination over a period of 1 year. PD-L1 immunoexpression was statistically analyzed and graded according to the Tumor Proportion Score in all cases and correlated with histopathological grade, stage, and survival of patients. Results This study included 56 cases of lung carcinoma with 64.2% cases showing PD-L1 positivity, out of which 44.6% were non-small cell and 19.6% were small cell lung carcinoma. In all, 32.1% cases with lymphovascular invasion, 53.5% with necrosis, and 37.5% cases with greater than 5/10 HPF mitotic figures showed positive PD-L1 expression. Paired cell blocks and histopathology showed 70% concordance for PD-L1 expression. 16.1% cT3N1M0 cases and 25% stage IIIA cases showed PD-L1 positivity. In all, 60.7% patients with positive PD-L1 expression did not survive for 12 months following diagnosis. Conclusion PD-L1 immunoexpression was increased in lung carcinoma cases and was associated with poor histomorphological features including lymphovascular invasion, necrosis, and increased mitotic activity. PD-L1 correlated with cases having decreased 12-month survival and stage IIIA carcinoma. Thus, it may be useful in the stratification of patients who benefit from the PD-L1 targeted therapy.

Efficacy and Safety of the PD-1 Inhibitor Combined with Albumin-Bound Paclitaxel and Nedaplatin in Preoperative Neoadjuvant Therapy of Unresectable Stage III Lung Squamous Cell Carcinoma.

To investigate the efficacy and safety of preoperative neoadjuvant therapy (PD-1 inhibitor plus nab-PTX and nedaplatin) for resectable stage III lung squamous cell carcinoma (SCC) patients. Patients with locally advanced lung SCC (stage IIIA, IIIB) who received PD-1 inhibitor combined with nab-PTX and NED between February 2019 and June 2021 in Weihai Municipal Hospital were included and underwent surgical treatment 4 weeks after 2-4 cycles neoadjuvant therapy. The rate of resection R0, the effective rate, the complete pathological remission rate (pCR) and the rate of major pathological remission (MPR) were observed. A total of 14 initially unresectable male patients with lung SCC were included and received neoadjuvant treatment after evaluation. Nine out of 14 patients (64.3%) experienced treatment-related adverse events (TRAE), among which 8 (57.1%) experienced grade (G) I-II TRAEs including nausea, vomiting, fatigue, constipation, elevated ALT and AST, hyperthyroidism, hypothyroidism, rash, granulocytopenia, and thrombocytopenia, and 1 (7.1%) experienced grade III-V TRAEs (G), including granulocytopenia and atelectasis. Thirteen patients (92.86%) achieved RECIST-assessed partial remission (PR), while 1 patient (7.14%) achieved stable disease (SD) on imaging assessment after neoadjuvant treatment and continued to be progression-free for 26 months. Of the 11 patients who underwent resection, all were alive and recurrence/progression-free. MPR and pCR were observed in 2 (18.18%) and 9 (81.82%), respectively. IHC results exhibited that all NSCLC patients exhibited positive PD-L1 expression (9/14, TPS ≥50% or greater; 5/14, 1% < TPS < 50%). Two were negative for ALK, EGFR, and ros-1, and the rest were not examined for driver oncogene mutation. The neoadjuvant therapy of the PD-1 inhibitor combined with nab-PTX and NED demonstrated remarkable therapeutic efficacy and good safety on stage III lung SCC without increasing the risk of TRAE, mortality and surgery-related complications, or impede surgery feasibility.

Preliminary Analysis of Concurrent Programmed Cell Death-1 Inhibitor Combination with Chemoradiation for Recurrent/Metastatic Nasopharyngeal Carcinoma Patients: A Phase II Study

