Programmed Cell Death Ligand 1 Therapy Research Articles

A Mesoporous Gold Sensor Unveils Phospho PD-L1 in Extracellular Vesicles as a Proxy for PD-L1 Expression in Lung Cancer Tissue.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death ligand 1 (PD-L1), or its receptor, PD-1 have improved survival in patients with non-small-cell lung cancer (NSCLC). Assessment of PD-L1 expression requires tissue biopsy or fine needle aspiration that are currently used to identify patients most likely to respond to single agent anti-PD-1/PD-L1 therapy. However, obtaining sufficient tissue to generate a PD-L1 tissue proportion score (TPS) ≥ 50% using immunohistochemistry remains a challenge that potentially may be overcome by liquid biopsies. This study utilized a mesoporous gold sensor (MGS) assay to examine the phosphorylation status of PD-L1 in plasma extracellular vesicles (EV pPD-L1) and PD-L1 levels in plasma from NSCLC patient samples and their association with tumor PD-L1 TPS. The 3-dimensional mesoporous network of the electrodes provides a large surface area, high signal-to-noise ratio, and a superior electro-conductive framework, thereby significantly improving the detection sensitivity of PD-L1 nanosensing. Test (n = 20) (Pearson's r = 0.99) and validation (n = 45) (Pearson's r = 0.99) cohorts show that EV pPD-L1 status correlates linearly with the tumor PD-L1 TPS assessed by immunohistochemistry irrespective of the tumor stage, with 64% of patients overall showing detectable EV pPD-L1 levels in plasma. In contrast to the EV pPD-L1 results, plasma PD-L1 levels did not correlate with the tumor PD-L1 TPS score or EV pPD-L1 levels. These data demonstrate that EV pPD-L1 levels may be used to select patients for appropriate PD-1 and PD-L1 ICI therapy regimens in early, locally advanced, and advanced NSCLC and should be tested further in randomized controlled trials. Most importantly, the assay used has a less than 24h turnaround time, facilitating adoption of the test into the routine diagnostic evaluation of patients prior to therapy.

Abstract PO1-13-09: Programmed cell death ligand 1 (PD-L1) is constitutively expressed on tumorspheres cultured from circulating cancer stem cells in breast cancer patients

Abstract Background Circulating cancer cells, and in particular their very rare subpopulation, circulating cancer stem cells (cCSCs), are responsible for recurrence and metastasis. The exact role of cCSCs in escape of cancer from immunosurveillance is still unknown, but recent studies revealed that enhanced PDL-1 expression in cancer stem cells is a novel mechanism to promoting cancer cell immune evasion and could crucially contribute to the maintenance of CSC self-renewal. Understanding the mechanisms behind this PDL-1 overexpression in cancer stem cells is critical for developing more effective anti-PD-1/PD-L1 therapy. Therefore the aim of the study was to determine the number of tumorspheres and expression of PD-L1 on tumorspheres cultured from cCSC in breast cancer patients. Methods: 110 patients with breast cancer in different stages of disease were included in this study. The determination of circulating cancer stem cells was performed using the sphere-forming assay. Additionally anti-PDL-1 antibody staining was applied to examine PDL-1 expression on breast tumorspheres. Results: We have developed an innovative in vitro platform for detection of cCSCs from peripheral blood of cancer patients. The number of tumorspheres increased significantly with tumor progression and aggressiveness of primary tumor. Patients with metastatic disease had statistically more tumorspheres as compared to patients without metastasis (30 vs 10/100µl blood, p< 0.05). Patients with multiple metastasis had more tumorspheres compared to patients with single metastases (60 vs 30/100µl blood, p< 0.05). The number of tumorspheres was positively correlated with Ki-67, Her2 status and grade score in primary breast tumors. We observed high PDL-1 expression and their considerable heterogeneity in enriched tumorspheres. Conclusion: The number of tumorspheres cultured from peripheral blood directly reflects aggressiveness and proliferation capacity of primary tumor. The presence of tumorspheres with expression of PDL-1 might suggest their immunomodulating potential. Better understanding of the interaction between cCSCs and tumor immunology may help to identify strategies to eradicate the minor subpopulation that escapes conventional therapy attack, thus providing a solution to the problem of drug resistance and metastasis. Citation Format: Monika PIZON, Dorothea Schott, Ulrich Pachmann, Katharina Pachmann. Programmed cell death ligand 1 (PD-L1) is constitutively expressed on tumorspheres cultured from circulating cancer stem cells in breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-13-09.

