Programmed Cell Death Ligand 1 Inhibitors Research Articles

The Effect of PD-1/PD-L1 Inhibitor and Statin Combination Therapy on Overall Survival and Gastrointestinal Toxicity.

Immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, have been approved to treat a variety of cancers. Recently, studies have suggested that ICIs and statins are synergistic. However, the addition of statins to ICI therapy may increase the risk of gastrointestinal immune-related adverse events (irAEs). We investigated the effect of combination therapy with PD-1 and/or L1 inhibitors and statins on overall survival and gastrointestinal irAEs. We reviewed the charts of patients with select cancers who received PD-1 and/or PD-L1 inhibitors and statins. The incidence of gastrointestinal irAEs and overall survival were compared with that in a matched control group of patients who received PD-1 and/or PD-L1 inhibitors without statins. Of the 823 patients in the statin group, 707 received PD-1 inhibitors, 86 received PD-L1 inhibitors, and 30 received both. Patients taking any statins (10.8%) and those taking high-intensity statins (15.8%) had higher rates of gastrointestinal irAEs than patients not taking statins (8.7%; P=0.046 and 0.006, respectively). Compared with the nonstatin treatments, statin use was associated with improved overall survival for patients taking PD-1 inhibitors (P<0.001) and for patients with (P=0.021) and without (P<0.001) gastrointestinal irAEs. Synergism of statins with PD-1 and PD-L1 inhibitors continues to be a developing field of interest. Our data demonstrate the survival benefit of combination therapy with PD-1 and/or PD-L1 inhibitors and statins, warranting further investigation.

In silico Prediction of Pranlukast as a Stabilizer of PD-L1 Homodimers.

Tumors can be targeted by modulating the immune response of the patient. Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are critical immune checkpoints in cancer biology. The efficacy of certain cancer immunotherapies has been achieved by targeting these molecules using monoclonal antibodies. Small-molecule drugs have also been developed as inhibitors of the PD-1/PD-L1 axis, with a mechanism of action that is distinct from that of antibodies: they induce the formation of PD-L1 homodimers, causing their stabilization, internalization, and subsequent degradation. Drug repurposing is a strategy in which new uses are sought after for approved drugs, expediting their clinical translation based on updated findings. In this study, we generated a pharmacophore model that was based on reported small molecules that targeted PD-L1 and used it to identify potential PD-L1 inhibitors among FDA-approved drugs. We identified 12 pharmacophore-matching compounds, but only 4 reproduced the binding mode of the reference inhibitors in docking experiments. Further characterization by molecular dynamics showed that pranlukast, an antagonist of leukotriene receptors that is used to treat asthma, generated stable and energyfavorable interactions with PD-L1 homodimers and induced homodimerization of recombinant PD-L1. Our results suggest that pranlukast inhibits the PD-1/PD-L1 axis, meriting its repurposing as an antitumor drug.

Efficacy and safety of immunotherapy combined with chemotherapy in patients with ES-SCLC: A systematic review and network meta-analysis of RCTs and RWSs.

To evaluate the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors in the treatment of extensive-stage small-cell lung cancer (ES-SCLC), we conducted a systematic review and meta-analysis that included randomized controlled trials (RCTs) and real-world studies (RWS). By scanning PubMed, Web of science, Embase, and other relevant clinical information public databases, nine RCTs and eight RWSs involving 5205 patients were included in the study. We directly compared the differences between chemotherapy and PD-1/PD-L1 inhibitors plus chemotherapy, and determined the optimal treatment strategy through network meta-analysis (NMA). Compared to chemotherapy, the addition of PD-1/PD-L1 inhibitors significantly improves the overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in SCLC patients. Regarding safety, both RCTs and RWSs indicated no significant difference in grade 3-4 adverse events between chemotherapy and chemoimmunotherapy. NMA showed serplulimab plus chemotherapy (Serp_Chemo) appears to provide the best OS, PFS, and ORR benefit, while nivolumab plus chemotherapy shows higher toxicity than other regimens. In subgroup analysis, for elderly patients (age ≥65) and non-elderly (age <65) patients, the most promising quality regimens for achieving better OS extension are atezolizumab plus chemotherapy (Atez_Chemo) and Serp_Chemo, respectively. For patients with PD-L1 ≥ 1% and lactate dehydrogenase (LDH) > upper limit of normal (ULN), there is no apparent OS benefit from immune therapy. In ES-SCLC treatment, adding PD-1/PD-L1 inhibitors to standard chemotherapy improves OS, PFS, and ORR, with Serp_Chemo shows the most promise. Atez_Chemo and Serp_Chemo provided better survival for elderly and non-elderly patients, respectively.

Discovery of Benzo[d]oxazoles as Novel Dual Small-Molecule Inhibitors Targeting PD-1/PD-L1 and VISTA Pathway.