<h3>Purpose/Objective(s)</h3> programmed cell death-1 (PD-1) inhibitors has been recommended as the first-line treatment for recurrent/metastatic nasopharyngeal carcinoma (R/M NPC), but progression-free survival (PFS) and overall survival (OS) was still unsatisfactory. Basic studies have already confirmed PD-1 inhibitors had concurrent synergistic effect with chemotherapy and radiotherapy. Few studies concerned about the treatment pattern for concurrent PD-1 inhibitors combination with chemoradiation for R/M NPC. There was still much uncertainty about the timing, fraction dose and total dose for PD-1 inhibitors combination with radiation. Therefore, we aimed to explore the substantial effect and toxicity of this new pattern for R/M NPC. <h3>Materials/Methods</h3> We prospectively enrolled 42 R/M NPC patients from August 2018 to May 2021 in out institution. All the patients received concurrent PD-1 inhibitor combination with chemoradiation, and followed with maintenance of PD-1 inhibitors, and we analyzed PD-L1 expression by 22C3 kit. Objective response rate (ORR) and disease control rate (DCR) were calculated by irRECIST 1.1. CTCAE-5.0 was used to evaluate the toxicity and Kaplan-Meier method was used to analyze survival rate. <h3>Results</h3> The median age was 48 years old (range 25-81), the median follow up time was 16.5 months (range 2-62). Nine patients had recurrent disease, 33 patients had metastatic disease, and 3 patients had both recurrence and metastasis disease. The median numbers of metastatic sites were 3 (range 1-7), and the most common metastatic sites were lung and liver. All the recurrent and measurable metastatic lesions were treated with radiotherapy. 9 recurrent patients received a median radiation dose of 60Gy. The measurable metastatic lesions received a median radiation dose of 54Gy. The median cycles of cisplatin-based chemotherapy were 5. Median time of PD-1 inhibitor was 9.5 months. At 3 months after the completion of chemoradiation, ORR and DCR were 90.5% and 100% respectively. The median PFS was 18 months, with 6 and 12 months PFS rates were 90.2% and 70.7%. 1 and 2-years OS rates were 94.6% and 86.2%, and the median OS had not reached. For the PD-L1 expression, 24 patients were positive, 18 were negative. The median PFS was 20.7 and 16.5 months for positive and negative group, respectively (p=0.01). Most common G3-4 toxicities were leucopenia (45.2%), anemia (38.1%), anorexia (7.1%), and fatigue (7.1%). There was no G3-4 toxicity for pneumonia, and no G5 toxicity was observed. <h3>Conclusion</h3> This new treatment pattern of concurrent PD-1 inhibitors combination with chemoradiation shows a promising efficacy and tolerable toxicity for R/M NPC. The patients with positive PD-L1 expression had better survival outcome than negative group. Keywords: PD-1 inhibitors, concurrent, recurrent, metastatic, nasopharyngeal carcinoma, chemoradiation

PD-1/PD-L1 inhibitors for advanced or metastatic cervical cancer: From bench to bed.

Advanced or metastatic cervical cancer has a poor prognosis, and the 5-year overall survival is <5% with conventional radiotherapy and chemotherapy. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), achieved initial success in advanced solid tumors, while their efficacy and safety in advanced or metastatic cervical cancer remains to be explored. Previous studies found high-risk HPV infection and elevated PD-L1 expression in cervical precancerous lesions and squamous cell carcinoma. Meanwhile, elevated PD-L1 expression, high cytotoxic T lymphocyte infiltration, and abnormal cytotoxic T lymphocyte function might benefit inflammation infiltration for ICIs in the tumor microenvironment. Patients with HPV infection, squamous cell carcinoma, advanced stage, large tumor size, poor differentiation, metastatic disease, history of multiple childbirth and abortion, or a previous history of receiving chemotherapy might be associated with positive PD-L1 expression. Although there is no correlation between PD-L1 expression and prognosis using conventional radiotherapy, patients with high PD-L1 expression have a poorer prognosis. Several clinical studies demonstrate preliminary safety and efficacy for PD-1/PD-L1 inhibitors, and the exploration of combination strategies such as immunotherapy combined with chemotherapy, radiotherapy, anti-angiogenesis therapy, or dual ICIs is ongoing. This paper systematically reviews PD-L1 expression patterns and their relationship with prognosis, along with reported and ongoing clinical trials of PD-1/PD-L1 inhibitors in cervical cancer to clarify the prospect of ICIs for cervical cancer from bench to bed.

