Immunotherapy For Treatment Research Articles

Circulating microRNAs as a Prognostic Tool to Determine Treatment Efficacy in Lung Cancer Patients Undergoing Pembrolizumab PD-1 Blockade Immunotherapy

Background: Pembrolizumab has recently emerged as a PD-1 blockade immunotherapy treatment for lung cancer. It is critical that such treatment strategies for lung cancer should be chosen not only on the basis of histopathological features and the expression of targetable cell surface proteins (such as PD-1), but should rather be selected based on other determinants of treatment success or risk factors for poor prognosis. One method to forecast cancer trajectory is the identification of biomolecular signatures such as microRNAs (miRNAs), non-protein-coding RNA molecules that play a regulatory role in gene expression by modulating the translation or stability of messenger RNA. Methods: To find out which miRNAs have an important influence on anti-PD-1 treatment outcomes, we evaluated miRNA levels in sera from 38 lung cancer patients undergoing 3 months of pembrolizumab treatment. We selected a panel of miRNAs previously shown to be involved in lung cancer or PD-1 signaling and performed qPCR analysis. Results: Overall, we observed a significant decrease in the levels of miR126-5p (4-fold), let-7a (5-fold), miR133a-3p (4-fold), miR3615 (2-fold), miR4516 (3-fold), miR16 (3-fold), miR34c-5p (2-fold), miR20b-5p (5-fold), miR106b-5p (5-fold), miR146a-5p (3-fold) and miR181b-5p (3-fold) in response to treatment indicating effectiveness of immunotherapy. Within our selected panel of miRNAs, we identified two markers relevant to cancer prognosis: miR-217, which is negatively associated with patient survival, and let-7a, which is positively associated with patient survival. Conclusions: Our findings suggest that circulating miRNAs can be used for future treatment evaluation and lung cancer prognosis, with potential as therapeutic targets.

Next generation sequencing-based MSI scoring predict benefit in mismatch repair deficient tumors treated with nivolumab: follow-up on NCI-MATCH arm Z1D.

Mismatch repair deficient (dMMR) tumors have demonstrated favorable responses to immune checkpoint inhibition targeting PD-1. However, more in-depth identification of predictors of response could further refine patient selection for immunotherapy treatment. We undertook integrated evaluation performed on samples collected from 28 of 42 patients enrolled on the NCI-MATCH arm Z1D trial that evaluated PD-1 inhibition treatment with nivolumab in patients with non-colorectal dMMR tumors. Genomic analyses were performed using next-generation sequencing (NGS), whole exome sequencing, and RNA sequencing and supplemented by multiplex immunofluorescence performed on tissue samples. In this dMMR population, more extensive alterations of microsatellites as assessed by measures of NGS was associated with clinical benefit and tumor mutational burden. RNA sequencing further revealed associations between clinical benefit and immune infiltration index. Gene sets enriched in patients with clinical benefit included interferon signaling, antigen processing and PI3K-AKT-mTOR signaling, while hedgehog signaling was found to be enriched in subjects lacking clinical benefit. These genomic data highlight the importance of immune infiltration and antigen presentation in dMMR tumors that respond to immune checkpoint blockade. In addition, they suggest that, even within a dMMR population, NGS based measures of MSI could serve as biomarkers of immunotherapy response.

Quantifying morphologic variations as an alternate to standard response criteria for unresectable primary liver tumors after checkpoint inhibition therapy.

The aim of this study was to assess the feasibility of quantifying morphologic changes in tumors during immunotherapy, as a reflection of response or survival. A retrospective single-center analysis was performed in patients with unresectable liver cancer previously enrolled in clinical trials combining immunotherapy (tremelimumab ± durvalumab) and locoregional treatment (either ablation or transarterial chemoembolization). Conventional response (RECIST 1.1) was assessed at 6-month follow-up. For morphologic assessment, the largest target lesion was manually segmented on axial slices in two dimensions using contrast-enhanced CT. Solidity and circularity of tumors were calculated at baseline, 3-month follow-up, and at 6-months follow-up. Survival analysis was performed. From the 68 patients enrolled in clinical trials, 28 did not have target lesions separate from lesions treated by locoregional therapies, and 3 had no follow-up imaging. Thirty-seven patients (9 with biliary cancer and 28 with hepatocellular carcinoma) were included. Shape features and shape variation were not correlated with RECIST 1.1 status at 6-month follow-up. However, patients with low solidity tumors at 6-month follow-up showed poorer prognosis compared with patients with high solidity tumors at 6-month follow-up (p = 0.01). Solidity variation analysis confirmed that a decrease of tumor solidity at 6-month follow-up was associated with poorer prognosis (p = 0.01). No association was found between shape features at baseline or shape features at 3-month follow-up with overall survival. Evolution and variation of tumor morphology during treatment may reflect or correlate with outcomes and contribute toward adapted response criteria.