The blockers of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway have achieved great clinical success. However, the limited efficacy and low tumor response rate of anti-PD-1/PD-L1 monotherapy limit the clinical application of PD-1/PD-L1 inhibitors. V-domain immunoglobulin suppressor of T-cell activation (VISTA), a novel checkpoint regulator, exhibits potential synergy with PD-1/PD-L1 in enhancing antitumor immunity. Herein, we report the discovery of benzo[d]oxazole B3 as novel dual small-molecule inhibitors targeting PD-1/PD-L1 and VISTA with high PD-1/PD-L1 inhibitory activity and VISTA binding affinity. B3 rescues the immunosuppression of T-cells mediated by PD-L1 and VISTA and activates antitumor immunity effectively. Moreover, B3 could induce degradation of PD-L1 and VISTA in tumor cell. Furthermore, B3 displays significant in vivo antitumor efficacy in a CT26 mouse model. Our results discover B3 as a promising dual PD-1/PD-L1 and VISTA inhibitor, providing a novel therapeutic strategy to overcome the limitations of current anti-PD-1/PD-L1 therapy.

Evaluation of immune checkpoint inhibitors for colorectal cancer: A network meta‑analysis.

Colorectal cancer (CRC) is challenging to treat due to its high metastatic rate. Recent strategies have focused on combining immune checkpoint inhibitors (ICIs) with other treatments. The aim of the present study was to conduct a network meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and adverse effects of different ICI treatments for CRC. A literature search for RCTs was conducted using PubMed, the Cochrane Library, Embase, ClinicalTrials.gov and Web of Science databases, covering the period from the inception of each database until April 2024. A total of 12 RCTs involving 2,050 participants were selected for inclusion in the analysis. The network meta-analysis employed the MetaInsight tool to assess multiple endpoints. The criteria for study selection were based on the Population, Intervention, Comparison, Outcome and Studies framework as follows: i) Population, patients with CRC; ii) intervention, studies using ICI to treat CRC; iii) comparison, active comparators, including placebo; iv) outcome, overall survival, progression-free survival, objective response rate and adverse events; and v) study design, RCTs. The results of the analysis revealed that programmed cell death-ligand 1 (PD-L1) inhibitors significantly improved overall survival time [mean difference (MD), 2.28 months; 95% confidence interval (CI), 0.44 to 4.11], while programmed cell death protein 1 (PD-1) inhibitors exhibited a superior progression-free survival time (MD, 4.79 months; 95% CI, 3.18 to 6.40) compared with active comparators. However, none of the ICI treatments had significant differences in odds ratios for the objective response rate and adverse events compared with active comparators. These findings indicate that treatment with PD-L1 and PD-1 inhibitors improved the overall survival time and delayed disease progression in patients with CRC. These findings offer valuable insights for future research aimed at improving CRC patient outcomes.

Sarcopenia predicts immune-related adverse events due to anti-PD-1/PD-L1 therapy in patients with advanced lung cancer.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of a number of patients with advanced cancer, and while this has resulted in increased survival times, it has also led to the emergence of novel immune-related adverse events (irAEs). In individuals with advanced cancer, sarcopenia is a significant symptom of cachexia and is linked to poor nutritional status and increased mortality. The present study aimed to evaluate sarcopenia and other risk variables that can affect the emergence of irAEs in patients with lung cancer. A single-center retrospective analysis of 129 patients with advanced lung cancer treated with programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) checkpoint inhibitors was conducted from August 2020 to August 2022. Data on baseline characteristics and adverse events of participants were collected. Computed tomography was used to determine the skeletal muscle index at the third lumbar vertebra (L3-SMI) and whether sarcopenia is present. The median age of all participants was 60 years old (range, 52-66 years), with men accounting for 68.9% of the total patient cohort. The present study showed that 44 (34%) participants presented with any degree of irAEs, and 79 (61.2%) patients presented with sarcopenia. There were no statistically significant differences in baseline characteristics, such as age and sex, between patients who presented with irAEs and those without irAEs. Using logistic regression analysis, individuals with sarcopenia were 2.635-times more likely to experience any grade of irAEs than those without sarcopenia. irAEs are prevalent side effects of PD-1/PD-L1 inhibitor therapy for patients with cancer. By diagnosing and treating sarcopenia early, it is possible to lower the potential risk of irAEs in patients with advanced cancer. Furthermore, sarcopenia can be utilized as a predictor of irAEs.

