Anti-programmed Death-ligand Research Articles

Ethiodized Oil Pickering Emulsion for Sustained Release of Anti-PD-L1 Antibodies.

This research aimed to develop and assess a Lipiodol Pickering emulsion containing anti-Programmed cell Death Ligand 1 (PD-L1) antibodies through in vitro experiments. The emulsion was created by combining Lipiodol with poly (lactic-co-glycolic acid) (PLGA) nanoparticles and anti-PD-L1 antibodies. Confocal laser microscopy was used to evaluate the encapsulation of the antibodies within the Pickering emulsion. To assess the stability, the emulsion was visually examined, and droplet sizes were measured under a light microscope. For the sustained release evaluation, the emulsion was introduced into saline and incubated in a shaking bath, after which the supernatant was collected over time. The concentration of anti-PD-L1 antibodies in the supernatant was determined using a bicinchoninic acid assay. Western blotting and flow cytometry were employed to confirm the functionality of the released antibodies. A conventional Lipiodol emulsion was used as a control for comparison. The anti-PD-L1 antibodies were encapsulated within the layer of PLGA nanoparticles, positioned at the interface between the water and oil phases, as confirmed by confocal laser microscopy. The Lipiodol Pickering emulsion demonstrated long-term stability with significantly smaller droplet sizes (P < 0.001). Moreover, the emulsion facilitated a gradual and sustained release of the anti-PD-L1 antibodies over an eight-week period (P < 0.001). The antibodies released from the emulsion specifically targeted PD-L1. This study demonstrated that Lipiodol Pickering emulsions effectively encapsulate anti-PD-L1 antibodies and enable their sustained release, highlighting their potential as a therapeutic agent for primary and secondary liver cancers.

Neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin in women with early HER2-positive breast cancer: the randomized phase 2 ABCSG-52/ATHENE trial.

The role of anthracyclines in the treatment of early breast cancer (EBC) is increasingly being challenged, especially in de-escalation strategies. However, owing to their immunogenic effects, anthracyclines are promising combination partners with immunotherapies. In the randomized phase 2 trial ABCSG-52 (EudraCT no. 2019-002364-27), we investigated epirubicin plus immunotherapy in women with human epidermal growth factor receptor 2 (HER2)-positive EBC. A total of 58 patients were randomized 1:1 to two cycles of a chemotherapy-free induction phase (part 1) of dual HER2 blockade with trastuzumab and pertuzumab (TP) plus the anti-programmed death ligand 1 antibody atezolizumab (TP-A) or TP alone. Thereafter, all patients received four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint, pathological complete response (pCR), was met in 35 patients (60.3%; 95% confidence interval (CI) 47.5% to 71.9%), 19 patients (65.5%) in the TP-A group and 16 patients (55.2%) in the TP group. The residual cancer burden 0/I rate and objective response rate (secondary endpoints) in all patients with evaluable data were 80.0% (n = 44/55; 95% CI 67.6% to 88.4%) and 89.3% (n = 50/56; 95% CI 78.5% to 95.0%), respectively. Grade ≥3 adverse events were reported in 17 patients (29.3%). Based on our findings, we conclude that a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab and epirubicin is effective and safe in patients with HER2-positive EBC.

Dual Checkpoint Inhibition in M2 Macrophages via Anti-PD-L1 and siRNA-Loaded M1-Exosomes: Enhancing Tumor Immunity through RNA-Targeting Strategies.

The interaction between a cluster of differentiation 47 (CD47) on cancer cells and signal regulatory protein alpha (SIRPα) on macrophages is thought to hinder macrophage phagocytic activity, which can be blocked by combining siRNAs targeting SIRPα (siSIRPα) with simultaneous involvement of activating receptors like FcRs (Fc receptors) anti-programmed death-ligand 1 (anti-PD-L1). For this study, M1 macrophage-derived exosomes were used to deliver the siRNAs, isolated from lipopolysaccharide (LPS)-stimulated RAW264.7 cells and electroporated with siSIRPα. The exosomes were characterized and used to treat M2 macrophages (RAW264.7 cells triggered by interleukin-4 (IL-4)), and the polarization of macrophages was evaluated using flow cytometry, real-time PCR, ELISA, and phagocytosis assays. The anti-tumor functions of treated macrophages were assessed by co-culturing them with 4T1 cells, evaluating the migration and invasion of 4T1 cells, and phagocytosis of 4T1 cells by macrophages. The results showed that siSIRPα-loaded M1-exosomes caused polarization of M2 macrophage toward M1 phenotype and enhanced anti-tumor effects by reducing migration and invasion of 4T1 cells and enhancing phagocytosis of 4T1 cells by macrophages, especially with combination of anti-PD-L1. This study suggests that blocking the SIRPα-CD47 interaction and the PD-1/PD-L1 pathway in M2 macrophages could be a promising therapeutic approach to enhance anti-tumor immune responses.

