Undergoing Immune Checkpoint Inhibitors Therapy Research Articles

Immuno-related cardiac toxicity in patients with cancer: A prospective study applying multiparametric cardiac MRI.

e24014 Background: Since Immune checkpoint inhibitor (ICI) immunotherapy has emerged as a cornerstone of modern oncology, oncologists are facing a new spectrum of ‘immune-related adverse events’ (irAEs), potentially affecting every tissue and organ. ICI-induced symptomatic myocarditis occurs only in around 1% of ICI-treated patients (pts), but is fatal in 50% of cases. Methods: Pts undergoing ICI therapy at the Humanitas Cancer Center from May 2021 to December 2023 were prospectively recruited and assigned to three study groups: 1) ICI given as monotherapy (Mono) 2) ICI given in combination (Combo) 3) history of cardiac disease or two cardiological risk factors other than smoke (Cardio). Exclusion criteria were: previous exposure to any immunotherapy, combination with other cardiotoxic therapies, and acute (in the last 3 months) cardiac events. All pts underwent a complete cardiological assessment with clinical visit, 12-lead ECG, and multiparametric cardiac MRI (cMRI) at two time-points: prior initiation of the ICI therapy, and around 8 weeks later. Peripheral blood samples for immunophenotyping analyses were collected at the same time-points. cMRI scans were performed using a 1.5 Tesla scanner. Chi-square, Fisher exact and paired t-test were used to compare groups; all analyses were performed using SAS v9.4. Objectives of the study were: detection of subclinical cardiac damage and identification of groups of patients at major risk, who may benefit from cardiological pre- or/and on-treatment assessment. Results: We present data on the first 47 pts enrolled, diagnosed with a wide range of solid tumors, including 16 renal carcinoma, 11 melanoma and 3 NSCLC; 15 (32%), 16 (34%) and 16 (34%) pts were assigned to the Mono, Combo and Cardio group, respectively. Most pts (42, 89%) were treated with ICI for locally advanced/metastatic disease (26 as first-line therapy, 16 from second-line on), while 5 (11%) as adjuvant therapy. All pts received an anti-PD-(L)1, either as single agent (25, 53%) or in combination, with ICI plus a TKI being the most frequent combinatorial strategy (16; 34%). Overall, the cMRI analysis showed a statistically significant left ventricle ejection fraction (LVEF) reduction pre- versus post-ICI treatment (p < 0.001), with 18 (38%) pts experiencing a loss of > 3 points of LVEF. No statistically significant differences in LVEF reduction were observed considering the three different groups (p = 0.6), tumor types (p = 0.2), or occurrence of any grade non-cardiological irAEs (p = 0.6). Conclusions: Our study was able to show a statistically significant reduction in LVEF, with more than 3% LVEF loss in a clinically significant proportion of ICI-treated patients (18; 38%), not selected for suspected cardiac symptoms, warranting prospective evaluation to eventually identify pts at higher risk. The trial is continuing prospective enrollment and immunophenotyping analyses are ongoing.

Examining 1-year mortality risk among patients with malignant melanoma undergoing immune checkpoint inhibitor therapy with a history of cannabis use.

11046 Background: Cannabis use has become an increased topic of discussion in the United States due to rise in legalization, thereby increasing its accessibility for recreational and medicinal use in diseases like cancer. Immune Checkpoint Inhibitor (ICI) therapy has also recently been increasing in patient with metastatic cancers such as melanoma by targeting PD1 or PD-L1 receptors to manipulate the body’s immune response to induce cancer cell death. Cannabis is mediated in part by the CB1 and CB2 receptors in the endocannabinoid system that is present in the natural immune system. Due to the body’s immune response to cannabis, it is hypothesized this could interfere with the activity of ICI therapy. However, research examining this is sparse. Therefore, the goal was to assess mortality in malignant melanoma patients with a history of cannabis use who undergo ICI therapy. Methods: A retrospective cohort study was performed with TriNetX, a federated database of ~100 million patients across 84 healthcare organizations. Patients >17 years from 2012-2023 were identified based on ICI-therapy initiation within 1 month of malignant melanoma diagnosis. Cohorts were then created by history of those with and without cannabis use disorder. 1:1 propensity score matching was conducted to control for confounding comorbidities and demographics. Unadjusted and adjusted hazard ratios (aHR) with 95% CI were calculated for 1-year mortality after therapy initiation. HR’s were estimated using the Cox proportional hazard model. Survival curves were compared using the log-rank test. Results: A total 14589 melanoma patients who underwent ICI therapy were identified, of which 2.3% had documented cannabis use disorder. Prior to matching, melanoma patients with cannabis history had a statistically significant higher 1-year mortality compared to those with no cannabis history (HR [95%CI] = 1.29 [1.04,1.6], log rank test: p=0.0197). After matching, two balanced cohorts of 344 patients remained and adjusting for confounders revealed that melanoma patients with cannabis history had no significant difference in 1-year mortality risk compared to patients without cannabis history (1.18 [0.87,1.6], log rank test: p=0.293). Conclusions: Cannabis use among melanoma patients was shown to not have any meaningful difference in 1-year mortality risk compared to patients without cannabis use history while undergoing ICI-therapy. Additional studies, such as examining cannabis frequency and dosage, is warranted to further examine its effect.