Abstract C067: Immune thrombocytopenia induced by PD-1/PD-L1 inhibitors in a patient with non-small cell lung adenocarcinoma: A case report and literature review

Abstract Introduction: The introduction of immunotherapy, particularly programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, has transformed the treatment paradigm for non-small cell lung adenocarcinoma (NSCLC), significantly improving patient survival rates. However, alongside their immune-activating effects, these agents can also lead to immune-related adverse events (irAEs), affecting various organ systems. Among these, immune thrombocytopenia (ITP) is a rare but potentially life-threatening complication characterized by the destruction of platelets by autoantibodies, resulting in decreased platelet counts and an increased risk of bleeding. While ITP has been identified as a complication of immunotherapy, particularly PD-1 or PD-L1 inhibitors, its incidence, clinical presentation, and management remain poorly understood. Case Presentation: The 73-year-old female with stage IIIA poorly differentiated NSCLC who received chemotherapy with Taxol/Carboplatin and concurrent radiation therapy followed by a right upper lobectomy, initiated on immunotherapy with durvalumab, a PD-L1 inhibitor, developed severe thrombocytopenia (grade 4) after receiving two cycles of durvalumab. Despite steroid treatment, her condition persisted, indicating immune-related adverse events (irAEs). After confirming the diagnosis through further investigation, including molecular analysis, the patient was treated with intravenous immunoglobulin (IVIG), which significantly increased her platelet counts. Durvalumab was discontinued, and fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, was initiated to manage the irAEs effectively. Discussion: ITP is recognized as an immune-related adverse event (irAE) associated with PD-1 or PD-L1 inhibitors, although it remains rare and poorly understood. Several case reports have highlighted the occurrence of ITP induced by these inhibitors, demonstrating varied clinical presentations and responses to treatment. Mechanisms underlying ITP induction by PD-1/PD-L1 inhibitors are not fully elucidated but may involve immune dysregulation, including CD4+ and CD8+ T cell activation, production of antiplatelet antibodies, and increased expression of PD-L1 on platelets. Management strategies for ITP induced by PD-1/PD-L1 inhibitors include steroids, intravenous immunoglobulin (IVIG) therapy, recombinant human thrombopoietin (TPO), interleukin-6 (IL-6) receptor antagonists, and immunosuppressive agents. However, the effectiveness of these treatments varies among patients, highlighting the need for individualized approaches and further research to optimize management strategies. Conclusion: The prompt recognition and management of ITP induced by PD-1/PD-L1 inhibitors are essential for ensuring favorable patient outcomes. Further research is needed to understand the underlying mechanisms and develop effective prevention and management strategies for this rare but serious immune-related adverse event. Citation Format: Aliya M Khan, Richa Dawar. Immune thrombocytopenia induced by PD-1/PD-L1 inhibitors in a patient with non-small cell lung adenocarcinoma: A case report and literature review [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C067.

Programmed cell death ligand 1 (PD-L1) inhibitors versus programmed cell death 1 (PD-1) inhibitors for the first-line therapy of extensive-stage small cell lung cancer: A propensity score-matched study.

206 Background: Addition of programmed cell death ligand 1 (PD-L1) inhibitors or programmed cell death 1 (PD-1) inhibitors to etoposide‐platinum (EP) chemotherapy has become the standard first-line regimen for ES-SCLC. The clinical efficacy and safety between the two types of immune checkpoint inhibitors (ICIs) remain controversial. We conduct the retrospective study and propensity score-matched analysis to explore the potential differences between them. Methods: Patients diagnosed with ES-SCLC and treated by EP plus PD-L1 or PD-1 inhibitors at Shandong Cancer Hospital between March 2019 and November 2022 were reviewed retrospectively. According to PD-L1 or PD-1 inhibitors, they were divided into two groups. Propensity score matching (1:1) was performed to balance the baseline characteristics of the two groups. The baseline characteristics and adverse events between the two groups were compared using the chi-squared test. The survival curves of overall survival (OS) and progression-free survival (PFS) were plotted by the Kaplan-Meier method and differences were analyzed by the log-rank test.The primary endpoints were OS and PFS. Results: As a result, 448 patients were analyzed in this study. 264 patients received PD-L1 inhibitors plus EP and 184 received PD-1 inhibitors plus EP. The median follow-up was 17.6 months. The median OS and PFS was 20.4 months and 7.8 months in the overall population. Before propensity score matching, the median OS was 20.1 months in PD-L1 inhibitor plus EP group and 20.7 months in PD-1 inhibitor plus EP group, respectively (HR 1.043, 95%CI 0.776-1.401; p= 0.781). The median PFS was 7.6 months in the PD-L1 inhibitor plus EP group and 8.5 months in PD-1 inhibitor plus EP group (HR 1.099, 95%CI 0.886-1.364; p= 0.390). After propensity score matching, the median OS and PFS were 20.4 months and 7.8months in PD-L1 inhibitor plus EP group, and those were 20.1 months and 8.6 months in PD-1 inhibitor plus EP group. There was no significant difference in OS and PFS between PD-L1 inhibitors plus EP and PD-1 inhibitors plus EP in the matched population (HR 1.104; p= 0.578 and HR 1.072; p= 0.602, respectively). The overall adverse events were comparable in the two groups. Only ≥3 grade neutropenia was more frequent in the PD-L1 inhibitors plus EP group (77.7% vs 69.0%, p= 0.040). Conclusions: In conclusion, the overall efficacy and safety profile was similar between PD-L1 inhibitors and PD-1 inhibitors for the first-line treatment of ES-SCLC.