Cell-Penetrating Peptide Like Anti-Programmed Cell Death-Ligand 1 Peptide Conjugate-Based Self-Assembled Nanoparticles for Immunogenic Photodynamic Therapy.

The tumor-specific efficacy of the most current anticancer therapeutic agents, including antibody-drug conjugates (ADCs), oligonucleotides, and photosensitizers, is constrained by limitations such as poor cell penetration and low drug delivery. In this study, we addressed these challenges by developing, a positively charged, amphiphilic Chlorin e6 (Ce6)-conjugated, cell-penetrating anti-PD-L1 peptide nanomedicine (CPPD1) with enhanced cell and tissue permeability. The CPPD1 molecule, a bioconjugate of a hydrophobic photosensitizer and strongly positively charged programmed cell death-ligand 1 (PD-L1) binding cell-penetrating peptide (CPP), is capable of self-assembling into nanoparticles with an average size of 199 nm in aqueous solution without the need for any carriers. These carrier-free nanoparticles possess the ability to penetrate the cell membrane of cancer cells and target tumors expressing PD-L1 on their surface. Notably, CPPD1 nanoparticles effectively blocked programmed cell death-1 (PD-1)/PD-L1 interactions and reduced PD-L1 expression via lysosomal degradation. They also demonstrated the responsiveness of CPPD1 nanoparticles in photodynamic therapy (PDT) to a 635 nm laser, leading to the generation of ROS, and induction of various immunogenic cell deaths (ICD). Highly penetrating CPPD1 nanoparticles could immunogenically modulate the microenvironment of CT26 cancer and were also effective in treating abscopal metastatic tumors, addressing major limitations of traditional PDT.

Dual-Enzyme-Instructed Peptide Self-Assembly to Boost Immunogenic Cell Death by Coordinating Intracellular Calcium Overload and Chemotherapy.

The concept of immunogenic cell death (ICD) induced by chemotherapy as a potential synergistic modality for cancer immunotherapy has been widely discussed. Unfortunately, most chemotherapeutic agents failed to dictate effective ICD responses due to their defects in inducing potent ICD signaling. Here, we report a dual-enzyme-instructed peptide self-assembly platform of CPMC (CPT-GFFpY-PLGVRK-Caps) that cooperatively utilizes camptothecin (CPT) and capsaicin (Caps) to promote ICD and engage systemic adaptive immunity for tumor rejection. Although CPT and Caps respectively prevent tumor progression by inhibiting type-I DNA topoisomerase and activating transient receptor potential cation channel subfamily V member 1 (TRPV1) for intracellular calcium overload, neither alone effectively stimulates sufficient ICD signaling to meet immunotherapeutic needs. CPMC, sequentially allowing an active Caps derivative of VRK-Caps and CPT to release extracellularly and intracellularly, can synergize two distinct apoptosis pathways stimulated by Caps and CPT to increase tumor immunogenicity and elicit systemic T-cell-based immunity. Consequently, CPMC facilitates the generation of improved tumor-specific cytotoxic T-cell responses and sustained immunological memory, successfully suppressing both primary and distant tumors. Moreover, CPMC can render tumors susceptible to PD-L1 blockade and synergize with an antiprogrammed cell death-ligand 1 (aPDL1) antibody for tumor inhibition. Combining two cancer chemotherapeutic drugs with low ICD-stimulating capacity using a peptide self-assembly strategy was demonstrated to boost ICD responses and potentiate cancer immunotherapy.

Final Analysis of Post-Marketing Surveillance for Avelumab + Axitinib in Patients With Renal Cell Carcinoma in Japan.