Overcoming Resistance Mechanisms to Melanoma Immunotherapy.

The advent of immune checkpoint inhibition has revolutionized treatment of advanced melanoma. While most patients derive survival benefit from established immunotherapies, notably monoclonal antibodies blocking cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1, a subset does not optimally respond due to the manifestation of innate or acquired resistance to these therapies. Combination regimens have proven efficacious relative to single-agent blockade, but also yield high-grade treatment toxicities that are often dose-limiting for patients. In this review, we discuss the significant strides made in the past half-decade toward expanding the melanoma immunotherapy treatment paradigm. These include newly approved therapies, adoption of neoadjuvant immunotherapy, and studies in the clinical trials pipeline targeting alternative immune checkpoints and key immunoregulatory molecules. We then review how developments in molecular and functional diagnostics have furthered our understanding of the tumor-intrinsic and -extrinsic mechanisms driving immunotherapy resistance, as well as highlight novel biomarkers for predicting treatment response. Throughout, we discuss potential approaches for targeting these resistance mechanisms in rational combination with established immunotherapies to improve outcomes for patients with melanoma.

Unique lymphocyte transcriptomic profiles in septic patients with chronic critical illness.

Despite continued improvement in post-sepsis survival, long term morbidity and mortality remain high. Chronic critical illness (CCI), defined as persistent inflammation and organ injury requiring prolonged intensive care, is a harbinger of poor long-term outcomes in sepsis survivors. Current dogma states that sepsis survivors are immunosuppressed, particularly in CCI. Investigation of this immune suppression in heterogeneous immune populations across distinct clinical trajectories and outcomes, along with limited sampling access, is accessible via single-cell RNA sequencing (scRNA-seq). scRNA-seq analysis was performed on healthy subjects (n=12), acutely septic patients at day 4 ± 1 (n=4), and those defined as rapid recovery (n=4) or CCI (n=5) at day 14-21. Differential gene expression and pathway analyses were performed on peripheral blood lymphocytes at both a population and annotated cell subset level. Cellular function was assessed via enzyme-linked immunosorbent spot (ELISpot), cytokine production analysis, and T-cell proliferation assays on an additional cohort of septic patients (19 healthy, 68 acutely septic, 27 rapid recovery and 20 classified as CCI 14-21 days after sepsis onset). Sepsis survivors that developed CCI exhibited proportional shifts within lymphoid cell populations, with expanded frequency of CD8+ and NK cells. Differential expression and pathway analyses revealed continued activation in T cells and NK cells, with generalized suppression of B-cell function. Both T and NK cell subsets displayed transcriptomic profiles of exhaustion and immunosuppression in CCI, particularly in CD8+ T effector memory (TEM) cells and NK cells. Functional validation of T-cell behavior in an independent cohort demonstrated T cells maintained proliferative responses in vitro yet exhibited a marked loss of cytokine production. IFN-γ production at the acute phase (day 4 ± 1) was significantly reduced in subjects later classified as CCI. Sepsis patients exhibit unique T-, B-, and NK-cell transcriptional patterns that are both time- and clinical trajectory-dependent. These transcriptomic and pathway differences in sepsis patients that develop CCI are associated with exhaustion in CD8+ TEM cells and NK cells. Understanding the specific immune system patterns of different cell subsets after sepsis at a molecular level will be key to the development of personalized immunotherapy and drug-targeting intervention. https://clinicaltrials.gov/, identifier NCT02276417.

Clinical Trial Eligibility and Outcomes in Patients With Metastatic NSCLC Treated Outside of Clinical Trials.