Efficacy and safety of low-dose versus standard-dose immune checkpoint inhibitor as monotherapy in patients with solid tumors: A meta-analysis and systematic review.

188 Background: Immunotherapy is a novel anti-cancer therapy with different mechanisms compared with chemotherapy. Several studies have reported that low dose of immune checkpoint inhibitors (ICIs) is effective. However, it is unknown whether the efficacy of low-dose immunotherapy is inferior to that of standard dose immunotherapy. We aimed to compare the existing randomized clinical trials on the efficacy of immunotherapy at low dose and standard dose as a single agent for patients with solid tumors. Methods: We searched PubMed, EMBASE, and the Cochrane Library for randomized clinical trials with the clinical outcomes of low dose and standard dose of programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitor as monotherapy until November 30, 2023. The low dose is defined as lower than the dose approved by FDA. The hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and disease control rate (DCR) were collected. The Stata 15.0 software was used to analyze the data. Results: Twenty-two studies with 3226 patients with five ICIs for 22 solid tumors were included. There is no difference in OS (HR 1.12, 95% CI = 0.97-1.31; p &gt; 0.05), ORR (Odds ratio (OR) 0.92, 95% CI = 0.76-1.11; p &gt; 0.05) and DCR (OR 0.83, 95% CI = 0.65-1.06; p &gt; 0.05) for patients with low dose and standard dose of PD-1/PD-L1 inhibitors. Conclusions: Our results suggested that PD-1/PD-L1 inhibitor as monotherapy with a low dose may be as effective as standard dose for patients with solid tumors. The regular dose-response relationship may not be appropriate for ICIs. Further work is needed to explore the optimal dose of ICIs based on the comprehensive consideration of efficacy, safety, and economic assessment.

Transarterial Embolization Enhances Programmed Cell Death Ligand 1 Expression and Influences CD8+T Lymphocytes Cytotoxicity in an Orthotopic Hepatocellular Carcinoma Rat Model.

To investigate the influence of transarterial embolization (TAE) on programmed cell death-ligand 1(PD-L1) expression and CD8+T tumour infiltrative lymphocyte cytotoxicity in the Sprague-Dawley (SD) rat model of hepatocellular carcinoma (HCC). An orthotopic HCC model was established in twenty SD rats treated with TAE (lipiodol, n = 10) or sham (normal saline, n = 10) using homologous N1S1 hepatoma cells. Rats were euthanized 1week after embolization. Flow cytometry was used to assess the proportion of CD4+T, CD8+T and programmed cell death-1+(PD-1+) CD8+T lymphocytes in the spleens and tumours. Distribution of CD8+T, granzyme-B+CD8+T lymphocytes and PD-L1+ cells was assessed by immunohistochemistry (IHC) or multiplex IHC. p value < 0.05 was considered statistically significant. The CD4/CD8 ratio and PD-1+CD8+ T lymphocytes exhibited higher values in TAE-treated tumours compared to sham-treated tumours (p = 0.021 and p = 0.071, respectively). Conversely, the number of CD8+T lymphocytes was decreased in TAE-treated tumours (p = 0.043), especially in the central region (p = 0.045). However, more CD8+T lymphocytes were found infiltrating the marginal region than central region in TAE-treated tumours (p = 0.046). The proportion of granzyme-B+CD8+T lymphocytes and the PD-L1 positive areas was elevated in tumours that treated with TAE (p all < 0.05). There was a negative correlation between PD-L1 expression and the number of infiltration of CD8+ T lymphocytes (p = 0.036). Immune cells are distributed unevenly in the tumours after TAE. The intrinsic induction state of the tumour after embolization may be insufficient to elicit a maximal response to PD-1/PD-L1 inhibitors.