Avelumab, an anti-programmed death ligand 1 antibody, was approved in combination with axitinib for curatively unresectable or metastatic renal cell carcinoma (RCC) in Japan in December 2019. Because the pivotal JAVELIN Renal 101 study included a limited number of Japanese patients, post-marketing surveillance (PMS) was required to evaluate outcomes (safety and effectiveness) in patients with RCC who received avelumab + axitinib treatment in clinical practice in Japan. We report data from prospective, noncomparative, multicenter, observational PMS in patients with RCC who received ≥ 1 dose of avelumab. Patients were enrolled between December 2019 (date of regulatory approval) and May 2021. The primary objective was to evaluate safety, defined as adverse drug reactions (ADRs) of safety specifications occurring during an observation period of ≤ 52 weeks for each patient. The secondary objective was to evaluate effectiveness, including best overall response and overall survival (OS). In total, 328 patients were included in the safety and effectiveness analysis sets. Overall, 173 patients (52.7%) had ADRs of safety specifications of any grade, most commonly thyroid dysfunction (n = 69 [21.0%]), infusion reaction (n = 65 [19.8%]), and hepatic disorders (n = 45 [13.7%]). Objective responses occurred in 118 patients (36.0%), including complete or partial responses in 13 (4.0%) and 105 (32.0%), respectively; the disease control rate was 75.6%. The 12-month OS rate was 83.7% (95% CI, 78.9%-87.4%). This PMS confirmed the safety, tolerability, and effectiveness of avelumab + axitinib in patients with RCC in clinical practice in Japan, with a benefit-risk profile comparable to that observed in clinical trials.

Personalized Multi-Epitope Nanovaccine Unlocks B Cell-Mediated Multiple Pathways of Antitumor Immunity.

B lymphocytes have emerged as an important immune-regulating target. Inoculation with tumor cell membrane-derived vaccines is a promising strategy to activate B cells, yet their efficiency is limited due to lack of costimulatory molecules. To amplify B cell responses against tumor, herein, a spatiotemporally-synchronized antigen-adjuvant integrated nanovaccine, termed as CM-CpG-aCD40, is constructed by conjugating the immune stimulative CpG oligonucleotide and the anti-CD40 antibody (aCD40) onto the membrane vesicles derived from triple negative breast cancer cells. CM-CpG-aCD40 actively accumulates in lymph nodes and is effectively captured by antigen-presenting cells via the recognition of CD40 by aCD40. Tumor antigens on CM-CpG-aCD40 bind to B cell receptors, providing the first stimulation signal for B cells. Meanwhile, the interaction between CpG/Toll like receptor and aCD40/CD40 provides superposed co-stimulation signals, improving the antibody-secreting and antigen-presenting abilities of B cells. The nanovaccine also stimulates dendritic cells to activate CD8+ T cells, and reprograms tumor associated macrophages. CM-CpG-aCD40 activating humoral, cellular, and innate antitumor immunity achieves a tumor inhibition rate of 89.3%, which is further improved to 95.4% when combined with the anti-programmed death ligand 1 (PD-L1) antibody. CM-CpG-aCD40, as a personalized multi-epitope nanovaccine, paves the way for ushering the era of B cell-based immunotherapy.

NK cells restrain cytotoxic CD8+ T cells in the submandibular gland via PD-1-PD-L1.

The increasing use of anti-programmed cell death 1 (PD-1) immune checkpoint blockade has led to the emergence of immune-related adverse events (irAEs), including dysfunction of the submandibular gland (SMG). In this study, we investigated the immunoregulatory mechanism contributing to the susceptibility of the SMG to irAEs. We found that the SMGs of PD-1-deficient mice and anti-programmed cell death ligand 1 (PD-L1)-treated mice harbor an expanded population of CD8+ T cells. We demonstrate that natural killer (NK) cells expressing PD-L1 tightly regulate CD8+ T cells in the SMG. When this immunoregulation is disrupted, CD8+ T cells clonally expand and acquire a unique transcriptional profile consistent with T cell receptor (TCR) activation. These clonally expanded cells phenotypically overlapped with cytotoxic GzmK+ CD8+ T autoimmune cells identified in patients with primary Sjögren's syndrome. Understanding how NK cells modulate CD8+ T cell activity in the SMG opens new avenues for preventing irAEs in patients undergoing checkpoint blockade therapies.