S1760 Metastatic Cervical Squamous Cell Carcinoma of the Distal Bile Duct

Introduction: Squamous cell carcinoma (SCC) of the bile duct is sporadic. Most cases are primary. Only 2 cases of cervical SCC metastatic to the bile ducts have been reported. Consideration of this diagnosis is essential in patients who have a history of malignancy and present with symptoms of biliary obstruction. Case Description/Methods: A 63-year-old female presented with persistent abdominal pain, nausea, and vomiting. Mild abdominal tenderness and scleral icterus were noted on physical examination. Bilirubin, AST, and ALT were elevated. Magnetic resonance cholangiopancreatography (MRCP) revealed dilated intra- and extra-hepatic bile ducts; however, there was no evidence of an apparent mass or gallstones. A lesion was observed at the ampullary level measuring around 1 cm that was brushed and biopsied on endoscopic cholangiopancreatography (ERCP). A metal stent was placed for decompression in the common bile duct. Pathology revealed poorly differentiated SCC with an immune profile favoring metastasis from the gynecologic tract. The patient was diagnosed with SCC of the cervix 15 months prior to presentation. A biopsy of the cervical tissue showed poorly differentiated cervical SCC with positivity in CK7 and HMWK, scattered positive staining of vimentin. Chemo-radiation was initiated with Cisplatin, Paclitaxel, and Bevacizumab. Next-generation sequencing (NGS) showed an immunohistochemical profile consistent with gynecological cancers, namely, MLH1, PMS2, MSH2, and MSH6. Pembrolizumab was also started due to positive PDL-1 expression and mutations in ATM and KMT2D. These agents were continued after she underwent the biliary decompression. Discussion: Metastatic SCC of the biliary tract is rare. Due to its low incidence, there is no standardized treatment strategy; however, there are reported cases of surgical resection in addition to chemoradiotherapy. Very few cases of cervical SCC have been reported to spread to gastrointestinal organs. NGS is a modality that has been widely implemented. The combination of immunohistology staining and NGS can aid in the diagnosis and help guide chemotherapy. The genetic variations present a valuable tool to aim the treatment of cervical cancer. While survival rates for patients with cervical carcinoma have improved, treatment remains difficult as not enough cases exist to compare treatment modalities. Limited knowledge is present regarding managing extra-hepatic duct squamous cell carcinoma since it is rare.

Correlation between PD-L1 expression and radiomic features in early-stage lung adenocarcinomas manifesting as ground-glass nodules.

BackgroundImmunotherapy might be a promising auxiliary or alternative systemic treatment for early-stage lung adenocarcinomas manifesting as ground-glass nodules (GGNs). This study intended to investigate the PD-L1 expression in these patients, and to explore the non-invasive prediction model of PD-L1 expression based on radiomics.MethodsWe retrospectively analyzed the PD-L1 expression of patients with postoperative pathological diagnosis of lung adenocarcinomas and with imaging manifestation of GGNs, and divided patients into positive group and negative group according to whether PD-L1 expression ≥1%. Then, CT-based radiomic features were extracted semi-automatically, and feature dimensions were reduced by univariate analysis and LASSO in the randomly selected training cohort (70%). Finally, we used logistic regression algorithm to establish the radiomic models and the clinical-radiomic combined models for PD-L1 expression prediction, and evaluated the prediction efficiency of the models with the receiver operating characteristic (ROC) curves.ResultsA total of 839 “GGN-like lung adenocarcinoma” patients were included, of which 226 (26.9%) showed positive PD-L1 expression. 779 radiomic features were extracted, and 9 of them were found to be highly corelated with PD-L1 expression. The area under the curve (AUC) values of the radiomic models were 0.653 and 0.583 in the training cohort and test cohort respectively. After adding clinically significant and statistically significant clinical features, the efficacy of the combined model was slightly improved, and the AUC values were 0.693 and 0.598 respectively.ConclusionsGGN-like lung adenocarcinoma had a fairly high positive PD-L1 expression rate. Radiomics was a hopeful noninvasive method for predicting PD-L1 expression, with better predictive efficacy in combination with clinical features.