Clinical evidence for the prognostic impact of metformin in cancer patients treated with immune checkpoint inhibitors

BackgroundPreclinical studies suggest that metformin might enhance the efficacy of immune checkpoint inhibitors (ICIs) and potentially influence the prognoses of cancer patients undergoing ICIs treatment. This study endeavors to assess the prognostic significance of metformin in cancer patients undergoing ICIs therapy, aiming to furnish evidence-based insights for clinical practice. MethodsA thorough literature search was conducted across electronic databases to encompass all potential records published before November 20th, 2023. A meta-analysis was executed utilizing Stata 17.0 to derive pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for both overall survival (OS) and progression-free survival (PFS). ResultsA total of 22 studies encompassing 9,011 patients met the inclusion criteria. Meta-analyses revealed a significant correlation between metformin use and poorer OS (HR, 1.13; 95 %CI, 1.04–1.23; P = 0.004) rather than PFS (HR, 1.04; 95 %CI, 0.96–1.14; P = 0.345) among cancer patients undergoing ICIs treatment. Subgroup analysis delineated that the concurrent administration of metformin and ICIs significantly associated with adverse prognoses in the European population (OS: HR, 1.23; 95 %CI, 1.10–1.39; P = 0.001; PFS: HR, 1.14; 95 %CI, 1.02–1.28; P = 0.024). ConclusionBased on current clinical evidence, concomitant metformin use does not appear to improve the prognostic outcomes for cancer patients undergoing ICIs therapy and may potentially correlate with inferior prognoses. Further studies are imperative to comprehensively elucidate the impact of metformin within the realm of ICIs therapy.

Epithelial-mesenchymal transition induced by tumor cell-intrinsic PD-L1 signaling predicts a poor response to immune checkpoint inhibitors in PD-L1-high lung cancer.

We investigated the role of tumor cell-intrinsic PD-L1 signaling in the epithelial-mesenchymal transition (EMT) in non-small-cell lung cancer (NSCLC) and the role of EMT as a predictive biomarker for immune checkpoint inhibitor (ICI) therapy. PD-L1-overexpressing or PD-L1-knockdown NSCLC cells underwent RNA-seq and EMT phenotype assessment. Mouse lung cancer LLC cells were injected into nude mice. Two cohorts of patients with NSCLC undergoing ICI therapy were analyzed. RNA-seq showed that EMT pathways were enriched in PD-L1-high NSCLC cells. EMT was enhanced by PD-L1 in NSCLC cells, which was mediated by transforming growth factor-β (TGFβ). PD-L1 promoted the activation of p38-MAPK by binding to and inhibiting the protein phosphatase PPM1B, thereby increasing the TGFβ production. Tumor growth and metastasis increased in nude mice injected with PD-L1-overexpressing LLC cells. In the ICI cohort, EMT signature was higher in patients with progressive disease than in those with responses, and EMT was significantly associated with poor survival in PD-L1-high NSCLC. In PD-L1-high NSCLC, EMT was associated with increased M2-macrophage and regulatory T-cell infiltrations and decreased cytotoxic T-cell infiltration. Tumor cell-intrinsic PD-L1 function contributes to NSCLC progression by promoting EMT. EMT may predict an unfavorable outcome after ICI therapy in PD-L1-high NSCLC.