There are limited data available regarding patient outcomes in those who would have been ineligible to receive therapy based on the original clinical trial eligibility criteria. We decided to conduct a retrospective study to evaluate outcomes based on clinical trial eligibility in patients with metastatic non-small cell lung cancer (NSCLC). A retrospective chart review of all patients with metastatic NSCLC who received first-line systemic therapy at a single academic institution was performed. Each patient's chart was reviewed to determine if they would have qualified for the phase 3 clinical trial that led to the approval of the specific treatment regimen which they received. Data were analyzed to determine if there was a difference in survival time between those who would have been eligible compared with those who were ineligible for the clinical trial of the treatment regimen administered. There were 170 patients with a diagnosis of metastatic NSCLC who received first-line systemic therapy. Of these, 109 received combined chemotherapy, 25 received immunotherapy, and 36 received targeted therapy. There is a statistically significant difference in the restricted mean survival time between the eligible and ineligible groups in those who received combined chemotherapy (19.9 months vs 13.2 months; P = .03), but not in either the immunotherapy group (22.4 months vs 12.9 months; P = .06) or the targeted therapy group (57.7 months vs 39.0 months; P = .14). These data support less restrictive clinical trial eligibility criteria for those with metastatic NSCLC. This is especially true regarding both targeted therapy and immunotherapy treatment regimens.

A minimalist multifunctional nano-prodrug for drug resistance reverse and integration with PD-L1 mAb for enhanced immunotherapy of hepatocellular carcinoma

Clinical treatment of hepatocellular carcinoma (HCC) with 5-fluorouracil (5-FU), the primary anticancer agent, remains unsatisfactory due to the glutathione (GSH)-associated drug resistance and immunosuppressive microenvironment of HCC. To develop a facile yet robust strategy to overcome 5-FU resistance for enhanced immunotherapy treatment of HCC via all dimensional GSH exhaustion, we report in this study construction of a minimalist prodrug consisting of 5-FU linked to an indoleamine-(2,3)-dioxygenase (IDO) inhibitor (IND) via a disulfide bridge, FU-SS-IND that can further self-assemble into stabilized nanoparticles, FU-SS-IND NPs. Specifically, besides the disulfide linker-induced GSH exhaustion, IND inhibits GSH biosynthesis and enhances the effector function of T cells for turning a “cold” tumor to a “hot” one, which synergistically achieving a tumor inhibition rate (TIR) of 92.5% in a 5-FU resistant mice model. Most importantly, FU-SS-IND NPs could upregulate programmed death ligand 1 (PD-L1) expression on the surface of tumor cells, which enables facile combination with immune checkpoint blockade (ICB) for a ultimate prolonged survival lifetime of 5-FU-resistant tumors-bearing mice. Overall, the minimalist bioreducible nano-prodrug developed herein demonstrates great translatable potential for efficiently reversing drug resistance and enhancing immunotherapy of HCC.

Differential neural network based adaptive average output feedback control design for dosage determination on cancer based immunotherapy treatment

Immunotherapy involves natural and synthetic substances to stimulate the body’s immune response. This treatment approach is practical not only for addressing immune deficiencies but also for combating malignancies. This paper describes a non-parametric approximated adaptive control process for managing cancer dynamics under immunotherapy treatment, utilizing a combination of a differential neural network (DNN) observer and nonlinear control techniques such as sliding mode and local optimal strategies. By employing the state estimation and control methods, close tracking between the estimated states provided by the neural network and the cancer model dynamics is possible. Internal model reconstruction and an observer provided by a variable structure model are essential for controlling unknown plants. Furthermore, the control design has successfully reduced tumor cells despite uncertainties and external perturbations affecting cancer dynamics. This robustness enhances the reliability of the proposed design. A virtual real-time scheme was developed to demonstrate this controller’s feasibility in real clinical scenarios. In this scheme, a simulated patient generates variables of immunotherapy dynamics as electrical signals, which are then analyzed by a real-time project.

O-GlcNAcylation-related genes mediate tumor microenvironment characteristics and prediction of immunotherapy response in gastric cancer.