Consistent expression of PD-L1 in tumor microenvironment with peripheral PD-1/PD-L1 in circulating T lymphocytes of operable breast cancer: a diagnostic test

BackgroundThe expression of PD-L1 in the immune microenvironment can guide the application of immunosuppressants. In order to monitor the immune status of the body, repeated biopsies have to be taken. Our research aims to find new and convenient means to evaluate this indicator.MethodsEighty-three cases of newly diagnosed operable breast cancer without receiving preoperative treatment, were recruited from Beijing Shijitan Hospital between November 2018 and November 2019. The expression of PD-1/PD-L1 on circulating T lymphocytes was detected by flow cytometry and the expression of PD-L1 on immune cells in tumor microenvironment was detected by immunohistochemistry.ResultsThe median percentage of positive PD-1 and PD-L1 expression on circulating T lymphocytes was 15.2% and 0.7%, respectively. The peripheral PD-1 had no relationship with clinicopathological characteristics, but the peripheral PD-L1 expression had a correlation with lymph node metastasis (p = 0.005) and Her-2 expression (p = 0.034) (p < 0.05). The positive rate of PD-L1 expression was 32.9% in tumor microenvironment. PD-L1 expression in tumor microenvironment had a significant correlation with PD-1/PD-L1 expression on circulating T lymphocytes, the correlation coefficients being 0.24 (p < 0.05) and 0.26 (p < 0.05), respectively. To predict the PD-L1 expression in tumor microenvironment, the area under the receiver operating characteristic curve was 0.65 and 0.66 for peripheral PD-1 and PD-L1, respectively. High level of peripheral PD-1/PD-L1 expression was associated with the odds ratios of 5.42 and 4.76 for positive PD-L1 expression in tumor microenvironment.ConclusionPeripheral PD-1/PD-L1 expression had a significant consistency with PD-L1 expression in tumor microenvironment and could act as an alternative choice of tissue detection, for the patients intolerable of biopsy.

PD-1/PD-L1 inhibitors in treatment-naïve, advanced non-small cell lung cancer patients with < 1% PD-L1 expression: a meta-analysis of randomized controlled trials.

PD-1/PD-L1 inhibitors prolong survival in treatment-naïve, locally advanced, and metastatic non-small cell lung cancer (NSCLC) with positive PD-L1 expression (> 1%/ > 50%). Recent evidence has suggested that tumors with < 1% PD-L1 expression may also be predictive of PD-1/PD-L1 inhibiting agents. Systematic review and meta-analysis were conducted of randomized controlled trials (RCTs) evaluating PD-1/PD-L1 inhibitors that have assessed tumors with < 1% PD-L1 expression (negative PD-L1 expression). PD-1/PD-L1 inhibitors-chemotherapy combinations (PC) were compared with histology-selected chemotherapy with respect to overall survival (OS) and progression-free survival (PFS). Twelve RCTs comprising 5410 participants (PD-1/PD-L1 inhibitors-chemotherapy: 3051; chemotherapy: 2359) met the inclusion criteria. Tumors with PD-L1 expression < 1% were evident in 38.9% of the pooled study population. A significant OS [hazard ratio (HR) 0.71 95% confidence interval (CI) 0.63-0.80, p < 0.00001] and PFS [HR 0.65 95% CI 0.58-0.72, p < 0.00001] benefit of PC was evident in tumors with negative PD-L1 expression. PD-1/PD-L1 inhibitors-chemotherapy combinations were more likely to achieve an objective response than chemotherapy [odds ratio, 1.86; 95% CI, 1.46-2.38, p < 0.00001]. Histologic subtypes and diagnostic assays did not modify the OS and PFS treatment effects for PC compared to chemotherapy. Tumors harboring < 1% PD-L1 expression are likely to benefit from PD-1/PD-L1 inhibitor-chemotherapy regimens in advanced NSCLC.

Expression of PD1 and PDL1 as immune-checkpoint inhibitors in mantle cell lymphoma

BackgroundMantle cell lymphoma (MCL) has remained incurable in most patients. The expression of PD-L1 as a prognostic and predictive marker has not been fully evaluated in MCL. The current study aimed to determine PD-1/PD-L1 expression in MCL specimens and its significance as an immune check point inhibitor.MethodsThis retrospective study was conducted on the formalin-fixed paraffin-embedded blocks of 79 confirmed MCL patients based on immunohistochemistry (IHC). The IHC method was used to stain patient samples for PD1 and PDL1. Positive PD-1/PD-L1 expression was defined as moderate to strong or memberanous or memberanous/cytoplasmic staining in at least 5% of tumor and/or 20% of associated immune cells. Tumor aggressiveness was determined based on Ki67 and variant.ResultsThe mean age of the patients was 60.08 ± 10.78 years old. Majority of the patients were male. The prevalence of aggressive tumor was 25%. Positive PD1 and PDL1 expression were identified in 12 (15.0%) and 3 (3.8%) of tumor cells, respectively. PD1 and PDL1 were positive in zero (0%) and 7 (8.9%) of background cells, respectively. There was no significant difference in terms of study parameters between positive and negative groups for both PD1 and PDL1 proteins. PD1 tumor cell percentage was negatively correlated with age (r = -0.254, p = 0.046).ConclusionOur results suggest that neither PD-1 nor its ligands represent relevant targets for MCL treatment. Age may impact the efficiency of immune checkpoint inhibitors and could be related to the increased incidence of MCL with age.