A Phase I Trial of Atezolizumab and Varlilumab in Combination With Radiation in Patients With Metastatic NSCLC

IntroductionAnti-programmed cell death ligand 1immunotherapy is the standard of care for metastatic NSCLC but many tumors develop resistance. We hypothesized that combining a T-cell agonist such as varlilumab (anti-CD27 antibody) with checkpoint inhibition may be synergistic and this synergy may be potentiated further by using targeted radiation (RT). MethodsWe conducted an open-label, single-center, phase I trial (NCT04081688) to determine the safety and clinical benefit of the atezolizumab and varlilumab in combination with palliative RT in patients with advanced or metastatic NSCLC with progression on prior programmed cell death ligand 1therapy. On day 1 of each 21-day cycle, patients received varlilumab followed by atezolizumab on day 2. RT to a lung lesion was administered between cycle 1 and cycle 2. ResultsA total of 15 patients were enrolled (one patient did not start treatment). The median age was 64 years; 10 patients were female. Eight patients (57%) had at least one treatment-related adverse event (AE) and 7 (50%) had at least one grade III or worse treatment-related AE. There was only one grade III immune-related AE requiring steroids (1 diarrhea or colitis); there were no treatment-related deaths. Of the 12 patients evaluable for efficacy, three patients had stable disease (2 with stable disease > 4 mo) and the clinical benefit rate was 25%. The median progression-free survival was two months and the median overall survival was 6.4 months. ConclusionsVarlilumab in combination with atezolizumab and RT was safe and well tolerated; no additional signal was identified for toxicity. Clinical activity for the combination was modest with 25% of patients with stable disease as the best response.

Tumor-derived exosomal PD-L1: a new perspective in PD-1/PD-L1 therapy for lung cancer.

Exosomes play a crucial role in facilitating intercellular communication within organisms. Emerging evidence indicates that a distinct variant of programmed cell death ligand-1 (PD-L1), found on the surface of exosomes, may be responsible for orchestrating systemic immunosuppression that counteracts the efficacy of anti-programmed death-1 (PD-1) checkpoint therapy. Specifically, the presence of PD-L1 on exosomes enables them to selectively target PD-1 on the surface of CD8+ T cells, leading to T cell apoptosis and impeding T cell activation or proliferation. This mechanism allows tumor cells to evade immune pressure during the effector stage. Furthermore, the quantification of exosomal PD-L1 has the potential to serve as an indicator of the dynamic interplay between tumors and immune cells, thereby suggesting the promising utility of exosomes as biomarkers for both cancer diagnosis and PD-1/PD-L1 inhibitor therapy. The emergence of exosomal PD-L1 inhibitors as a viable approach for anti-tumor treatment has garnered significant attention. Depleting exosomal PD-L1 may serve as an effective adjunct therapy to mitigate systemic immunosuppression. This review aims to elucidate recent insights into the role of exosomal PD-L1 in the field of immune oncology, emphasizing its potential as a diagnostic, prognostic, and therapeutic tool in lung cancer.

Correlation Between ImageJ and Conventional Manual Scoring Methods for Programmed Death-Ligand 1 Immuno-Histochemically Stained Sections.