We aim to identify molecular clusters related to O-GlcNAcylation and establish a novel scoring system for predicting prognosis and immunotherapy efficacy in patients with gastric cancer (GC). The transcriptomic and clinical data are obtained from XENA-UCSC and GEO databases. The O-GlcNAcylation-related genes are obtained from the GSEA database. Consensus clustering analysis is employed to identify O-GlcNAcylation-related molecular clusters, and principal component analysis (PCA) is utilized to develop a novel prognostic scoring system for predicting GC outcomes and immunotherapy efficacy. The prognostic accuracy of the scoring system is assessed across five real-world cohorts. The biological function of actin alpha 2, smooth muscle (ACTA2) in GC is determined through experimental verification. Using 34 O-GlcNAcylation-related genes associated with prognosis in GC patients, these individuals are divided into two distinct subgroups characterized by different outcomes, tumor microenvironment profiles, and clinical case characteristics. The DEGs between the two subgroups are subsequently used to further divide the GC patients into two subgroups by consensus cluster analysis. PCA is used to construct a prognostic scoring system, which reveal that patients in the low-score subgroup have a better prognosis and greater benefit from immunotherapy. The accuracy of the scoring system is confirmed through validation in a cohort of patients receiving immunotherapy in the real world. ACTA2 promotes proliferation and inhibits apoptosis in GC cells. These findings suggest that we successfully establish molecular clusters associated with O-GlcNAcylation and develop a scoring system that demonstrates strong performance in predicting the prognosis of patients with GC and the effect of immunotherapy interventions.

Blood based immune biomarkers associated with clinical frailty scale in older patients with melanoma receiving checkpoint inhibitor immunotherapy

IntroductionImmunotherapy with checkpoint inhibition (ICI) is increasingly prescribed to older patients with cancer. High age, especially in combination with frailty, has been associated to immune senescence, which is the age-related decline in immune function, thereby possibly hindering ICI effectiveness. This cross-sectional study aimed to assess whether blood cell immune senescence markers are associated with age, frailty and response to anti-PD-1 treatment in older patients with metastatic melanoma.MethodsIn a prospective observational study, sixty patients with stage IIIC or IV melanoma undergoing anti-PD1 treatment were categorized into young (< 65 years; n = 22), old (> 65 years) without frailty (n = 19), and old with frailty (n = 19). In-depth immune cell phenotyping was performed in baseline blood samples (prior to treatment) using multispectral flow cytometry and compared between groups and with immunotherapy treatment response. Antigen-presenting cell capacity was evaluated using mixed lymphocyte reaction and T cell proliferative potential was assessed using PHA proliferation assay.ResultsNo significant differences in treatment response rates were observed across age groups. Older patients, irrespective of frailty, showed lower levels of naïve CD8 + T cells, with the old and frail group also exhibiting reduced tissue-resident effector memory CD8 + T cells and CD8 + mucosal associated invariant T (MAIT) cells. These differences were not associated with treatment outcomes. T cell proliferation and antigen-presenting cell capacities did not differ across groups.ConclusionSeveral ageing and frailty associated changes were detected among circulating immune cells in blood but were not associated with response to immunotherapy in our study. While these findings suggest that the level of frailty and ageing may not necessarily preclude the efficacy of ICI therapy, further investigation is needed to fully understand the impact of frailty and ageing on immunotherapy.

“Motion Capture Suit Sign” for Immunotherapy-Induced Inflammatory Arthritis on 99mTc-MDP Bone Scintigraphy

Abstract We report the 99mTc-MDP bone scan of a 44-year-old man with a history of lung adenocarcinoma and recent multiple joint pain after completing pembrolizumab immunotherapy treatment. This interesting image of symmetric uptakes around bilateral joints throughout the skeleton resembles the ball sensors on a motion capture suit. Hence, we recommend naming this distinctive imaging appearance as the “motion capture suit” sign.

Predicting survival in bladder cancer with a novel apoptotic gene-related prognostic model

BackgroundApoptosis and apoptotic genes play a critical role in the carcinogenesis and progression of bladder cancer. However, there is no prognostic model established by apoptotic genes.MethodsMessenger RNA (mRNA), Expression data, and related clinical data were obtained from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. After extracting the apoptosis-related genes, the survival-related apoptosis genes were screened by univariate Cox regression analysis in the TCGA cohort. Following the Least Absolute Shrinkage and Selection Operator (LASSO) regression method, these genes were modeled by multivariate Cox analysis. The predictive abilities of the Apoptosis-Related Gene Model (ARGM) for overall survival (OS) rate, disease-specific survival (DSS) measures, and progression-free survival (PFS) were verified by the Kaplan–Meier(K-M)survival analysis and time-dependent Receiver Operating Characteristic (ROC) curve. Functional enrichment analyses were performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG). CIBERSORT and Single-Sample Gene Set Enrichment Analysis (ssGSEA) were used to calculate the type of immune cell infiltration and immune functions. The model’s predictive ability for immunotherapy were evaluated using Tumor Immune Dysfunction and Exclusion (TIDE) and the Imvigor210 study.The single-cell sequencing was used to display the expression level of the ARGM.Finally,qRT-PCR was executed to validate the expression level of ARGM.ResultsSeveral apoptosis genes were identified through the model, including ANXA1, CASP6, CD2, F2, PDGFRB, SATB1, and TSPO. The prognostic value of the model for OS, DSS, and PFS were verified using the TCGA and GEO cohort. The model can predict patient response to immunotherapy treatment as established through the model’s score which was linked to different types of immune cell infiltration and identified significant differences in the signal pathways between high-risk and low-risk groups. Nomogram variables, prompted from ARGM and clinical parameters, also generate a high predictive value for patient survival.ConclusionOurestablished apoptosis-related gene model (ARGM) has a substantial predictive value for prognosis and immunotherapy of bladder cancer. It may help with clinical consultation, clinical stratification, and treatment selection. The immune infiltration status and signal pathway of different risk groups also provide direction for further research.