Association of the Advanced Lung Cancer Inflammation Index (ALI) and Gustave Roussy Immune (GRIm) score with immune checkpoint inhibitor efficacy in patients with gastrointestinal and lung cancer

ObjectiveThis study aimed to conduct a comprehensive analysis, evaluating the prognostic significance of the baseline Advanced Lung Cancer Inflammation Index (ALI) and Gustave Roussy Immune (GRIm) Score in patients undergoing immune checkpoint inhibitor (ICI) therapy.MethodsA comprehensive search was performed across various databases, including PubMed, the Cochrane Library, EMBASE, and Google Scholar, until October 21, 2023, to compile relevant articles for analysis. The investigation encompassed diverse clinical outcomes, including overall survival (OS) and progression-free survival (PFS).ResultsThis analysis included a total of 15 articles, comprising 19 studies involving 3335 patients. Among the 19 studies, nine studies focused on NSCLC, and six studies were conducted on HCC. Pooled results revealed that patients with elevated ALI levels experienced prolonged OS (HR: 0.51, 95% CI: 0.37–0.70, p < 0.001) and extended PFS (HR: 0.61, 95% CI: 0.52–0.72, p < 0.001). Furthermore, a GRIm score > 1 was associated with reduced OS (HR: 2.07, 95% CI: 1.47–2.92, p < 0.001) and diminished PFS (HR: 1.78, 95% CI: 1.35–2.34, p < 0.001) in cancer patients receiving ICIs. Subgroup analysis indicated that ALI cutoff values of 18 exhibited enhanced predictive potential. Additionally, for HCC patients, those with HCC-GRIm score > 2 showed a substantially decreased risk of mortality compared to individuals with HCC-GRIm score ≤ 2 (HR: 2.63, 95% CI: 1.89–3.65, p < 0.001).ConclusionThe ALI and GRIm score served as dependable prognostic indicators for patients undergoing ICI therapy in the context of cancer treatment.

Acute coronary syndrome in a patient with gastric cancer treated by immune checkpoint inhibitor: A case report

AbstractObjectiveTo highlight the incidence and management of acute coronary syndrome (ACS) in patients with gastric cancer undergoing immune checkpoint inhibitor (ICI) therapy, emphasizing the need for early detection and intervention in this high‐risk population.Patients and methodsWe presented a case of a 71‐year‐old male patient with poorly differentiated adenocarcinoma of the gastric antrum, clinical stage cT4N2M0, phase III, with no prior history of chronic diseases or cardiovascular risk factors. The patient was treated with a combination of ICI therapy (sintilimab) and chemotherapy using the albumin‐bound paclitaxel combined with S1 regimen. Following therapy, he developed symptoms and diagnostic findings consistent with ACS, which was managed with percutaneous coronary stenting.ResultsThe patient's presentation with ACS during ICI therapy underscored the potential cardiovascular risks associated with cancer treatments, particularly in patients without traditional cardiovascular risk factors. Management involved collaboration between oncologists and cardiologists, leading to successful coronary stenting and continuation of antitumor therapy.ConclusionACS is a significant risk in patients with malignancies undergoing ICI therapy, even in those without prior cardiovascular disease. Early recognition and management of ACS in this context are crucial to enable the continuation of cancer treatment and improve patient outcomes. This case underscores the importance of interdisciplinary collaboration in managing complex patients with concurrent cancer and cardiovascular disease.

Abstract 7621: Serum albumin and derived neutrophil-to-lymphocyte ratio are potential predictive biomarkers for immune checkpoint inhibitors in small cell lung cancer