Background: One of the most frequently used methods for quantifying PD-L1 (programmed cell death-ligand 1) expression in tumor tissue is IHC (immunohistochemistry). This may predict the patient's response to anti-PD1/PD-L1 therapy in cancer. Methods: ImageJ software was used to score IHC-stained sections for PD-L1 and compare the results with the conventional manual method. Results: In diffuse large B cell lymphoma, no significant difference between the scores obtained by the conventional method and ImageJ scores obtained using the option "RGB" or "Brightness/Contrast." On the other hand, a significant difference was found between the conventional and HSB scoring methods. ImageJ faced some challenges in analyzing head and neck squamous cell carcinoma tissues because of tissue heterogenicity. A significant difference was found between the conventional and ImageJ scores using HSB or RGB but not with the "Brightness/Contrast" option. Scores obtained by ImageJ analysis after taking images using 20 × objective lens gave significantly higher readings compared to 40 × magnification. A significant difference between camera-captured images' scores and scanner whole slide images' scores was observed. Conclusion: ImageJ can be used to score homogeneous tissues. In the case of highly heterogeneous tissues, it is advised to use the conventional method rather than ImageJ scoring.

Trial in Progress: Phase 1 Trial Evaluating the Safety and Tolerability of Odronextamab in Combination with Cemiplimab in Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

Background and Significance CD20×CD3 bispecific antibodies (bsAbs) have emerged as an important immunotherapeutic approach for relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). These agents have shown compelling efficacy in indolent B-NHL, with the CD20×CD3 bsAb odronextamab demonstrating 75% complete response (CR) rates and encouraging durability of responses (median duration of response [DoR], 20.5 months) in heavily pretreated patients with R/R follicular lymphoma in the ELM-2 study (Kim TM, et al. ASH. 2022). In comparison, patients with R/R diffuse large B-cell lymphoma who were treated with odronextamab in the same study demonstrated a CR rate of 31%, and median DoR was 10.2 months (Kim WS, et al. ASH. 2022). These data indicate an unmet need for treatment strategies that can improve the depth and durability of responses in patients with aggressive R/R B-NHL. Combination therapy with drugs that complement the mechanism of action of CD20×CD3 bsAbs may provide an opportunity to address this unmet need. Cemiplimab is a human immunoglobulin G4 (IgG4) monoclonal antibody directed against programmed cell death protein 1 (PD-1), blocking PD-1- and programmed cell death ligand 1 (PD-L1)-driven inhibitory T-cell signaling. Combining odronextamab and cemiplimab provides an attractive therapeutic opportunity to improve anti-tumor efficacy while restricting T-cell exhaustion, and preliminary results for this combination provided proof of concept, with evidence of clinical activity and manageable tolerability in patients with B-lymphoid malignancies (n=12; Topp MS, et al. ASH. 2017). Here, we investigate whether the addition of cemiplimab to odronextamab can improve the depth and durability of response in patients with previously treated aggressive B-NHL. Study Design and Methods This is a Phase 1, open-label, multicenter, dose-escalation and -expansion study that will take place at up to 28 sites globally (NCT02651662). Intravenous (IV) odronextamab is administered in 21-day cycles, initially as monotherapy and with step-up dosing during Cycle (C) 1 to mitigate the risk of cytokine release syndrome (Figure). Full-dose odronextamab is administered on Day (D) 1, D8 and D15 of C2-C4, and then on D15 of each cycle during maintenance (C5 onwards) until disease progression or treatment discontinuation. IV cemiplimab starts on C2D15 at the specified dose level (DL1-DL7) and is administered on D15 of subsequent cycles. The dose-limiting toxicity (DLT) period is 28 days from the start of cemiplimab administration. At the end of dose escalation, a regimen will be selected for further investigation in dose expansion. Approximately 60 patients will be enrolled. Patients will be aged ≥18 years with aggressive CD20+ B-NHL that is R/R after ≥2 lines of systemic therapy containing an anti-CD20 antibody and an alkylating agent. Patients must have measurable disease, Eastern Cooperative Oncology Group performance score (ECOG PS) ≤1, and adequate bone marrow and organ function. Exclusion criteria include primary central nervous system lymphoma, prior allogeneic stem cell transplantation, autoimmune disease, prior adverse events from anti-PD-1/PD-L1 therapy, and uncontrolled infections. Primary endpoints are safety, tolerability, DLTs, and to determine the recommended Phase 2 dose of the combination regimen of odronextamab and cemiplimab. Secondary endpoints include pharmacokinetics, immunogenicity, and preliminary anti-tumor activity (overall response rate, CR rate, and DoR, according to the Lugano classification). There are no formal hypotheses for this study and analyses will be descriptive in nature.