Health-related Quality of Life in Jack Jumper Ant venom Allergy: Validation of the “Venom-Allergy Quality of Life Questionnaire” VQLQ

Assessment of health-related quality of life (HRQoL) in patients with allergy to the venom of the Jack Jumper Ant (JJA), Myrmecia pilosula - a Hymenoptera order species native and endemic to the South-Eastern quarter of Australia. This has not previously been studied, despite an estimated population prevalence of generalised allergic symptoms as high as 3% in some areas. To validate the VQLQ HRQoL instrument - previously validated in wasp and bee venom allergic patients - for use in this specific ant venom-allergic population. The 14-item VQLQ survey instrument was administered to patients with clinical allergy to JJA venom presenting at the state treatment centre for venom-immunotherapy. Surveys were performed at different time points of the progression through visits for venom immunotherapy treatment. Cross-sectional and longitudinal validation was performed against 'expectation of outcome'(EO) questionnaire by determining correlation and agreement. 271 individuals contributed survey data, comprising a median age of 52 years (3-85) with a bimodal distribution, with 25% being < 18 years of age. Internal consistency was excellent, with a Cronbach of 0.95. Cross-sectional validity was demonstrated with a positive correlation VQLQ to EO of 0.44 (p < 0.001). Performance was nearly identical when stratified into adults and children(<18 yo). Longitudinal Validity was suggested as both VQLQ and EO improved over time in both adults and children, but this only had paired correlation at two time points in adults. Bland-Altman analysis demonstrated an acceptable agreement between VQLQ and EO and no evidence of systematic bias. The VQLQ appears to offer similar performance of HRQoL measurement in patients suffering from JJA venom allergy, as has previously been demonstrated in other Hymenoptera species. In addition, this is the first study to demonstrate cross-sectional validity specifically in a paediatric population 3-18 years of age.

Sex-Related Differences in Immunotherapy Outcomes of Patients with Advanced Non-Small Cell Lung Cancer.

Immunotherapy with ICIs has revolutionized the treatment for NSCLC. The impact of sex on treatment outcomes remains unclear. The aim of this study was to evaluate sex-related differences in immunotherapy outcomes in a real-world population of NSCLC patients. Demographics, clinical, pathological characteristics, and treatment-related variables were analyzed to understand the differences in efficacy and safety outcomes in relation to sex. 174 advanced NSCLC patients receiving first-line ICIs, either alone or in conjunction with chemotherapy, were included. No differences based on gender were observed in PFS and OS. Prognostic factors for OS and PFS included liver metastases and CRP levels at treatment discontinuation (TD). IrAE-related TD occurred at a significantly higher rate in females. GI toxicity, including hepatitis and colitis, was predominantly observed in females, whereas pneumonitis was the most frequent irAE leading to TD in males. Despite no significant differences based on gender being observed in survival outcomes, our study showed that female patients with advanced NSCLC receiving ICIs are at a substantially greater risk of severe symptomatic irAEs and TD. This finding indicates that broad-based sex differences could potentially exist and emphasizes the need for further investigations into the role played by gender in immunity and cancer immunotherapy treatment.