Design, synthesis, anti-tumor activity and mechanism of novel PROTACs as degraders of PD-L1 and inhibitors of PD-1/PD-L1 interaction

Currently, antibody drugs targeting programmed cell death ligand 1 (PD-L1) have achieved promising results in cancer treatment, while the development of small-molecule drugs lags behind. In this study, we designed and synthesized a series of PD-L1-degrading agents based on the PROTAC design principle, utilizing the PD-L1 inhibitor A56. Through systematic screening of ligands and linkers and investigating the structure–activity relationship of the degraders, we identified two highly active compounds, 9i and 9j. These compounds enhance levels of CD4+, CD8+, granzyme B, and perforin, demonstrating significant in vivo antitumor effects with a tumor growth inhibition (TGI) of up to 57.35 %. Both compounds facilitate the internalization of PD-L1 from the cell surface and promote its degradation through proteasomal and lysosomal pathways, while also maintaining inhibition of the PD-1/PD-L1 interaction. In summary, our findings provide a novel strategy and mechanism for developing biphenyl-based PROTAC antitumor drugs targeting and degrading PD-L1.

AML cell-derived exosomes suppress the activation and cytotoxicity of NK cells in AML via PD-1/PD-L1 pathway.

Exosomes are bilayer lipid bodies and contain a variety of bioactive molecules such as proteins, lipids, and nucleic acids, and so forth. Exosomes derived from solid tumors may play critical roles in tumor development and immune evasion. However, the underlying effects of tumor-derived exosomes on immune function in modulating intercellular crosstalk within the bone marrow niche during acute myeloid leukemia (AML) development and immune evasion remain largely elusive. In this study, we aimed to explore the role of AML-exos in AML immune evasion. First, we isolated tumor-derived exosomes from AML cells (AML-exos) and revealed the presence of programmed cell death ligand-1 (PD-L1) protein in AML-exos. Next, we demonstrated that AML-exos can directly suppress the activation of natural killer (NK) cells and inhibit the cytotoxicity of NK cells, probably through activating the programmed cell death-1 (PD-1)/PD-L1 pathway. Furthermore, the inhibitory effect of AML-exos on NK cells could be alleviated by either PD-L1 inhibitor or antagonist. In summary, we demonstrated that AML-exos possess a PD-L1-dependent tumor-promoting effect which may contribute to immune tolerance in antitumor therapy, but blocking the PD-1/PD-L1 pathway may alleviate the tumor immunosuppression induced by AML-exos. Our findings in this study may offer a new immunotherapy strategy to cure AML.

Periodontitis is an immune-related adverse event associated with immune checkpoint inhibitors: A multi-center cohort study

Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs) across various organ systems including oral health complications such as dry mouth and stomatitis. In this study, we aimed to determine the risk of periodontitis among patients on immune checkpoint inhibitors (ICIs) and to test the associations between ICI-associated periodontitis and other immune-related adverse events (irAEs). We performed a retrospective cohort study involving adult cancer patients between January 2010 and November 2021. Patients on an ICI were propensity score-matched to patients not on an ICI. The primary outcome was the occurrence of periodontitis. ICIs included programmed cell death 1 (PD-1) inhibitors programmed cell death ligand 1 (PD-L1) inhibitors, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. The risk of periodontitis following ICI use was derived through a Cox proportional hazard model and Kaplan-Meier survival analysis. Overall, 868 patients on an ICI were matched to patients not on an ICI. Among the ICI cohort, 41 (4.7 %) patients developed periodontitis. The incidence rate of periodontitis was significantly higher in patients on an ICI than in patients not on an ICI (55.3 vs 25.8 per 100 patient-years, incidence rate ratio = 2.14, 95 % CI = 1.38–3.33). Both the use of PD-L1 inhibitors (multivariate HR = 2.5, 95%CI = 1.3–4.7) and PD-1 inhibitors (multivariate HR = 2.0, 95%CI = 1.2–3.2) were associated with the risk of periodontitis. The presence of immune-related periodontitis was associated with better overall survival (not reached vs 17 months, log-rank p-value<0.001), progression-free survival (14.9 vs 5.6 months, log-rank p-value = 0.01), and other concomitant immune-related cutaneous adverse events. In conclusion, ICI was associated with an increased risk of periodontitis. Immune-related periodontitis as an irAE was associated with better cancer survival and concomitant cutaneous irAEs.

Treatment-related Adverse Events, Including Fatal Toxicities, in Patients With Extensive-stage Small-cell Lung Cancer Receiving Adjuvant Programmed Cell Death 1/Programmed Cell Death Ligand 1 Inhibitors: A Meta-analysis and Trial Sequential Analysis of Randomized Controlled Trials