Programmed cell death ligand-1 (PD-L1) expression in desmoid tumors: a retrospective study.

Desmoid tumor is a rare benign but locally aggressive monoclonal and fibroblastic proliferation. It lacks metastatic potential but is associated with a high local recurrence after surgery. It is either characterized by the Beta-catenin gene (CTNNB1) or the adenomatous polyposis coli gene (APC) mutation. The most appropriate treatment approach is watchful waiting with periodic follow-ups for asymptomatic patients. However, symptomatic patients who are not good candidates for surgery due to high morbidity risk may benefit from medical therapy. The new drugs targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) display promising results in many cancer types. This study assessed the PD-L1 status of desmoid tumors in 18 patients.Biopsy and resection materials of 18 patients diagnosed with desmoid tumors between April 2016 and April 2021 were retrieved and assessed for PD-L1 expression. The prepared slides were immunohistochemically stained with PD-L1 antibody using Leica Bond® automated immunohistochemistry stainer.No positive PD-L1 staining of the desmoid tumor cells was detected in any specimens. Intratumoral lymphocytes were present in all specimens. However, five of them were positively stained for PD-L1.Based on the results of our study, anti-PD-1/PD-L1 therapy may not be a valuable option in desmoid tumor treatment due to the lack of expression of PD-L1 by desmoid tumor cells. Nevertheless, the presence of positively stained intratumoral lymphocytes may warrant further studies.

Immunotherapy Targeting PD-1/PD-L1 in Early-Stage Triple-Negative Breast Cancer.

The advent of immunotherapy, especially immune checkpoint inhibitors (ICIs), has revolutionized antitumor therapy. Programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are among the most promising targets for encouraging the immune system to eliminate cancer cells. PD-1/PD-L1 have made clinical remission for numerous solid tumors, including metastatic triple-negative breast cancer (TNBC). In recent years, integrating PD-1/PD-L1 inhibitors into existing treatments in early-stage TNBC has attracted wide attention. Herein, we summarize the clinical benefit of PD-1/PD-L1 inhibitors plus neoadjuvant chemotherapy, adjuvant chemotherapy, and targeted therapy in early-stage TNBC. Possible immunotherapy biomarkers, immune-related adverse events (irAEs), and the key challenges faced in TNBC anti-PD-1/PD-L1 therapy are also concluded. Numerous studies on immunotherapy are ongoing, and PD-1/PD-L1 inhibitors have demonstrated great clinical prospects in early-stage TNBC. To maximize the efficacy of anti-PD-1/PD-L1 therapy, further research into the challenges which still exist is necessary.

Predictive value of serum high-mobility group box 1 levels for checkpoint inhibitor pneumonitis.

Checkpoint inhibitor pneumonitis (CIP), caused by the anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) antibody, can be a fatal adverse event in cancer patients. However, no predictive biomarkers for CIP have been identified. Because high-mobility group box 1 (HMGB1) can aggravate lung injury and potentially increase the immune response, it was investigated as a predictive blood marker. Blood samples, prospectively stored before anti-PD-1/PD-L1 monotherapy between December 2015 and October 2020, were obtained at two university hospitals from 87 and 43 non-small cell lung cancer (NSCLC) patients (discovery and validation cohorts, respectively). We retrospectively evaluated the association of serum HMGB1 levels with the incidence of CIP developed within 3months of initiating anti-PD-1/PD-L1 therapy. CIP was observed in 9 (10.3%) and 6 (14.0%) patients in the discovery and validation cohorts, respectively. In each cohort, serum HMGB1 levels were significantly and reproducibly higher in patients with CIP. In the discovery cohort, an HMGB1 cut-off level of 11.24 ng/ml was identified by receiver operating characteristic analysis. CIP incidence in the HMGB1high subgroup was significantly higher than that in the HMGB1low subgroup in the discovery (41.2% vs. 2.9%) and validation cohorts (36.4% vs. 6.3%). In an exploratory pooled analysis, three patients died of grade 5 CIP; a 19.29 ng/ml HMGB1 cut-off level detected grade 5 CIP with 100% sensitivity and 96.85% specificity. Our results suggest that HMGB1 may be a potential blood marker to predict the development and severity of CIP in NSCLC patients.