Abstract Background: Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of small cell lung cancer (SCLC), but only a minority of patients benefit from this therapy. Therefore, it is critical to identify potential risk factors that could predict the efficacy of ICI treatment in SCLC patients and identify patient subgroups who may benefit the most from ICI therapy. Methods: Our study included a total of 183 SCLC patients who had received at least one dose of ICI treatment. We utilized both logistic regression and Cox proportional hazard regression to evaluate whether various patient clinical factors and serum biomarkers, could serve as predictors of patient response to treatment and overall survival (OS) during ICI therapy. Results: Logistic regression showed that patients with a history of surgery (p=0.003, OR 9.06, 95% CI: (2.17, 37.9)) and no metastasis (p=0.008, OR 7.82, 95% CI: (1.73, 35.4)) exhibited a higher odds of response to ICI treatment. Cox regression analyses demonstrated that pretreatment blood albumin (p=0.003, HR 1.72, 95% CI: (1.21, 2.45)) and derived neutrophil to lymphocyte ratio (dNLR) (p=0.003, HR 1.71, 95% CI: (1.20-2.44)) were independent predictors for OS in SCLC patients. By establishing a pre-treatment prognostic scoring system based on baseline albumin and dNLR, we found that patients with high albumin and low dNLR exhibited a significantly better prognosis than those with low albumin and high dNLR in both the full (P&amp;lt;.0001, HR 0.33, 95% CI: 0.20-0.55) and the metastatic cohort (P&amp;lt;.0001, HR 0.28, 95% CI: 0.15-0.51). The better prognostic group also had younger age, higher BMI and lower systemic inflammatory biomarker values than the unfavorable group (P&amp;lt;.0001). Conclusion: Our data reveals the significant role of metastasis status and treatment history in predicting the initial response of SCLC patients to ICI treatment. However, baseline serum albumin and dNLR provide a more precise prognostic prediction for patient OS. The scoring system based on albumin and dNLR enhances the ability to stratify patient prognosis and holds the potential to guide clinical decision-making for SCLC patients undergoing ICI therapy. Citation Format: Zhanpeng Kuang, Jessica Miao, Xiaoli Zhang. Serum albumin and derived neutrophil-to-lymphocyte ratio are potential predictive biomarkers for immune checkpoint inhibitors in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7621.

Evaluating the influence of sarcopenia and myosteatosis on clinical outcomes in gastric cancer patients undergoing immune checkpoint inhibitor.

The development and progression of gastric cancer (GC) are closely linked to the nutritional status of patients. Although immunotherapy has been demonstrated to be clinically effective, the relationships of sarcopenia and myosteatosis with the use of immune checkpoint inhibitors (ICIs) in patients with gastric cancer remain to be characterized. To assess the effects of sarcopenia and myosteatosis on the clinical outcomes of patients with GC undergoing treatment with an ICI. We performed a retrospective study of patients who were undergoing immunotherapy for GC. For the evaluation of sarcopenia, the optimal cut-off value for the skeletal muscle index was established using receiver operating characteristic analysis of data obtained from pre-treatment computed tomography images at the L3 vertebral level. Myosteatosis was defined using the mean skeletal muscle density (SMD), with a threshold value of < 41 Hounsfield units (HU) for patients with a body mass index (BMI) < 25 kg/m² and < 33 HU for those with a BMI ≥ 25 kg/m². The log-rank test was used to compare progression-free survival (PFS) and overall survival (OS), and a Cox proportional hazard model was used to identify prognostic factors. Nomograms were developed to predict the PFS and OS of patients on the basis of the results of multivariate analyses. We studied 115 patients who were undergoing ICI therapy for GC, of whom 27.4% had sarcopenia and 29.8% had myosteatosis. Patients with sarcopenia or myosteatosis had significantly shorter PFS and OS than those without these conditions. Furthermore, both sarcopenia and myosteatosis were found to be independent predictors of PFS and OS in patients with GC administering an ICI. The prediction models created for PFS and OS were associated with C-indexes of 0.758 and 0.781, respectively. The presence of sarcopenia or myosteatosis is a reliable predictor of the clinical outcomes of patients with GC who are undergoing treatment with an ICI.

TG468: a text graph convolutional network for predicting clinical response to immune checkpoint inhibitor therapy.

Enhancing cancer treatment efficacy remains a significant challenge in human health. Immunotherapy has witnessed considerable success in recent years as a treatment for tumors. However, due to the heterogeneity of diseases, only a fraction of patients exhibit a positive response to immune checkpoint inhibitor (ICI) therapy. Various single-gene-based biomarkers and tumor mutational burden (TMB) have been proposed for predicting clinical responses to ICI; however, their predictive ability is limited. We propose the utilization of the Text Graph Convolutional Network (GCN) method to comprehensively assess the impact of multiple genes, aiming to improve the predictive capability for ICI response. We developed TG468, a Text GCN model framing drug response prediction as a text classification task. By combining natural language processing (NLP) and graph neural network techniques, TG468 effectively handles sparse and high-dimensional exome sequencing data. As a result, TG468 can distinguish survival time for patients who received ICI therapy and outperforms single gene biomarkers, TMB and some classical machine learning models. Additionally, TG468's prediction results facilitate the identification of immune status differences among specific patient types in the Cancer Genome Atlas dataset, providing a rationale for the model's predictions. Our approach represents a pioneering use of a GCN model to analyze exome data in patients undergoing ICI therapy and offers inspiration for future research using NLP technology to analyze exome sequencing data.