Proteomic profiling of oral squamous cell carcinoma tissues reveals altered immune-related proteins: implications for personalized therapy

ABSTRACT Objectives Oral squamous cell carcinoma poses a substantial global health challenge marked by rising mortality rate. Recently, immunotherapy has shown promising results in cancer management by enhancing immune response. Thus, identifying additional immune-related markers is critical for advancing immunotherapy treatments. Methods Data-independent acquisition (DIA) mass spectrometry approach was used to explore differentially expressed immune-related proteins in oral cancer tissues compared to adjacent non-cancerous tissues. Functional significance was identified through Gene Ontology, pathway, and network analysis. Gene expression of identified proteins was validated using transcriptomic data. Results DIA analysis identified 29,459 precursors corresponding to 3429 proteins. Among these, 1060 proteins were differentially expressed, with 166 being immune-related. Differentially regulated proteins were involved in innate immune response, mitochondrial ATP synthesis, and neutrophil degranulation. Pathway analysis of immune-related proteins showed perturbation in anti-tumor immunity-related pathways such as interferon signaling, TCR signaling, PD-1 signaling, and antigen processing and presentation. Significance of these pathways was further reinforced by the strong interactions identified in the protein–protein interaction network analysis. Additionally, gene expression analysis showed similar mRNA expression patterns for key proteins involved in altered pathways, including ISG15, IFIT1/3, HLA-A/C and OAS2/3. Conclusions Further validation of these proteins could establish them as potential targets for personalized therapy.

Predictable regulation of gut microbiome in immunotherapeutic efficacy of gastric cancer.

Immunotherapy has showcased remarkable progress in the management of gastric cancer (GC), prompting the need to proactively identify and classify patients suitable for immunotherapy. Here, 30 patients were enrolled and stratified into three groups (PR, partial response; SD, stable disease; PD, progressive disease) based on efficacy assessment. 16S rRNA sequencing were performed to analyze the gut microbiome signature of patients at three timepoints. We found that immunotherapy interventions perturbed the gut microbiota of patients. Additionally, although differences at the enterotype level did not distinguish patients' immunotherapy response, we identified 6, 7, and 19 species that were significantly enriched in PR, SD, and PD, respectively. Functional analysis showed that betalain biosynthesis and indole alkaloid biosynthesis were significantly different between the responders and non-responders. Furthermore, machine learning model utilizing only bacterial biomarkers accurately predicted immunotherapy efficacy with an Area Under the Curve (AUC) of 0.941. Notably, Akkermansia muciniphila and Dorea formicigenerans played a significant role in the classification of immunotherapy efficacy. In conclusion, our study reveals that gut microbiome signatures can be utilized as effective biomarkers for predicting the immunotherapy efficacy for GC.

Evaluating the Efficacy of Immunotherapy in Fragile Hospitalized Patients.

Immunotherapy is the cornerstone of treatment for many cancers. The effectiveness of immunotherapy in hospitalized patients is unknown due to the exclusion of this fragile population from clinical trials. This study evaluates the efficacy of immunotherapy in fragile hospitalized patients. We conducted a single-center retrospective study involving 49 patients who started an immunotherapy (IO) during a hospitalization or within 3 months after a hospitalization at the Centre Hospitalier de l'Université de Sherbrooke (CHUS). Efficacy analysis included objective response rate (ORR), overall survival (OS), and progression-free survival (PFS). Immunotherapy resulted in 30.6% of all grades combined and 18.4% of grade three to four immune-related adverse events (irAE). Efficacy outcomes were inferior in the fragile cohort of patients with ORR of 38.9%, PFS of 2.8 months (95% CI [2.17-3.35]), and OS of 3.2 months (95% CI [1.60-4.84]). Performance status of ECOG three to four compared to ECOG zero predicts poor OS (HR 5.666 [1.207-26.594]; p = 0.028) and PFS (HR 4.136 [0.867-19.733]; p = 0.075). Fitness to receive four to six cycles (HR 0.335 [0.152-0.0.738]; p < 0.007) or more predicts greater OS compared to one to three cycles of immunotherapy. Low levels of serum albumin (HR 0.917 [0.852-0.987]; p = 0.021) and elevated levels of serum LDH (HR 2.224 [1.469-3.367]; p < 0.001) are associated with a reduced OS. The effectiveness of immunotherapy in fragile hospitalized patients is compromised, although they exhibit significant irAE. Excellent performance status, fitness to receive many IO treatments, and normal levels of serum LDH and albumin may be useful in selecting patients who will benefit from immunotherapy.