Genomic landscape, immune characteristics, and a prognostic mutation signature of advanced cervical cancer in China (162)

Objectives: This study aimed to analyze genomic alteration profiles and immune characteristics of a cohort of Chinese advanced cervical cancer patients to understand why certain patients benefited from molecular targeted therapies, immunotherapy, and their prognostic significance. Methods: PD-L1 expression and clinical-pathologic information from 98 cervical cancer samples were obtained. Cervical cancer data were obtained from The Cancer Genome Atlas (TCGA). Differences in PD-L1 expression and gene mutations between squamous cell carcinoma (SCC) and adenocarcinoma (AC) were analyzed using the Chi-square test or Fisher’s exact test. Differences in gene mutations between our cohort and TCGA cohort were tested by Fisher’s exact test. The relationship between gene mutation and TMB was analyzed by the Mann-Whitney U test. Logistic regression was used to analyze factors influencing TMB-high. Kaplan-Meier survival analyses were applied. Results: Positive PD-L1 expression was significantly higher in cervical SCC than in cervical AC (87% vs 39%, p < 0.001). Frequently mutated genes in cervical cancer included PIK3CA, KMT2D, and KMT2C genes, among others. PIK3CA gene mutation rates were significantly higher in SCC than in AC (p = 0.004). TERT gene mutation rate was significantly higher in our cohort than TCGA cohort (12% vs 1%, p < 0.001). SCC had a significantly higher TMB than AC (p < 0.001). The independent predictors of TMB-high were KMT2C and LRP1B gene mutations (p <0.05). In this study, the median progression-free survival (PFS) was 12.16 months in the PTEN mutant group versus 21.75 months in the wild-type group (p=0.0024). Conclusions: Cervical SCC and AC have different molecular profiling and immune characteristics, suggesting that targeted treatments for SCC and AC patients may improve clinical outcomes. KMT2C and LRP1B gene mutations are independent predictors of TMB-high status in cervical cancer. We have also proposed the prognostic value of PTEN mutation. Objectives: This study aimed to analyze genomic alteration profiles and immune characteristics of a cohort of Chinese advanced cervical cancer patients to understand why certain patients benefited from molecular targeted therapies, immunotherapy, and their prognostic significance. Methods: PD-L1 expression and clinical-pathologic information from 98 cervical cancer samples were obtained. Cervical cancer data were obtained from The Cancer Genome Atlas (TCGA). Differences in PD-L1 expression and gene mutations between squamous cell carcinoma (SCC) and adenocarcinoma (AC) were analyzed using the Chi-square test or Fisher’s exact test. Differences in gene mutations between our cohort and TCGA cohort were tested by Fisher’s exact test. The relationship between gene mutation and TMB was analyzed by the Mann-Whitney U test. Logistic regression was used to analyze factors influencing TMB-high. Kaplan-Meier survival analyses were applied. Results: Positive PD-L1 expression was significantly higher in cervical SCC than in cervical AC (87% vs 39%, p < 0.001). Frequently mutated genes in cervical cancer included PIK3CA, KMT2D, and KMT2C genes, among others. PIK3CA gene mutation rates were significantly higher in SCC than in AC (p = 0.004). TERT gene mutation rate was significantly higher in our cohort than TCGA cohort (12% vs 1%, p < 0.001). SCC had a significantly higher TMB than AC (p < 0.001). The independent predictors of TMB-high were KMT2C and LRP1B gene mutations (p <0.05). In this study, the median progression-free survival (PFS) was 12.16 months in the PTEN mutant group versus 21.75 months in the wild-type group (p=0.0024). Conclusions: Cervical SCC and AC have different molecular profiling and immune characteristics, suggesting that targeted treatments for SCC and AC patients may improve clinical outcomes. KMT2C and LRP1B gene mutations are independent predictors of TMB-high status in cervical cancer. We have also proposed the prognostic value of PTEN mutation.