Soluble lymphocyte activation gene-3 (sLAG3) and CD4/CD8 ratio dynamics as predictive biomarkers in patients undergoing immune checkpoint blockade for solid malignancies

BackgroundThe search for biomarkers to identify suitable candidates for immune checkpoint inhibitor (ICI) therapy remains ongoing. We evaluate how soluble levels of the next generation immune checkpoint Lymphocyte Activation Gene-3 (sLAG-3) and its association with circulating T lymphocyte subsets could pose as a novel biomarker to predict outcome to ICI therapy.MethodsCirculating levels of sLAG3 were analyzed using multiplex immunoassay in n = 84 patients undergoing ICI therapy for advanced solid cancer, accompanied by flow cytometry analyses of peripheral blood mononuclear cells (PBMCs).ResultsUni- and multivariate analysis shows that patients with higher sLAG3 concentrations before ICI therapy had a significantly impaired progression-free (PFS) and overall survival (OS) (HRPFS: 1.005 [95%CI: 1.000–1.009], p = 0.039; HROS: 1.006 [95%CI: 1.001–1.011], p = 0.015). The CD4/CD8 cell ratio and its dynamics during therapy were strong predictors of PFS and OS with patients with a decreasing ratio between baseline and after 1–2 cycles having an improved median OS compared to patients with increasing values (p = 0.012, HR: 3.32). An immunological score combining sLAG3 and the CD4/CD8 ratio showed the highest predictive potential (HROS: 10.3).ConclusionPending prospective validation, sLAG3 and correlating circulating T-cell subsets can be used as a non-invasive predictive marker to predict outcome to ICI therapy to help identifying ideal ICI candidates in the future.

The Symptom Experience of Patients with Advanced Melanoma Undergoing Immune Checkpoint Inhibitor (ICI) Therapy

ObjectivesThe advent of immune checkpoint inhibitor (ICI) therapy has vastly improved outcomes for patients with advanced melanoma. However, the symptom burden and intensity with their impact on quality-of-life (HRQoL) and functionality are heterogeneous and unpredictable. We used descriptive exploratory content analysis from interviews to capture the patient experience after they had completed quantitative data collection of their symptom burden and interference with the use of two patient-reported outcome (PRO) instruments. Data SourcesParticipants from a single center with advanced melanoma (n = 19) who are undergoing ICI therapy completed the Modified MD Anderson Symptom Inventory and Functional Assessment of Cancer Therapy-Melanoma and recorded semistructured interviews. Interpretive description informed the inductive and iterative analysis approach. ConclusionParticipants had a heterogenous experience of ICI and melanoma-related symptoms: distress (84%), fatigue (68%), rash or skin changes (53%), pain (30%), diarrhea (30%), itching (26%), and shortness of breath (21%), with varying interference within HRQoL domains, mood (47%), relations with other people (26%), and activity (21%). Some noted a lack of physical interference (79%). Uncertainty was a pervasive theme in the interviews (68%) despite the majority having positive thoughts about ICI therapy (58%) and expectations of the success of therapy (53%). The physical and emotional burden of a melanoma diagnosis, undergoing therapy, and the uncertainty of the outcomes are pervasive for patients. Implications for Nursing PracticeCommunication surrounding the diagnosis, prognosis, treatment options, and outcomes need to be clear and acknowledge there are unknowns. Nurses may benefit from using a validated PRO instrument to help document and understand the patient's symptom experience while undergoing ICI therapy.

Increased Thyroidal Activity on Routine FDG-PET/CT after Combination Immune Checkpoint Inhibition: Temporal Associations with Clinical and Biochemical Thyroiditis.