Development of an automated combined positive score prediction pipeline using artificial intelligence on multiplexed immunofluorescence images

Immunotherapy targeting immune checkpoint proteins, such as programmed cell death ligand 1 (PD-L1), has shown impressive outcomes in many clinical trials but only 20%–40% of patients benefit from it. Utilizing Combined Positive Score (CPS) to evaluate PD-L1 expression in tumour biopsies to identify patients with the highest likelihood of responsiveness to anti-PD-1/PD-L1 therapy has been approved by the Food and Drug Administration for several solid tumour types. Current CPS workflow requires a pathologist to manually score the two-colour PD-L1 chromogenic immunohistochemistry image. Multiplex immunofluorescence (mIF) imaging reveals the expression of an increased number of immune markers in tumour biopsies and has been used extensively in immunotherapy research. Recent rapid progress of Artificial Intelligence (AI)-based imaging analysis, particularly Deep Learning, provides cost effective and high-quality solutions to healthcare. In this article, we propose an imaging pipeline that utilizes three-colour mIF images (DAPI, PD-L1, and Pan-cytokeratin) as input and predicts the CPS using AI techniques. Our novel pipeline is composed of three modules employing algorithms of image processing, machine learning, and deep learning techniques. The first module of quality check (QC) detects and removes the image regions contaminated with sectioning and staining artefacts. The QC module ensures that only image regions free of the three common artefacts are used for downstream analysis. The second module of nuclear segmentation uses deep learning to segment and count nuclei in the DAPI images wherein our specialized method can accurately separate touching nuclei. The third module of cell phenotyping calculates CPS by identifying and counting PD-L1 positive cells and tumour cells. These modules are data-efficient and require only few manual annotations for training purposes. Using tumour biopsies from a clinical trial, we found that the CPS from the AI-based models shows a high Spearman correlation (78%, p = 0.003) to the pathologist-scored CPS.

Research Progress of Anti-PD-1/PD-L1 Therapy for Non-small Cell Lung Cancer with EGFR Mutation

The use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the first line treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC), but drug resistance will be acquired within 1-2 years, and the following treatment efficacy is poor. The invention of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors has dramatically changed the situation of tumor treatment. PD-1/PD-L1 inhibitors are less effective in patients with NSCLC harboring EGFR mutation. It is a challenge to make patients with EGFR-mutated advanced NSCLC benefit from anti-PD-1/PD-L1 therapy. In this paper, the research progress on the impact of EGFR mutation on the immune status of NSCLC and related clinical studies in recent 5 years are reviewed. .

From rough to precise: PD-L1 evaluation for predicting the efficacy of PD-1/PD-L1 blockades.

Developing biomarkers for accurately predicting the efficacy of immune checkpoint inhibitor (ICI) therapies is conducive to avoiding unwanted side effects and economic burden. At the moment, the quantification of programmed cell death ligand 1 (PD-L1) in tumor tissues is clinically used as one of the combined diagnostic assays of response to anti-PD-1/PD-L1 therapy. However, the current assays for evaluating PD-L1 remain imperfect. Recent studies are promoting the methodologies of PD-L1 evaluation from rough to precise. Standardization of PD-L1 immunohistochemistry tests is being promoted by using optimized reagents, platforms, and cutoff values. Combining novel in vivo probes with PET or SPECT will probably be of benefit to map the spatio-temporal heterogeneity of PD-L1 expression. The dynamic change of PD-L1 in the circulatory system can also be realized by liquid biopsy. Consider PD-L1 expressed on non-tumor (immune and non-immune) cells, and optimized combination detection indexes are further improving the accuracy of PD-L1 in predicting the efficacy of ICIs. The combinations of artificial intelligence with novel technologies are conducive to the intelligence of PD-L1 as a predictive biomarker. In this review, we will provide an overview of the recent progress in this rapidly growing area and discuss the clinical and technical challenges.