Background/AimsThe safety profile of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors when associated with chemotherapy for the treatment of patients with extensive-stage small-cell lung cancer is still not fully unraveled. MethodsWe performed a comprehensive searrch of the PubMed, Embase, and Cochrane databases for randomized controlled trials that investigated the addition of PD-1 or PD-L1 inhibitors to standard investigator choice chemotherapy. We used risk -ratios (RRs) with 95% confidence intervals (CIs) for all endpoints. ResultsSix studies and 2,995 patients were included. At the baseline, the median age of the patients varied from 62 to 65 years, 311 (10.4%) had brain metastases, and 1,060 (35.4%) had liver metastases. PD-1/PD-L1 inhibitors were found to reduce fatal toxicities-related mortality (RR: 0.85; 95% CI: 0.80–0.91; p < 0.001; I2 = 49%). The intervention group had a higher incidence of decreased appetite (RR: 1.19; 95% CI: 1.02–1.40; p = 0.03; I2 = 0%), hyponatremia (RR: 1.51; 95% CI: 1.08–2.12; p = 0.02; I2 = 0%), and hypothyroidism (RR: 3.14; 95% CI: 1.10–8.95; p = 0.03; I2 = 81%) of any grade. Regarding adverse events of grade 3–4, there was no association of the addition of PD-1/PD-L1 inhibitors with an increased occurrence of any of the evaluated outcomes. ConclusionIn this systematic review and meta-analysis, the incorporation of PD-1/PD-L1 inhibitors to chemotherapy demonstrated an excellent safety profile and to be a promising prospect for reshaping the established treatment paradigms for patients with extensive-stage small cell lung cancer.

Design, synthesis, pharmacological evaluation, and computational study of benzo[d] isothiazol-based small molecule inhibitors targeting PD-1/PD-l1 interaction

Blockade of the programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an attractive strategy for immunotherapy, but the clinical application of small molecule PD-1/PD-L1 inhibitors remains unclear. In this work, based on BMS-202 and our previous work YLW-106, a series of compounds with benzo[d]isothiazol structure as scaffold were designed and synthesized. Their inhibitory activity against PD-1/PD-L1 interaction was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay. Among them, LLW-018 (27c) exhibited the most potent inhibitory activity with an IC50 value of 2.61 nM. The cellular level assays demonstrated that LLW-018 exhibited low cytotoxicity against Jurkat T and MDA-MB-231. Further cell-based PD-1/PD-L1 blockade bioassays based on PD-1 NFAT-Luc Jurkat cells and PD-L1 TCR Activator CHO cells indicated that LLW-018 could interrupt PD-1/PD-L1 interaction with an IC50 value of 0.88 μM. Multi-computational methods, including molecular docking, molecular dynamics, MM/GBSA, MM/PBSA, Metadynamics, and QM/MM MD were utilized on PD-L1 dimer complexes, which revealed the binding modes and dissociation process of LLW-018 and C2-symmetric small molecule inhibitor LCH1307. These results suggested that LLW-018 exhibited promising potency as a PD-1/PD-L1 inhibitor for further investigation.

Programmed Cell Death Ligand 1 (PD-L1) Immunohistochemical Expression in Advanced Urothelial Bladder Carcinoma: An Updated Review with Clinical and Pathological Implications.

The management of advanced bladder carcinoma involves a multidisciplinary approach, but the prognosis remains poor for many patients. The immune system plays a crucial role in this disease, influencing both tumor development and response to treatment, and exploiting the immune system against the tumor can be a valuable strategy to destroy neoplastic cells. This is the biological principle underlying Bacillus Calmette-Guérin (BCG) use and, more recently, immune checkpoint inhibitors (ICIs), like PD-1 (programmed death-1)/PD-L1 (programmed death-ligand 1) inhibitors. In fact, one of the best studied immune checkpoints is represented by the PD-1/PD-L1 axis, which is a well-known immune escape system adopted by neoplastic bladder cells. PD-L1 expression has been associated with a higher pathologic stage and has shown prognostic value in bladder carcinoma. Interestingly, high-grade bladder cancers tend to express higher levels of PD-1 and PD-L1, suggesting a potential role of such an axis in mediating disease progression. Immunotherapy with PD-1 and PD-L1 inhibitors has therefore emerged as a valuable treatment option and has shown efficacy in advanced bladder cancer patients, with high PD-L1 expression levels associated with better treatment responses. Our review aims to provide a comprehensive overview of the role of PD-L1 in advanced bladder cancer, focusing on its implications for treatment decisions and the prediction of treatment response. Overall, our work aims to contribute to the understanding of PD-L1 as a predictive biomarker and highlight its role in shaping therapeutic approaches for advanced bladder cancer.

Programmed cell death ligand 1 (PD-L1) inhibitors versus programmed cell death 1 (PD-1) inhibitors for the first-line therapy of extensive-stage small cell lung cancer: A propensity score-matched study.