PVR/TIGIT and PD-L1/PD-1 expression predicts survival and enlightens combined immunotherapy in lung squamous cell carcinoma

PVR/TIGIT and PD-L1/PD-1 axes play essential roles in tumor immune evasion and could be potential targets for combined immunotherapy. We aimed to evaluate the expression status of the above-mentioned immune markers in lung squamous cell carcinoma (LUSC), and investigate their survival impact and relevance with the immune microenvironment and clinicopathological features. We retrospectively collected specimens from 190 LUSC patients, who underwent pulmonary surgeries, and we performed immunohistochemistry assays of PVR, TIGIT, PD-L1, PD-1 and CD8. In our cohort, the positive rate of PVR was 85.8%, which was much higher than the positive rate of PD-L1 at 26.8%. A total of 32 (16.8%) patients demonstrated co-expression of PVR/PD-L1. High TIGIT density was correlated with positive PD-L1 expression, high PD-1 density, and high CD8 density (PD-L1, P=0.033; PD-1, P<0.001; CD8, P<0.001), and positive PVR expression was correlated with positive PD-L1 expression (P=0.046). High TIGIT density and high PVR/TIGIT expression were correlated with advanced TNM stage (TIGIT density, P=0.020; PVR/TIGIT expression, P=0.041). Patients with positive PVR expression, high TIGIT density, high PVR/TIGIT expression and PVR/PD-L1 co-expression exhibited a significantly worse prognosis (PVR, P=0.038; TIGIT, P=0.027; PVR/TIGIT, P=0.014; PVR/PD-L1, P=0.018). Multivariate analysis demonstrated that PVR/PD-L1 co-expression (Hazard ratio [HR], 1.756, 95% CI, 1.152-2.676, P=0.009) was an independent prognostic factor in LUSC patients. In conclusion, we demonstrated the expression status of PVR/TIGIT and PD-L1/PD-1 in LUSC. PVR/PD-L1 co-expression was an independent prognostic factor in LUSC patients and may serve as a potential predictive biomarker for dual-targeting immunotherapy.

Efficacy and safety of serplulimab (an anti-PD-1 antibody) combined with albumin-bound paclitaxel in patients with advanced cervical cancer who have progressive disease or intolerable toxicity after first-line standard chemotherapy (074)

<b>Objectives:</b> Limited effective treatments are available for advanced cervical cancer patients who have failed first-line chemotherapy. Historical data indicate that PD-1 antibodies and albumin-bound paclitaxel monotherapy have certain antitumor activity (ORR: 14.3% for pembrolizumab and 28.6% for albumin-bound paclitaxel) in recurrent/advanced cervical cancer patients. This study aimed to determine the efficacy and safety of serplulimab (a recombinant humanized anti-PD-1 monoclonal antibody) plus albumin-bound paclitaxel in patients with advanced cervical cancer who have progressed on or are intolerant to first-line standard chemotherapy. <b>Methods:</b> This is an ongoing, single-arm, open-label, multi-center phase II study (NCT04150575). Twenty eligible patients aged between 18 and 75 years, who had ECGO PS 0 or 1, with histologically or cytologically diagnosed cervical cancer and positive PD-L1 expression (combined positive score [CPS] ≥1) were planned to be enrolled and given intravenous infusions of serplulimab (4.5 mg/kg) plus albumin-bound paclitaxel (260 mg/m²) every three weeks. The primary endpoints of this study were the adverse events, serious adverse events, and ORR (assessed by independent radiological review committee [IRRC] per RECIST v1.1). After all patients completed two tumor evaluations (every six weeks), a safety evaluation and a preliminary evaluation of antitumor efficacy were conducted. <b>Results:</b> By cut-off date July 15, 2021, 21 eligible patients were enrolled with a median age of 50.8 years (range: 31-64) and an average CPS of 39.3 (1 ≤CPS <20: <i>n</i>=7 [33.3%], CPS ≥20: <i>n</i>=14 [66.7%]). The median follow-up duration was 12.5 months; 71.4% patients had ECOG PS 1. The ORR assessed by IRRC and investigators were 57.1% (<i>n</i>=12; 95% CI: 34.0%-78.2%) and 47.6% (<i>n</i>=10; 95% CI: 25.7%-70.2%), respectively. The disease control rate (DCR) assessed by IRRC and investigators were both 76.2% (<i>n</i>=16; 95% CI: 52.8%-91.8%). The median PFS assessed by IRRC was 5.7 months (95% CI: 3.0-not reached). The median OS was not reached (95% CI: 10.5 months-not reached). The most common grade 3 or worse treatment-emergent adverse events (TEAEs) were decreased neutrophil count (<i>n</i>=7, 33.3%), decreased white blood cell count (<i>n</i>=6, 28.6%) and anemia (<i>n</i>=5, 23.8%). The most common immune-related adverse events (irAEs) were hypothyroidism (<i>n</i>=6, 28.6%), hyperthyroidism (<i>n</i>=3, 14.3%) and pruritus (<i>n</i>=3, 14.3%), all of which were grade 1 to 2. No TEAEs leading to drug discontinuation were observed. <b>Conclusions:</b> The results demonstrated a manageable safety profile and encouraging efficacy (IRRC-ORR: 57.1%) of serplulimab plus albumin-bound paclitaxel in advanced cervical cancer patients who have progressive disease or intolerable toxicity to first-line standard chemotherapy, representing a novel potential treatment option that warranted further investigation.