Engineered nanomedicines block the PD-1/PD-L1 axis for potentiated cancer immunotherapy.

Immunotherapy, in particular immune checkpoint blockade (ICB) therapy targeting the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis, has remarkably revolutionized cancer treatment in the clinic. Anti-PD-1/PD-L1 therapy is designed to restore the antitumor response of cytotoxic T cells (CTLs) by blocking the interaction between PD-L1 on tumour cells and PD-1 on CTLs. Nevertheless, current anti-PD-1/PD-L1 therapy suffers from poor therapeutic outcomes in a large variety of solid tumours due to insufficient tumour specificity, severe cytotoxic effects, and the occurrence of immune resistance. In recent years, nanosized drug delivery systems (NDDSs), endowed with highly efficient tumour targeting and versatility for combination therapy, have paved a new avenue for cancer immunotherapy. In this review article, we summarized the recent advances in NDDSs for anti-PD-1/PD-L1 therapy. We then discussed the challenges and further provided perspectives to promote the clinical application of NDDS-based anti-PD-1/PD-L1 therapy.

124I-Labeled Monoclonal Antibody and Fragment for the Noninvasive Evaluation of Tumor PD-L1 Expression In Vivo

Lung cancer is a highly heterogeneous cancer and is divided broadly into small and nonsmall cell lung cancer (SCLC or NSCLC). In all NSCLC patients, it is estimated that 50%-60% are programmed cell death ligand 1 (PD-L1) positive, and anti-PD-1/PD-L1 therapies have shown their clinical application prospects in advanced NSCLC. To avoid unnecessary adverse effects and provide anti-PD-1/PD-L1 therapy to the most appropriate patient population, the PD-L1 expression in patients preparing for treatment must be evaluated accurately and in real time. In this study, we noninvasively evaluate the PD-L1 expression in an NSCLC xenograft using 124I-labeled F(ab')2 fragments of durvalumab (Durva) and compared it with the 124I-labeled intact antibody in terms of the biodistribution and dosimetry. The aim is to develop a nuclide labeled molecular probe with better performance for PD-L1 immunoPET imaging. After cleaving using IdeS protease, the F(ab')2 fragments of Durva were labeled with 124I. The radioligand showed a high radiochemical purity (>96%) and outstanding stability. Western blot, quantitative real-time polymerase chain reaction, and flow cytometry were performed on the two selected NSCLC cell lines to measure the in vitro PD-L1 expression. The H460 cells showed a much higher PD-L1 expression than the A549 cells, both at the protein level and the mRNA level. In the following cell binding experiment and binding specificity assay, the labeled radioligand showed good affinity to high PD-L1 expression cells and could be blocked with excess unlabeled intact Durva. The results of the biodistribution and the positron emission tomography (PET) image showed that the peak tumor uptake of 124I-Durva-F(ab')2 was close to 124I-Durva, but much earlier (5.29 ± 0.42% ID/g for 124I-Durva-F(ab')2 at 12 h vs 5.18 ± 0.73% ID/g for 124I-Durva at 48 h). Compared with 124I-Durva, an accelerated blood clearance was observed for 124I-Durva-F(ab')2. The faster blood clearance allowed for a higher tumor-to-background ratio, which was reflected on the image in contrast. The H460 tumors showed excellent contrast as early as 4 h after injection with 124I-Durva-F(ab')2, and for 124I-Durva, the xenograft could not be distinguished clearly until 24 h after injection. Interestingly, 124I-Durva-F(ab')2 showed lower accumulations compared to other metal isotopes labeled PD-L1 antibodies in bone, liver, spleen etc., which will be beneficial for metastasis detection. Another benefit of accelerated blood clearance was a reduction in the radiation dose. According to the results of the OLINDA/EXM, the effective dose for the total body of 124I-Durva was 4.25-times greater than that of 124I-Durva-F(ab')2 (186 μSv/MBq vs 43.8 μSv/MBq). All of these data indicated that 124I-Durva-F(ab')2 is a promising immunoPET tracer for evaluating the in vivo PD-L1 levels in an NSCLC model and is expected to be successful in future clinical application.