Phase II randomized study of dostarlimab alone or with bevacizumab versus non-platinum chemotherapy in recurrent gynecological clear cell carcinoma (DOVE/APGOT-OV7/ENGOT-ov80).

Recurrent gynecological clear cell carcinoma (rGCCC) has a low objective response rate (ORR) to chemotherapy. Previous preclinical and clinical data suggest a potential synergy between immune checkpoint inhibitors and bevacizumab in rGCCC. Dostarlimab, a humanized monoclonal antibody targeting programmed cell death protein 1 (PD-1), combined with the anti-angiogenic bevacizumab, presents a novel therapeutic approach. This study will investigate the efficacy of dostarlimab +/- bevacizumab in rGCCC. DOVE is a global, multicenter, international, open-label, randomized phase 2 study of dostarlimab +/- bevacizumab with standard chemotherapy in rGCCC. We will enroll 198 patients with rGCCC and assign them to one of three groups in a 1:1:1 ratio: arm A (dostarlimab monotherapy), B (dostarlimab + bevacizumab), and C (investigator's choice of chemotherapy [weekly paclitaxel, pegylated liposomal doxorubicin, doxorubicin, or gemcitabine]). Patients with disease progression in arm A or C will be allowed to cross over to arm B. Stratification factors include prior bevacizumab use, prior lines of therapy (1 vs. >1), and primary site (ovarian vs. non-ovarian). Key inclusion criteria are histologically proven recurrent or persistent clear cell carcinoma of the ovary, endometrium, cervix, vagina, or vulva; up to five prior lines of therapy; disease progression within 12 months after platinum-based chemotherapy; and measurable disease. Key exclusion criteria are prior treatment with an anti-PD-1, anti-programmed death-ligand 1, or anti-programmed death-ligand 2 agent. The primary endpoint is progression-free survival determined by investigators. Secondary endpoints are ORR, disease control rate, clinical benefit rate, progression-free survival 2, overall survival, and toxicity. Exploratory objectives include immune biomarkers. ClinicalTrials.gov Identifier: NCT06023862.

A Smart Nanomedicine Unleashes a Dual Assault of Glucose Starvation and Cuproptosis to Supercharge αPD-L1 Therapy.

Combination therapy has become a promising strategy for promoting the outcomes of anti-programmed death ligand-1 (αPD-L1) therapy in lung cancer. Among all, emerging strategies targeting cancer metabolism have shown great potency in treating cancers with immunotherapy. Here, alteration in glucose and copper metabolisms is found to synergistically regulate PD-L1 expression in lung cancer cells. Thus, an intelligent biomimetic nano-delivery system is synthesized by camouflaging lung cancer cell membranes onto glucose oxidase-loaded Cu-LDHs (CMGCL) for cancer metabolism targeted interference. Such novel nanomedicine is able to induce lung cancer cell cuproptosis and PD-L1 upregulation significantly via self-amplified cascade reactions. Meanwhile, with a decent cancer cell membrane coating, CMGCL exhibited great biosafety, tumor-targeted efficiency and anti-tumor effects in LLC lung tumor-bearing mice models. Additionally, a combination of CMGCL can sensitize the therapeutic effects of αPD-L1, substantially promoting tumor inhibition in both subcutaneous and lung metastasis LLC-bearing mice models. Overall, these findings highlight the potential connections between glucose metabolism and cell cuproptosis, offering a promising approach for treating lung cancer by integrating starvation, cuproptosis, and immunotherapy.

Immune microenvironment of Epstein-Barr virus (EBV)-negative compared to EBV-associated gastric cancers: implications for immunotherapy

BackgroundGastric carcinomas (GC) are aggressive malignancies, and only ~15% of patients respond to anti-programmed cell death (ligand) 1 (PD-(L)1) monotherapy. However, Epstein-Barr virus (EBV)-associated GCs (~5–10% of GCs) often harbor...