FDG-PET/CT used for immune checkpoint inhibitor (ICI) response assessment can incidentally identify immune-related adverse events (irAEs), including thyroiditis. This study aimed to correlate the time course of FDG-PET/CT evidence of thyroiditis with clinical and biochemical evolution of thyroid dysfunction. A retrospective review was performed by two independent blinded nuclear medicine physicians (NMPs) of thyroidal FDG uptake in 127 patients who underwent PET/CT between January 2016 and January 2019 at baseline and during treatment monitoring of combination ICI therapy for advanced melanoma. Interobserver agreement was assessed and FDG-PET/CT performance defined by a receiver-operating characteristic (ROC) curve using thyroid function tests (TFTs) as the standard of truth. Thyroid maximum standardized uptake value (SUVmax) and its temporal changes with respect to the longitudinal biochemistry were serially recorded. At a median of 3 weeks after commencing ICI, 43/127 (34%) had a diagnosis of thyroiditis established by abnormal TFTs. FDG-PET/CT was performed at baseline and at a median of 11 weeks (range 3-32) following the start of therapy. ROC analysis showed an area under the curve of 0.87 (95% CI 0.80, 0.94) for FDG-PET/CT for detection of thyroiditis with a positive predictive value of 93%. Among patients with biochemical evidence of thyroiditis, those with a positive FDG-PET/CT were more likely to develop overt hypothyroidism (77% versus 35%, p < 0.01). In the evaluation of the index test, there was an almost perfect interobserver agreement between NMPs of 93.7% (95% CI 89.4-98.0), kappa 0.83. Increased metabolic activity of the thyroid on routine FDG-PET/CT performed for tumoral response of patients undergoing ICI therapy is generally detected well after routine biochemical diagnosis. Elevation of FDG uptake in the thyroid is predictive of overt clinical hypothyroidism and suggests that an ongoing robust inflammatory response beyond the initial thyrotoxic phase may be indicative of thyroid destruction.

Clinical characteristics and outcomes of patients with primary liver cancer and immune checkpoint inhibitor-associated adrenal insufficiency: A retrospective cohort study

BackgroundAdrenal insufficiency (AI) is a rare, but potentially serious adverse event associated with immune checkpoint inhibitors (ICIs). This study aims to examine the incidence, clinical features and the clinical correlation between occurrence of AI and efficacy in primary liver cancer (PLC) patients treated with ICIs; and to evaluate the significance of the continuation of ICIs treatment in PLC patients who developed AI. MethodsBetween January 2020 and March 2022, 47 PLC patients with ICIs-associated AI (AI cohort) were screened from Zhongshan Hospital, Fudan university, a general hospital in China. Between December 2019 and August 2021, 419 PLC patients who were treated with ICIs were reviewed to identify those without immune- associated adverse events (irAEs) (control cohort). Clinical features and outcomes of the PLC patients from the two cohorts were compared. ResultsTotally, 47 PLC patients with AI (AI cohort) and 63 PLC patients without irAEs (control cohort) were included. The incidence of grades 3–4 of AI and all irAEs were 40.4 % and 48.9 %, respectively. The median three-year survival was significantly longer in the AI cohort than that in the control cohort (26.3 months (95 % CI: 18.9––33.5) vs.16.1 months (95 % CI:10.4––21.7); p = 0.021). Multivariable cox proportional hazards regression model showed that the development of AI remained significantly associated with improved overall survival (HR = 0.561; p = 0.033) in the adjusted regression analysis. ConclusionThe current study demonstrated that PLC patients undergoing ICIs therapy and developing AI after ICIs treatment had favorable survival outcomes compared to those without irAEs.

Early kinetics of C reactive protein for cancer-agnostic prediction of therapy response and mortality in patients treated with immune checkpoint inhibitors: a multicenter cohort study

BackgroundC reactive protein (CRP) kinetics have recently been suggested as predictive biomarkers for the efficacy of immune checkpoint inhibitor (ICI) therapy in selected cancer types. The aim of this study...

Navigating the Hepatic Hurdles of Immune Checkpoint Inhibition

The introduction of immune checkpoint inhibitors (ICIs) has revolutionized cancer therapy, offering promising outcomes in various malignancies. However, the use of these agents is associated with a spectrum of immunerelated adverse events (irAEs), including liver complications commonly referred to as ICI-induced hepatitis. This review article aims to provide a comprehensive overview of the epidemiology, pathophysiology, clinical manifestations, diagnosis, and management strategies for ICI-induced hepatitis. We also discuss the histopathological features that distinguish this condition from other liver diseases like autoimmune hepatitis. Additionally, the article explores existing guidelines and recommendations for managing ICI-induced hepatitis. As the application of ICIs continues to expand, understanding the nuances of associated hepatic complications becomes increasingly critical for clinicians involved in cancer care. Therefore, this review serves as a timely resource for oncologists, gastroenterologists, and other healthcare professionals engaged in the management of patients undergoing ICI therapy