117TiP A phase II study of toripalimab combined with paclitaxel/carboplatin for the first-line treatment of advanced thymic carcinoma

117TiP A phase II study of toripalimab combined with paclitaxel/carboplatin for the first-line treatment of advanced thymic carcinoma

Association of hepatitis B virus infection status with outcomes of non-small cell lung cancer patients undergoing anti-PD-1/PD-L1 therapy.

BackgroundThe aim of this study was to evaluate the safety and survival outcomes of anti-programmed cell death (PD)-1/programmed cell death-ligand 1 (PD-L1) monotherapy in patients with advanced non-small cell lung cancer (NSCLC) and different hepatitis B virus (HBV) infection status.MethodsPatients with advanced NSCLC and both chronic and/or resolved HBV infection who were treated with anti-PD-(L)1 monotherapy were retrospectively enrolled. The primary endpoint was the safety of PD-1/PD-L1 monotherapy, while the secondary endpoints included the survival outcomes.ResultsOf the 62 eligible patients, 10 (16.1%) were hepatitis B surface antigen (HBsAg) positive [chronic hepatitis B (CHB) infection] and 52 (83.9%) were HBsAg negative and HBcAb positive [resolved hepatitis B (RHB) infection]; 42 (67.7%) patients had at least 1 treatment-related adverse event (AE), with 4 patients (6.5%) developing grade 3 AEs and 6 (9.7%) developing hepatic AEs. One CHB patient experienced HBV reactivation during anti-PD-1 immunotherapy due to the interruption of antiviral prophylaxis. The objective response rate and durable clinical benefit (DCB) rate were 17.7% and 29.0%, respectively. Median overall survival (OS) and progression-free survival (PFS) were 23.6 months [95% confidence interval (CI): 14.4–32.8] and 2.1 months (95% CI: 1.2–3.0), respectively. The DCB rate was significantly higher in the CHB group than in the RHB group (60% vs. 23.1%; P=0.048). Patients with CHB experienced a longer PFS (8.3 vs. 2.0 months; P=0.103) and OS (35.0 vs. 18.2 months, P=0.119) than did RHB patients.ConclusionsAnti-PD-(L)1 monotherapy was safe and effective in patients with NSCLC and HBV infection. This population should not be excluded from receiving immunotherapy in routine clinical practice or within clinical trials if HBV biomarkers are monitored and antiviral prophylaxis is properly used.

Programmed cell death-ligand 1 expression in hepatocellular carcinoma and its correlation with clinicopathological characteristics.

Background and AimProgrammed cell death‐ligand 1 (PD‐L1) immunohistochemistry score has been approved as the predictive biomarker for anti‐PD1/PD‐L1 therapy in several advanced malignancies. Although its predictive role remained inconclusive in hepatocellular carcinoma, ongoing study of anti‐PD1/PD‐L1 therapy showed promising results. However, less is known about the PD‐L1 immunohistochemistry score and factors correlated with it in hepatocellular carcinoma. We investigated PD‐L1 immunohistochemistry scores in a large cohort of hepatocellular carcinoma, as well as its correlation with various clinical and genomic factors.MethodsImmunohistochemistry was performed to detect the expression of PD‐L1 protein in 315 hepatocellular carcinoma tissues. All slides were independently reviewed by three senior pathologists. Next‐generation YS panel (450 genes) sequencing was performed on 309 patients.ResultsHigher PD‐L1 expression as measured by combined positive score (CPS) was associated with increased Edmondson–Steiner grade (grade III vs II, P = 0.041) and TP53 mutations (P = 0.021). PD‐L1 CPS had no correlation with tumor mutational burden (Spearman's correlation coefficient 0.067). PD‐L1 CPS was not significantly associated with hepatitis B virus infection.ConclusionsOur data indicated that patients with higher Edmondson–Steiner grade (grade III) had significantly higher PD‐L1 CPS than patients with lower Edmondson–Steiner grade (grade II). Patients with TP53 mutations had significantly higher PD‐L1 expression.