Overview of Systematic Reviews of ICIs in NSCLC With EGFR, ALK, ROS1, and RET Actionable Driver Mutations

The effectiveness and safety of immune checkpoint inhibitor (ICI) monotherapy in patients with previously treated advanced or metastatic non–small cell lung cancer with EGFR, ALK, ROS1, or RET actionable driver mutations or chromosomal rearrangements is currently uncertain. We assessed the efficacy and safety of ICIs in patients with this condition whose disease did not respond well to previous chemotherapy. We reviewed 13 systematic reviews of randomized controlled trials (RCTs). The quality assessment of these reviews revealed critical methodological flaws. All 13 systematic reviews focused on survival and progression-free survival (PFS) for patients with non–small cell lung cancer and EGFR gene mutations. The systematic reviews generally considered the same set of 4 clinical trials and did not report on other outcomes or patient groups, except for 1 review that looked at patients with different levels of anti-PD-L1 expression. We found no evidence on the efficacy and safety of ICIs in patients with ALK, ROS1, or RET mutations. Overall, the systematic reviews concluded that using ICIs alone, as a second-line therapy or beyond, does not significantly improve overall survival (OS) and PFS compared to chemotherapy in patients with non–small cell lung cancer with EGFR gene mutations. No conclusions can be made regarding the benefits of ICIs in patients with EGFR mutations based on histology or high antiprogrammed death-ligand 1 antibody expression levels. The safety of ICIs in patients with EGFR, ALK, ROS1, or RET actionable driver mutations could not be assessed because of the lack of evidence provided in the included systematic reviews.

Gadoxetic Acid-Enhanced Magnetic Resonance Imaging Features Can Predict Immune-Excluded Phenotype of Hepatocellular Carcinoma

Introduction: Immunotherapy is the first-line treatment for intermediate-advanced stage hepatocellular carcinoma (HCC), although its outcomes vary. This study aimed to identify imaging biomarkers of immunotherapy susceptibility linked to gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) and immune phenotypes, particularly immune-excluded phenotypes, with a tumor immune barrier. Methods: We performed immunohistochemical staining with a CD8+ antibody, and samples were classified into immune-inflamed, -intermediate, -excluded, and -ignored phenotypes. We assessed EOB-MRI findings obtained from 104 patients who underwent hepatectomy for HCC and evaluated the relationship between MRI findings and immune phenotype. Spatial transcriptome analysis of tumor tissues in each immune phenotype was performed to characterize the MRI findings. For validation, we analyzed the treatment effect on 60 nodules in another cohort of 27 patients who received combined immunotherapy using anti-programmed death-ligand 1 and anti-vascular endothelial growth factor (VEGF) antibodies. Results: HCCs with rim arterial phase hyperenhancement (APHE) (odds ratio [OR] 17.3, p = 0.009), peritumoral enhancement in the arterial phase (OR: 8.6, p < 0.004), and intermediate intensity on the hepatobiliary phase (HBP) measured with a visual 3-point scale (OR: 28.2, p = 0.002) were associated with immune-excluded phenotype, where tumors tended to be larger and of the single nodular type with extranodular growth and confluent multinodular rather than the simple nodular type. Spatial transcriptome analysis revealed a spatial relationship among cytotoxic T lymphocytes, VEGF signals, and cancer-associated fibroblasts at the tumor-invasive margins in this phenotype. From the validation study, nodules with any one of these three imaging findings had a significantly prolonged time to-nodular progression (p = 0.007, median not reached vs. 226 days). Conclusion: HCCs with rim APHE, peritumoral enhancement in arterial phase, and intermediate intensity on HBP with visual 3-point scale could be non-invasive biomarkers to predict the immune-excluded phenotype with the tumor immune barrier. These HCCs were most likely to respond to combined immunotherapy.

Seasonal influences on the efficacy of anti-programmed cell death (ligand) 1 inhibitors in lung cancer.