Abstract 16478: Effect of Sodium Glucose Cotransporter 2 Inhibitors on Major Adverse Cardiovascular Events in Cancer Patients Treated With Immune Checkpoint Inhibitors

Introduction: The cardiac adverse events (irAEs) secondary to immune checkpoint inhibitors (ICI) are associated with a high rate of morbidity and mortality. There are no data on the effect of concomitant sodium glucose cotransporter 2 inhibitors (SGLT2i) on the rates of major adverse cardiovascular events (MACE) among patients treated with an ICI. Hypothesis: Whether, the use of SGLT2i among ICI-treated patients may reduce MACE. Methods: This was a population-based cohort study between 2014 and 2023 including cancer patients treated with ICI aged over 18 years across the United States. SGLT2i use while on an ICI was defined as the initiation of SGLT2i therapy after the first record of ICI treatment among patients currently undergoing ICI therapy. The risk of incident MACE in patients on an ICI who were also prescribed an SGLT2i therapy was compared with 1:1 propensity score-matched patients on ICI who were never prescribed an SGLT2i. Hazard ratios (HRs) and 95% confidence intervals (CIs) for MACE were estimated using Cox proportional hazards regression. MACE was defined as a composite of myocardial infarction, heart failure (HF), and ischemic stroke. Results: There were 216 cancer patients undergoing ICI therapy who were newly treated with SGLT2i. These were compared to 216 controls. Over a mean follow-up period of six years, there were 107 MACE events. There were 44 events (20.4%) among those on an SGLT2i and 63 among controls (HR=0.61, 95% CI: 0.41-0.90; log-rank test p=0.011). Of the individual components of MACE, rates of HF were lower where there were 22 HF events (20.4%) among those on an SGLT2i and 37 among controls (HR=0.51, 95% CI: 0.30-0.86; log-rank test p=0.010). There were no differences in the rates of stroke (HR: 0.55, 95% CI: 0.29-1.04) and myocardial infarction (HR: 0.97, 95% CI: 0.38-2.43). Conclusions: In an observational, retrospective study, SGLT2i therapy was associated with a reduced risk for cardiac events compared to those who never treated with SGLT2i. These findings underscore the potential therapeutic value of SGLT2i in the prevention of MACE in cancer patients receiving immunotherapy and warrant further research.

Blood Immune Cells as Biomarkers in Long-Term Surviving Patients with Advanced Non-Small-Cell Lung Cancer Undergoing a Combined Immune/Chemotherapy.

An important challenge remains in identifying the baseline characteristics of cancer patients who will mostly benefit from immune checkpoint inhibitor (ICI) therapies. Furthermore, biomarkers could help in the choice of an optimal therapy duration after a primary therapy response. In this pilot study, the time courses of four different immune cell parameters were followed in 12 patients with advanced non-small-cell lung cancer (NSCLC) undergoing ICI therapy combined with chemotherapy and surviving at least 12 months. Blood was collected at the time point of the first and third antibody administration, as well as after 12 months of patients' survival. Using multi-color flow cytometry, two suppressive markers (neutrophil/lymphocyte ratio (NLR) and the frequency of circulating HLA-DRlow monocytes), as well as two markers of an ongoing immune response (6-Sulfo LacNAc (slan)+ non-classical monocytes and dendritic cell (DC) subtypes), were determined. In most of those who survived > 12 months, a low NLR and a low number of HLA-DRlow monocytes combined with clearly detectable numbers of slan+ non-classical monocytes and of DC subtypes were seen. Two of the patients had an increase in the suppressive markers paired with a decrease in slan+ non-classical monocytes and in DC subtypes, which, in at least one patient, was the correlate of an ongoing clinical progression. Our results implicate that the NLR, specific subtypes of monocytes, and the number of blood DCs might be useful predictive biomarkers for cancer patients during long-term treatment with ICI/chemotherapy.

Carpal Tunnel Syndrome Associated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic approach to diverse malignancies, leading to substantial enhancements in patient prognosis. However, along with their benefits, ICIs also increase the incidence of immune-related adverse events (irAEs). In the present paper, we highlight four cases of carpal tunnel syndrome (CTS) as an uncommon manifestation of toxicity induced by ICIs. Although diagnosed with different malignancies, the patients were undergoing ICI therapy when they developed CTS-consistent side effects accompanied by severe neuropathy. Prompt treatment with corticosteroids, intravenous immunoglobulins, or methotrexate resulted in complete symptomatic relief for all patients. This article therefore emphasizes the importance of recognizing and managing rare adverse events associated with ICI use to ensure optimal patient care.