8086 Background: Addition of programmed cell death ligand 1 (PD-L1) inhibitors or programmed cell death 1 (PD-1) inhibitors to etoposide‐platinum (EP) chemotherapy has become the standard first-line regimen for ES-SCLC. The clinical efficacy and safety between the two types of immune checkpoint inhibitors (ICIs) remain controversial. We conduct the retrospective study and propensity score-matched analysis to explore the potential differences between them. Methods: Patients diagnosed with ES-SCLC and treated by EP plus PD-L1 or PD-1 inhibitors at Shandong Cancer Hospital between March 2019 and November 2022 were reviewed retrospectively. According to PD-L1 or PD-1 inhibitors, they were divided into two groups. Propensity score matching (1:1) was performed to balance the baseline characteristics of the two groups. The baseline characteristics and adverse events between the two groups were compared using the chi-squared test. The survival curves of overall survival (OS) and progression-free survival (PFS) were plotted by the Kaplan-Meier method and differences were analyzed by the log-rank test.The primary endpoints were OS and PFS. Results: As a result, 448 patients were analyzed in this study. 264 patients received PD-L1 inhibitors plus EP and 184 received PD-1 inhibitors plus EP. The median follow-up was 17.6 months. The median OS and PFS was 20.4 months and 7.8 months in the overall population. Before propensity score matching, the median OS was 20.1 months in PD-L1 inhibitor plus EP group and 20.7 months in PD-1 inhibitor plus EP group, respectively (HR 1.043, 95%CI 0.776-1.401; p= 0.781). The median PFS was 7.6 months in the PD-L1 inhibitor plus EP group and 8.5 months in PD-1 inhibitor plus EP group (HR 1.099, 95%CI 0.886-1.364; p= 0.390). After propensity score matching, the median OS and PFS were 20.4 months and 7.8months in PD-L1 inhibitor plus EP group, and those were 20.1 months and 8.6 months in PD-1 inhibitor plus EP group. There was no significant difference in OS and PFS between PD-L1 inhibitors plus EP and PD-1 inhibitors plus EP in the matched population (HR 1.104; p= 0.578 and HR 1.072; p= 0.602, respectively). The overall adverse events were comparable in the two groups. Only ≥3 grade neutropenia was more frequent in the PD-L1 inhibitors plus EP group (77.7% vs 69.0%, p= 0.040). Conclusions: In conclusion, the overall efficacy and safety profile was similar between PD-L1 inhibitors and PD-1 inhibitors for the first-line treatment of ES-SCLC.

Comparing clinical outcomes between PD-1 and PD-L1 inhibitors plus bevacizumab combined with hepatic arterial interventional therapies in unresectable hepatocellular carcinoma: A single-center real-world study.

e16229 Background: Systemic therapies combined with locoregional therapies were considered a potent therapeutic strategy in treating patients with unresectable hepatocellular carcinoma (uHCC). Given the A+T strategy became the first-line treatment for advanced HCC patients, the roles of programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors in the combination therapies for treating patients with uHCC needed to be further discussed. The current study compared the clinical outcomes between PD-1 and PD-L1 inhibitors plus bevacizumab combined with hepatic arterial interventional therapies (HAIT) among patients with uHCC. Methods: From October 2019 to May 2023, 142 uHCC patients were retrospectively analyzed in Sun Yat-sen University Cancer Center, including 73 or 69 patients treated with either PD-1 (PD-1 group) or PD-L1 (PD-L1 group) inhibitors, respectively, combined with HAIT plus bevacizumab. The progression-free survival (PFS) and tumor responses were analyzed per mRECIST. Results: At the data cut-off, the median PFS was 5.5 months (95% CI 5.3-7.1 months) in the PD-1 group and 7.5 months (95% CI 7.0-9.6 months) in the PD-L1 group, respectively ( P=0.280; HR=0.74; 95%CI 0.43-1.28). The PD-L1 group showed a significantly better median intrahepatic PFS (8.1 months, 95%CI 7.6-10.2 months) than the PD-1 group (6.5 months, 95%CI 6.2-9.0 months; P=0.014; HR=0.35; 95%CI 0.16-0.81). The overall response rate (ORR; 49.3% vs. 66.7%, P=0.054), intrahepatic control rates (53.4% vs. 69.6%, P=0.070) and overall disease control rate (DCR; 68.5% vs. 78.3%, P=0.261) showed no significant difference in both groups, while the PD-L1 group demonstrated significantly higher intrahepatic disease control rate than the PD-1 group (76.7% vs. 92.6%, P=0.016). Conclusions: PD-1 and PD-L1 plus bevacizumab combined HAIT shared similar PFS, DCRs, and ORRs in treating uHCC patients. The PD-L1 plus bevacizumab combined with HAIT demonstrated a better intrahepatic control than those of PD-1, which needed further validation at a higher evidence level.