Seasonal variations in systemic immunity have been reported. This study aimed to evaluate whether seasonality affects the efficacy of anticancer immunotherapy. A total of 604 patients with lung cancer receiving single anti-programmed cell death (ligand) 1 (anti-PD-[L]1) inhibitors from two prospective observational cohorts were screened. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Patients were classified into two groups according to the season when the treatment started: winter (November-February) and other seasons (March-October). Kaplan-Meier analysis and Cox proportional hazards models were fitted to evaluate the impact of seasonality on survival. For validation, propensity score matching was performed. A total of 484 patients with advanced non-small cell lung cancer were included. In an unmatched population, multivariable analysis demonstrated that the winter group (n=173) had a significantly lower risk of progression or death from immunotherapy than the other group (n=311) (PFS: hazard ratio [HR],0.77 [95% confidence interval (CI), 0.62-0.96]; p=.018; OS: HR,0.77 [95% CI, 0.1-0.98]; p=.032). In a propensity score-matched population, the winter group (n=162) showed significantly longer median PFS (2.8 months [95% CI, 1.9-4.1 months] vs. 2.0 months [95% CI, 1.4-2.7 months]; p=.009) than the other group (n=162). The winter group's median OS was also significantly longer than that of the other group (13.4 months [95% CI, 10.2-18.0 months] vs. 8.0 months [95% CI, 3.6-8.7 months]; p=.012). The trend toward longer survival in the winter group continued in subgroup analyses. Starting an anti-PD-(L)1 inhibitor in winter was associated with better treatment outcomes in patients with lung cancer compared to other seasons.

Association Between Multisystem Immune-related Adverse Events and Progression-free Survivals in PD-1/PD-L1 Inhibitor Monotherapy.

Immune-related adverse events (irAEs) occur in various organs, and sometimes multiply following treatment with immune checkpoint inhibitors (ICIs). This study aimed to determine the association between the number of irAEs and clinical outcomes. This was a retrospective study that included patients with lung cancer, melanoma, and head and neck cancer who were treated with anti-programmed cell death (ligand) 1 (PD-1/PD-L1) monotherapy. We evaluated the association between the number of irAEs and progression-free survival (PFS) in the simple Cox regression analysis. To eliminate the immortal-time bias, an additional landmark analysis was performed. In total, 92, 69, and 37 patients were allocated to the no, single, and multisystem irAEs groups, respectively. The multisystem irAEs were associated with better PFS compared to the no irAE group. In contrast, at the 12-week landmark, multisystem irAEs were associated with poor PFS compared to the no irAEs group. Furthermore, the rate of treatment suspension owing to irAEs in the multisystem irAEs group (62.5%) was higher than that in the single irAE group (17.3%) at the 12-week landmark. The incidence of multisystem irAEs was associated with improved clinical outcomes in patients with lung cancer, melanoma, and head and neck cancer treated with PD-1/PD-L1 inhibitor monotherapy. However, these results may be influenced by a potential immortal-time bias. When accounting for this bias, the early development of multisystem irAEs within 12 weeks was linked to treatment suspension and poorer clinical outcomes.

Anti–Programmed Death Ligand 1 Plus Targeted Therapy in Anaplastic Thyroid Carcinoma

Anaplastic thyroid carcinoma (ATC) is a rare and lethal cancer. Although progress has been made in recent years in patients with mutated BRAF tumors, those who respond initially eventually die of their disease; furthermore, there are no approved therapies for non-BRAF mutated tumors. To determine whether treatment with matched-targeted therapy plus immune checkpoint inhibitors were associated with improved overall survival (OS). A phase 2 trial at a single center, tertiary institution with parallel cohorts, assigning treatment with targeted therapy according to the tumor mutation status. Patients with mutated BRAF V600E tumors received vemurafenib/cobimetinib plus atezolizumab (cohort 1); those with mutated RAS (NRAS, KRAS, or HRAS) or NF1/2 tumors received cobimetinib plus atezolizumab (cohort 2). Patients without any of these variants were assigned to receive bevacizumab plus atezolizumab (cohort 3). Patients were enrolled from August 3, 2017, to July 7, 2021. All consecutive, systemic therapy-naive patients with ATC with active disease and who met eligibility criteria were considered for participation. The analysis was conducted in September 2023. Patients were assigned to targeted therapy based on the driver mutation as follow: BRAF V600E (cohort 1, vemurafenib plus cobimetinib), RAS/NF (cohort 2, cobimetinib), or non-BRAF/RAS/NF (cohort 3, bevacizumab). All received atezolizumab. The primary outcome of the study was median OS of the entire targeted therapy cohort, compared with historical median OS of 5 months. Forty-three patients with ATC were enrolled in the targeted therapy cohorts, of which 42 were included in the primary analysis. The median OS in patients across these 3 cohorts was 19 months (95% CI, 7.79-43.24). Median OS and progression-free survival per cohort were as follows: cohort 1: 43 months (95% CI, 16-not estimable [NE]), 13.9 months (6.6-64.1); cohort 2: 8.7 months (95% CI, 5.1-37.0) and 4.8 months (1.8-14.7); cohort 3 (vascular endothelial growth factor inhibitor group): 6.21 months (4.1-NE) and 1.3 months (1.3-NE), respectively. In this nonrandomized clinical trial, atezolizumab combined with targeted therapy resulted in a longer median OS than historical landmark, achieving the study's primary end point, with cohort 1 achieving the longest OS. ClinicalTrials.gov Identifier: NCT03181100.