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

The combination of gemcitabine-based chemotherapy and immune checkpoint inhibitors has a good efficacy in advanced biliary tract cancer (BTC). The multi-target TKI lenvatinib and NGS-guided targeted therapy are also promising in BTC treatment. This study aimed to explore the performance of GemOX plus sintilimab and TKI (either lenvatinib or by NGS-guided targeted therapy) for local advanced or metastatic BTCs. This prospective single-arm study included patients with local advanced or metastatic BTCs and applied intravenous infusion of standard GemOX plus sintilimab and lenvatinib (no targetable gene alterations) or targeted therapy based on NGS (olaparib for BRCA1/2 mutation, dasatinib for IDH1/2 mutation, afatinib for EGFR amplification, lenvatinib for PDGFR and KIT mutation, and lenvatinib for FGFR/KIT mutation). From November 2020 to December 2021, 22 patients BTCs (6 GBC, 14 iCCA, 1 pCCA and 1 dCCA cases) were enrolled, with an average age of 58.4years. 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%. 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 targeted therapy and there were 1 SD and 4 PR cases. For four patients with positive PD-L1 expression, the ORR was 100%. While among the three patients with super-progression markers such as RET, MDM2 and FGF14/STK24, there were two SD and one PD cases. 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.

SFRP4 Is a Potential Biomarker for the Prognosis and Immunotherapy for Gastric Cancer.

Purpose Secreted frizzled-related protein 4 (SFRP4) is a member of the SFRP family, which functions as either a tumor suppressor or a prooncogenic factor in distinct tumor types. Our research aimed to explore the expression of SFRP4 in gastric cancer, its prognostic significance, and its relationship with immune cell infiltration. Materials and Methods Gastric cancer and paracancerous tissue specimens from surgically resected gastric cancer patients were collected to construct tissue microarrays, and immunohistochemistry was used to detect the expression of SFRP4, PD-L1, CD3+T, CD4+T, and CD8+T in these microarrays. The differential expression of SFRP4 and its relationship with the immune microenvironment were evaluated using the TIMER and TISIDB databases. Finally, patient survival was assessed. Results SFRP4 expression was elevated in gastric cancer tissues and linked to a poor prognosis (P=0.021). The 5-year survival rate for patients with high SFRP4 expression was only 39.81% but reached 60.02% for patients with low SFRP4 expression. Increased SFRP4 expression correlated with high CD8+ T-cell infiltration (P=0.015) and positive PD-L1 expression (P=0.036). High SFRP4 expression was an independent predictor of overall survival (P=0.024 in univariable analysis, P=0.011 in multivariable analysis). Using online databases, we found that SFRP4 expression was higher in gastric cancer tissues and substantially was associated with the immune microenvironment. Conclusion SFRP4 is an oncogenic driver that can predict patient survival time in gastric cancer, as well as an important immune-related factor. SFRP4 may be important for guiding immunotherapy in gastric cancer patients.