Peripheral blood CD3+HLADR+ cells and associated gut microbiome species predict response and overall survival to immune checkpoint blockade.

The search for biomarkers to identify ideal candidates for immune checkpoint inhibitor (ICI) therapy is fundamental. In this study, we analyze peripheral blood CD3+HLADR+ cells (activated T-cells) as a novel biomarker for ICI therapy and how its association to certain gut microbiome species can indicate individual treatment outcomes. Flow cytometry analysis of peripheral mononuclear blood cells (PBMCs) was performed on n=70 patients undergoing ICI therapy for solid malignancies to quantify HLA-DR on circulating CD3+ cells. 16s-rRNA sequencing of stool samples was performed on n=37 patients to assess relative abundance of gut microbiota. Patients with a higher frequency of CD3+HLADR+ cells before treatment initiation showed a significantly reduced tumor response and overall survival (OS), a worst response and experienced less toxicities to ICI therapy. As such, patients with a frequency of CD3+HLADR+ cells above an ideal cut-off value of 18.55% had a median OS of only 132 days compared to 569 days for patients below. Patients with increasing CD3+HLADR+ cell counts during therapy had a significantly improved OS. An immune signature score comprising CD3+HLADR+ cells and the neutrophil-lymphocyte ratio (NLR) was highly significant for predicting OS before and during therapy. When allied to the relative abundance of microbiota from the Burkholderiales order and the species Bacteroides vulgatus, two immune-microbial scores revealed a promising predictive and prognostic power. We identify the frequencies and dynamics of CD3+HLADR+ cells as an easily accessible prognostic marker to predict outcome to ICIs, and how these could be associated with immune modulating microbiome species. Two unprecedented immune-microbial scores comprising CD3+HLADR+, NLR and relative abundance of gut bacteria from the Burkhorderiales order or Bacteroides vulgatus species could accurately predict OS to immune checkpoint blockade.

Effect of SARS-CoV-2 mRNA-Vaccine on the Induction of Myocarditis in Different Murine Animal Models.

In the course of the SARS-CoV-2 pandemic, vaccination safety and risk factors of SARS-CoV-2 mRNA-vaccines were under consideration after case reports of vaccine-related side effects, such as myocarditis, which were mostly described in young men. However, there is almost no data on the risk and safety of vaccination, especially in patients who are already diagnosed with acute/chronic (autoimmune) myocarditis from other causes, such as viral infections, or as a side effect of medication and treatment. Thus, the risk and safety of these vaccines, in combination with other therapies that could induce myocarditis (e.g., immune checkpoint inhibitor (ICI) therapy), are still poorly assessable. Therefore, vaccine safety, with respect to worsening myocardial inflammation and myocardial function, was studied in an animal model of experimentally induced autoimmune myocarditis. Furthermore, it is known that ICI treatment (e.g., antibodies (abs) against PD-1, PD-L1, and CTLA-4, or a combination of those) plays an important role in the treatment of oncological patients. However, it is also known that treatment with ICIs can induce severe, life-threatening myocarditis in some patients. Genetically different A/J (most susceptible strain) and C57BL/6 (resistant strain) mice, with diverse susceptibilities for induction of experimental autoimmune myocarditis (EAM) at various age and gender, were vaccinated twice with SARS-CoV-2 mRNA-vaccine. In an additional A/J group, an autoimmune myocarditis was induced. In regard to ICIs, we tested the safety of SARS-CoV-2 vaccination in PD-1-/- mice alone, and in combination with CTLA-4 abs. Our results showed no adverse effects related to inflammation and heart function after mRNA-vaccination, independent of age, gender, and in different mouse strains susceptible for induction of experimental myocarditis. Moreover, there was no worsening effect on inflammation and cardiac function when EAM in susceptible mice was induced. However, in the experiments with vaccination and ICI treatment, we observed, in some mice, low elevation of cardiac troponins in sera, and low scores of myocardial inflammation. In sum, mRNA-vaccines are safe in a model of experimentally induced autoimmune myocarditis, but patients undergoing ICI therapy should be closely monitored when vaccinated.