Comprehensive population pharmacokinetic modelling of sugemalimab, an anti-programmed death-ligand 1 (PD-L1) human monoclonal antibody, in patients with solid tumours or lymphomas across multiple Phase I-III studies.

The aim of this study was to develop a population pharmacokinetics model for sugemalimab, a monoclonal antibody that targets programmed death-ligand 1 (PD-L1), using data from Phase I-III trials and to assess clinical factors affecting sugemalimab exposure. A nonlinear mixed-effect modelling approach was employed to analyse pooled data from nine studies involving 1628 subjects to characterize the PopPK of sugemalimab. This investigation examined the influence of various covariates on sugemalimab pharmacokinetics (PK), encompassing demographics, baseline hepatic and renal function-related covariates, and others (including anti-drug antibody [ADA], combination treatment, Eastern Cooperative Oncology Group [ECOG] performance score, tumour burden and tumour type). Estimation accuracy and predictive ability of the final model were evaluated using various methods. The influence of covariates on sugemalimab exposure was assessed by simulation from the final model. A two-compartment model with first-order elimination and time-varying clearance effectively described the PK of sugemalimab. Covariate analyses revealed significant relationships between sugemalimab clearance and body weight, albumin, gender, ADA, tumour burden and tumour type. The statistically significant covariates on central volume were body weight, albumin, gender and tumour type. No significant relationships were found in the final model for age, race, alanine aminotransferase, aspartate aminotransferase, creatinine, total bilirubin, alkaline phosphatase, combination treatment, creatinine clearance, ECOG, renal function or hepatic function. All significant covariates demonstrated less than a 20% effect on sugemalimab exposure. The PopPK model adequately described the pharmacokinetic profile of sugemalimab with no clinically meaningful impact observed on its exposure across all covariates. Dose adjustment does not appear to be necessary.

Benmelstobart plus anlotinib in patients with EGFR-positive advanced NSCLC after failure of EGFR TKIs therapy: a phase I/II study

The effect of immune‐based therapies on patients with epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitor (TKI) therapy remains unclear. The ALTER-L038 study aimed to evaluate efficacy and safety of a chemotherapy-free combination of benmelstobart, an anti-programmed cell death ligand 1 antibody, and anlotinib, a small-molecule multi-target anti-angiogenic TKI, in EGFR-positive advanced NSCLC patients who progressed after EGFR TKI therapy. Patients were enrolled in a phase I/II study. In phase I (dose-escalation), patients received anlotinib (8, 10, 12 mg) plus benmelstobart (1200 mg). Recommended phase II dose, determined during phase I, was used in phase II dose-expansion cohort. Primary endpoints were maximum tolerable dose in phase I and progression-free survival (PFS) in phase II. At the data cutoff date (March 10, 2024), 55 patients were enrolled in phase II dose-expansion cohort. Median PFS of patients included in phase II cohort was 9.0 months, median overall survival was 28.9 months, objective response rate was 25.5%, disease control rate was 87.3%, and median duration of response was 19.8 months. Incidence of grade ≥3 treatment-related adverse events in study population was 25.5% (14/55), whereas grade ≥3 immune-related adverse events occurred in 10.9% (6/55) of patients. Benmelstobart plus anlotinib showed promising anti-tumor efficacy with tolerable safety profile, supporting the value of further development of this convenient chemotherapy-free regimen for patients with EGFR-positive advanced NSCLC who progressed after EGFR TKI therapy. Trial Registration: ChiCTR1900026273.