Ultrasound-triggered nano delivery of lenvatinib for selective immunotherapy treatment against hepatocellular carcinoma

Although there have been remarkable advances in the treatment of hepatocellular carcinoma (HCC), the prognosis remains poor in those with advanced stage and more effective therapeutic options are urgently needed. Lenvatinib (Len), a multiple receptor tyrosine kinase inhibitor, is an emerging molecular targeted agent for HCC, whose immunomodulatory activities have been investigated. However, Len utilization is limited because of its low metabolic stability, poor bioavailability and dose-dependent toxicity, rendering its direct use insufficient for immune modulation. Stimuli-responsive nanoparticles, which are drug-targeted delivery platforms for on-demand drug release, facilitate deeper and uniform tumour penetration, providing alternative solutions to overcome current limitations. Ultrasound (US) exhibits superior tissue penetration abilities and can produce reactive oxygen species (ROS) at the tumour site to treat deeper tumours. In addition, US serves as an excellent and selective drug delivery mediator for tumour treatment. Herein, we designed US-triggered lenvatinib nanoparticles (Len-RNPs) for selective drug delivery that utilize US-triggered ROS to induce in situ oxidation reactions, resulting in nanoparticle disintegration. Len-RNPs mitigate the toxicity of Len and effectively trigger robust systemic anti-tumour immune responses in a H22 tumour model, resulting in a tumour suppression rate of 95.7%, with 60% of mice being cured. Our study elucidates a novel and precise strategy of combining Len and US therapy for enhanced HCC immunotherapy.

Fluorescence Lifetime Imaging Enables In vivo Quantification of PD-L1 Expression and Inter-tumoral Heterogeneity.

Patient selection for cancer immunotherapy requires precise, quantitative readouts of biomarker expression in intact tumors that can be reliably compared across multiple subjects over time. The current clinical standard biomarker for assessing immunotherapy response is programmed death-ligand-1 (PD-L1) expression, typically quantified using immunohistochemistry. This method, however, only provides snapshots of PD-L1 expression status in microscopic regions of ex vivo specimens. While various targeted probes have been investigated for in vivo imaging of PD-L1, non-specific probe accumulation within the tumor microenvironment (TME) has hindered accurate quantification, limiting the utility for preclinical and clinical studies. Here, we demonstrated that in vivo time-domain (TD) fluorescence imaging of an anti-PD-L1 antibody tagged with the near-infrared fluorophore IRDye 800CW (αPDL1-800) can yield quantitative estimates of baseline tumor PD-L1 heterogeneity across untreated mice, as well as variations in PD-L1 expression in mice undergoing clinically relevant anti-PD1 treatment. The fluorescence lifetime (FLT) of PD-L1 bound αPDL1-800 was significantly longer than the FLT of nonspecifically accumulated αPDL1-800 in the TME. This FLT contrast allowed quantification of PD-L1 expression across mice both in superficial breast tumors using planar FLT imaging and in deep-seated liver tumors (>5 mm depth) using the asymptotic TD algorithm for fluorescence tomography. These findings suggest that fluorescence lifetime imaging can accelerate the preclinical investigation and clinical translation of new immunotherapy treatments by enabling robust quantification of receptor expression across subjects.

Construction and validation of a prognostic signature based on microvascular invasion and immune-related genes in hepatocellular carcinoma

Background: Microvascular invasion (MVI) is an independent risk factor of poor prognosis in hepatocellular carcinoma (HCC) and can be used to guide the diagnosis and treatment of HCC. The immune system serves as an integral role in the incidence and progression of HCC. However, the molecular biology correlation between MVI and tumor immunity and the value of combining the two parameters to predict patient prognosis and HCC response to treatment remain to be evaluated. Results: In this study, we used univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) Cox analysis to establish the MVI and immune-related gene index (MIRGPI) including eight genes. We demonstrated that the MIRGPI was an independent risk factor in predicting the prognosis of HCC. Subsequently, our research established a nomogram model combining pathologic characteristics and verified its good clinical application value. In addition, our study found that the TP53 gene had a higher mutation frequency and a lower degree of immune infiltration in the high-risk group. The low-risk group had higher sensitivity to immunotherapy, sorafenib, and TACE treatment, and the high-risk group had higher sensitivity to common chemotherapeutic agents. Finally, SEMA3C was found to facilitate the proliferation, migration and invasive ability of HCC by in vitro and in vivo experiments, and its mechanism may be associated with the activation of the NF-Κb/EMT signaling pathway. Conclusions: In summary, the MIRGPI signature we developed is a reliable marker for the prediction of prognosis and treatment response, and is important for the prognostic assessment and individualized treatment of HCC.