Impact of the tumor proportion score (TPS) and the combined positive score (CPS) on the use of immunotherapy in patients with metastatic non-small cell lung cancer.

e14611 Background: Expression of programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) has often been measured by the Tumor Proportion Score (TPS) (1). Recently, the Combined Positive Score (CPS), which evaluates PD-L1 expression in tumor and inflammatory cells and applies to other types of cancer including gastric and head and neck cancers, was found to be equally predictive of the response to immunotherapy in NSCLC (1). In this study, we aimed to conduct a single center retrospective analysis to evaluate the clinical use and impact of using TPS and CPS data in patients with metastatic NSCLC. Methods: Patients with NSCLC who had TPS and CPS scores and received PD-1/PD-L1 inhibitors between 2021-2022 as a monotherapy or in combination with chemotherapy were included. Patients’ data was retrieved from the electronic medical record data and analysis included histopathological data, lung cancer surgical history, presence of EGFR mutation, ALK mutation, Ki67, use of adjuvant chemotherapy, type of immunotherapy used, and development of immune checkpoint inhibitor- related toxicity and treatment as applicable. TPS and CPS positivity was defined as &gt;1 % and &gt;1 respectively. Statistical methods employed included descriptive approaches such as calculated means as well as the Kaplan-Meier estimate. Results: 40 patients with NSCLC were included. Patients’ age ranged from 19 to 82 years old with an average age of 64.3 years old. Most patients had adenocarcinoma (65 %) and were at stage IV (72.5 %). TPS positivity was identified in 29 patients (72.5 %) and CPS positivity was identified in 35 patients (87.5 %). Patients received immunotherapy mostly as first or second line of treatment (90 %). Immune checkpoint inhibitors received by patients were pembrolizumab (50 %), nivolumab (35 %), atezolizumab (12.5 %), and durvalumab (2.5 %). The median overall survival was 16, 12, and 17 months in the &lt;1 %, 1-49 % and &gt; 49 % TPS groups respectively (p= 0.354); while the median overall survival was 11, 16 and 17 months in the &lt;1, 1-49, and &gt; 49 CPS groups respectively (p= 0.417). It is critical to highlight that there were 7 patients (17.5 %) with TPS of zero who had CPS positivity (score range: 1-10). Most of these patients had adenocarcinoma (71.4 %), received pembrolizumab or atezolizumab (85.7 %) and had a median survival of 16 months. Conclusions: The Combined Positive Score (CPS) has proven to be an effective method in evaluating the level of expression of PD-L1 in NSCLC (1,2). Similar to TPS, CPS provides critical information that can be applied to guide the use of immunotherapy, and which can greatly impact patients with NSCLC. 1. De Marchi et al., 2021. 2. Ulas et al., 2023.

A phase 3, randomized study of adjuvant rilvegostomig plus chemotherapy in resected biliary tract cancer: ARTEMIDE-Biliary01.

TPS4199 Background: Biliary tract cancer (BTC) is a rare but aggressive heterogenous group of gastrointestinal cancers that arise from the intra- or extrahepatic bile ducts (cholangiocarcinoma [CCA]) or the gallbladder (GBC). In early-stage disease following curative resection, adjuvant chemotherapy with a fluoropyrimidine- or gemcitabine-based regimen is usually recommended, however, recurrence rates remain high (e.g. in the BILCAP study, 5-year recurrence-free survival with adjuvant capecitabine was 34%). Immunotherapy is efficacious as adjuvant therapy in other cancer types. Results from the TOPAZ-1 and KEYNOTE-966 studies support combining immunotherapy and chemotherapy in advanced BTC, including in locally advanced non-metastatic disease. Furthermore, dual inhibition of programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) and the novel immune checkpoint, T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), has shown promising results across multiple tumor types without major increases in high-grade toxicity compared with PD-1 or PD-L1 inhibition alone. Rilvegostomig is an anti-PD-1/-TIGIT bi-specific monoclonal antibody that appears active and well tolerated in non-small-cell lung cancer. ARTEMIDE-Biliary01 will investigate the efficacy of rilvegostomig plus standard of care adjuvant chemotherapy in patients with BTC after curative intent resection. Methods: ARTEMIDE-Biliary01 (NCT06109779) is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, global study to assess the efficacy and tolerability of rilvegostomig IV every three weeks versus placebo in combination with investigator's choice of chemotherapy (capecitabine, S-1 [tegafur/gimeracil/oteracil] or gemcitabine/cisplatin) as adjuvant treatment in patients with BTC after curative intent resection. This study will enroll approximately 750 adults with histologically confirmed adenocarcinoma of the biliary tract (intrahepatic or extrahepatic CCA or muscle-invasive GBC) after macroscopically complete resection (R0 or R1) and an ECOG PS of 0–1. Key exclusion criteria include locally advanced, unresectable, or metastatic disease at initial diagnosis and any anti-cancer therapy for BTC prior to surgery. The primary endpoint is recurrence-free survival, and the key secondary endpoint is overall survival. Additional endpoints include progression-free survival following recurrence, patient-reported tolerability, and safety. Enrollment has begun, and approximately 200 sites will be recruiting globally across Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT06109779 .