6529 The Risk of Hypophysitis Following Treatment With Relatlimab+Nivolumab Appears Higher Than Expected

Abstract Disclosure: N. Chamorro-Pareja: None. A.T. Faje: None. K.K. Miller: Stock Owner; Self; Bristol-Myers Squibb. Hypophysitis is a recognized complication of immune checkpoint inhibitor therapy; the risk of developing hypophysitis in patients receiving nivolumab (an anti-programmed death-ligand 1 [anti-PD-1]) is estimated to be &amp;lt; 1%. Relatlimab is a human monoclonal antibody targeting lymphocyte activation gene 3 (LAG-3) recently approved in combination with nivolumab for the treatment of unresectable or metastatic melanoma. The risk of hypophysitis as a complication of relatlimab therapy is not well-defined. Objective: To examine the prevalence, identify risk factors, and characterize the clinical presentation of hypophysitis in patients receiving relatlimab+nivolumab. Methods: 159 patients received relatlimab+nivolumab at the Mass General Brigham health care system between 6/2015 and 11/2023. Twenty-seven patients were excluded because they were either diagnosed with adrenal insufficiency (AI) before receiving relatlimab+nivolumab or AI was secondary to other factors, primarily exogenous glucocorticoid administration, leaving a total of 122 patients. The medical records of these patients, including provider encounters, laboratory results, medication records, and radiologic images were reviewed. Data are presented as mean ± SD. Results: Central AI was diagnosed in 10 patients (7.5% of the cohort) after relatlimab+nivolumab administration. The mean age was 64.5±13.8 vs. 67.1±14.4 in patients with AI vs. patients without AI (p= 0.58). Sixty percent of patients in the AI group were male compared to 53% of patients without AI (p= 0.68). The development of AI was not related to the cumulative dose of relatlimab+nivolumab (mean number of cycles 6.4±3.2 vs. 4.9±5.0, p=0.35). The most common presenting symptoms of AI were fatigue, anorexia, nausea, and vomiting. No patients were diagnosed with additional anterior pituitary hormone deficiencies, though not all patients were evaluated for these diagnoses; none had diabetes insipidus. Nine patients had MRIs performed after the diagnosis of central AI; 7 of these patients had pre-treatment MRIs for comparison. Diffuse pituitary enlargement was seen on MRI after initiation of relatlimab+nivolumab in 3 patients up to 8 weeks prior to the diagnosis of hypopituitarism. All patients had persistent hypopituitarism at the most recent evaluation. Conclusions: This study is the first cohort analysis of hypophysitis in patients treated with relatlimab+nivolumab. A significant portion of patients were diagnosed with central AI, presumptively due to hypophysitis given the lack of an identifiable alternative etiology. Although the clinical phenotype of these patients paralleled published studies analyzing anti-PD-1 monotherapy, combination treatment with relatlimab+nivolumab appeared to confer a significantly higher risk of developing hypophysitis. Presentation: 6/3/2024

MerTK+ macrophages promote melanoma progression and immunotherapy resistance through AhR-ALKAL1 activation.

Despite our increasing understanding of macrophage heterogeneity, drivers of macrophage phenotypic and functional polarization in the microenvironment are not fully elucidated. Here, our single-cell RNA sequencing data identify a subpopulation of macrophages expressing high levels of the phagocytic receptor MER proto-oncogene tyrosine kinase (MerTK+ macrophages), which is closely associated with melanoma progression and immunotherapy resistance. Adoptive transfer of the MerTK+ macrophages into recipient mice notably accelerated tumor growth regardless of macrophage depletion. Mechanistic studies further revealed that ALK And LTK Ligand 1 (ALKAL1), a target gene of aryl hydrocarbon receptor (AhR), facilitated MerTK phosphorylation, resulting in heightened phagocytic activity of MerTK+ macrophages and their subsequent polarization toward an immunosuppressive phenotype. Specifically targeted delivery of AhR antagonist to tumor-associated macrophages with mannosylated micelles could suppress MerTK expression and improved the therapeutic efficacy of anti-programmed cell death ligand 1 therapy. Our findings shed light on the regulatory mechanism of MerTK+ macrophages and provide strategies for improving the efficacy of melanoma immunotherapy.