PD-L1 expression by Tumor Proportion Score (TPS) and Combined Positive Score (CPS) are similar in non-small cell lung cancer (NSCLC)

BackgroundFor non-small cell lung cancer (NSCLC) the most used method for analysing programmed cell death ligand 1 (PD-L1) expression is the Tumor Proportion Score (TPS). Nevertheless, for other tumour types,...

Gastrointestinal tract metastasis of lung cancer: The PD-L1 expression and correlated clinicopathological variables.

The gastrointestinal tract is a rare site for metastatic lung cancer. Programmed cell death-ligand 1 (PD-L1) expression in lung cancer is a biomarker for the response to anti-PD-1/PD-L1 therapy. We investigated clinicopathological features and PD-L1 expression in 25 gastrointestinal metastatic tumors from the lung and primary adenocarcinoma of the small bowel. The small bowel was the most common site (16/25; 64%) of gastrointestinal tract lung cancer metastasis. A total of 19 (76%) of the gastrointestinal metastasis showed PD-L1 expression in ≥5% of tumor cells, with 14 (56%) showing high expression levels (≥50%). In contrast, 21 (84%) expressed PD-L1 in ≥5% immune cells, including 4 (16%) showing a high expression levels (≥50%). The PD-L1 expression on tumor cells and immune cells in primary lung cancer and corresponding gastrointestinal metastasis was concordant in 13 (68%) and 11 (58%) of the 19 paired cases, respectively. Small-bowel metastasis of lung cancer was characterized by a higher incidence of perforation (31% vs. 0%), ulcerated mass (83% vs. 60%), and neoplastic PD-L1 expression (75% vs. 0%) compared to primary small-bowel adenocarcinoma. Gastrointestinal metastasis from lung cancer might be a potential target for immune checkpoint inhibitor therapy, given its high expression of PD-L1.

Pemetrexed Enhances Membrane PD-L1 Expression and Potentiates T Cell-Mediated Cytotoxicity by Anti-PD-L1 Antibody Therapy in Non-Small-Cell Lung Cancer.

Immunotherapy has significantly changed the treatment landscape for advanced non-small-cell lung cancer (NSCLC) with the introduction of drugs targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1). In particular, the addition of the anti-PD-1 antibody pembrolizumab to platinum-pemetrexed chemotherapy resulted in a significantly improved overall survival in patients with non-squamous NSCLC, regardless of PD-L1 expression. In this preclinical study, we investigated whether chemotherapy can modulate PD-L1 expression in non-squamous NSCLC cell lines, thus potentially affecting immunotherapy efficacy. Among different chemotherapeutic agents tested, only pemetrexed increased PD-L1 levels by activating both mTOR/P70S6K and STAT3 pathways. Moreover, it also induced the secretion of cytokines, such as IFN-γ and IL-2, by activated peripheral blood mononuclear cells PBMCs that further stimulated the expression of PD-L1 on tumor cells, as demonstrated in a co-culture system. The anti-PD-1/PD-L1 therapy enhanced T cell-mediated cytotoxicity of NSCLC cells treated with pemetrexed and expressing high levels of PD-L1 in comparison with untreated cells. These data may explain the positive results obtained with pemetrexed-based chemotherapy combined with pembrolizumab in PD-L1-negative NSCLC and can support pemetrexed as one of the preferable chemotherapy partners for immunochemotherapy combination regimens.