Checkpoint Inhibitor Treatment Research Articles

Immunotherapy for metastatic gastric cancer

This editorial discusses the article written by Chen et al that was published in the latest edition of the World Journal of Gastrointestinal Surgery . The current study found that programmed cell death 1 ligand 1 (PD-L1) expression is considered as one of the pan-cancer biomarkers of immune checkpoint inhibitors (ICIs) treatment response. Four molecular subtypes are widely used to guide and evaluate the prognosis and diagnosis and treatment of gastric cancer (GC) patients. Clinical trials of ICI treatment including Nivolumab, Pembrolizumab, Avelumab have been conducted for metastatic GC (mGC). The effects of various single agent ICIs on mGC therapy varied. ICIs combined with chemotherapy can indeed bring survival benefits to patients with mGC. Combining ICIs with chemotherapy can give more patients the chance of surgery in the treatment of GC transformation. However, not all PD-L1 positive patients can benefit from it. It is urgent to find better biomarkers to predict the response of ICIs for more precise clinical treatment.

Abstract B047: Monitoring treatment response and toxicity in BRAF V600-mutant metastatic melanoma with circulating cell-free DNA

Abstract Background: The DREAMseq trial (EA6134, NCT02224781) was a national multi-center randomized phase III trial coordinated by ECOG-ACRIN that found that immune checkpoint inhibitor (IO) treatment achieves improved survival outcomes compared to targeted therapy (TT) in patients with BRAF V600-mutant metastatic melanoma. Still, approximately 40% of patients do not respond to IO, and existing biomarkers fail to distinguish this subset of patients who do not benefit from IO therapy. Additionally, as many as 80% of patients may experience immune- related adverse events (irAEs), which range from mild dermatological symptoms to life- threatening myocarditis. Here, we explore the use of the methylation status of cell-free DNA (cfDNA) in serially collected blood samples to measure response and toxicity in the context of IO- and TT-treated metastatic melanoma. Methods: Serial serum samples were collected from patients with BRAF V600-mutant metastatic melanoma treated with ipilimumab/nivolumab (IO) or dabrafenib/trametinib (TT). Circulating cfDNA was isolated from serially collected serum samples, enriched for regions of interest by hybridization capture and sequenced using enzymatic methyl-seq. Cell-type deconvolution was performed to determine the abundance of cell type- specific methylation patterns of cfDNA molecules in patient serum at different time points of treatment. The BRAF V600 mutation abundance in total cfDNA was also assessed. Results: We identified melanocyte lineage-specific DNA methylation regions and demonstrate that the methylation status of these regions remains conserved in malignant melanoma. We characterized the changes in abundance of the melanocyte-lineage cfDNA over the course of treatment and show that these changes distinguish responders from non-responders to either IO or TT. Furthermore, we track the abundance of cell type-specific DNA from normal tissues to identify markers indicative of adverse effects or disease progression. Conclusions: We established melanocyte-lineage methylation markers and evaluated the use of cell-type specific DNA methylation to monitor treatment effects of immune checkpoint or BRAF/MEK inhibitors in metastatic melanoma using serially collected blood samples. Citation Format: Sidharth S Jain, A. Patrick IV McDeed, Megan E McNamara, Amber R Alley, Dori S Rosenstrauch, Harry Sun, Natalie Thompson, John M Kirkwood, Geoffrey T Gibney, Michael B Atkins, Anton Wellstein. Monitoring treatment response and toxicity in BRAF V600-mutant metastatic melanoma with circulating cell-free DNA [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B047.

Real-world analysis of the incidence and risk factors of pneumonitis in non-small cell lung cancer patients treated with combined thoracic radiotherapy and immunotherapy

Abstract Objectives Combining radiotherapy with immune checkpoint inhibitor (ICI) treatment has emerged as an important therapeutic regimen. However, this combined treatment may increase the risk of pneumonitis. The aim of this study is to analyze the incidence and risk factors for pneumonitis in non-small cell lung cancer (NSCLC) patients receiving combined thoracic radiotherapy and ICI (RT + ICI) treatment in the real-world clinical setting, offering a reference and guidance for clinical physicians. Methods This study identified 447 patients with pathologically confirmed NSCLC at West China Hospital of Sichuan University from 2016 to 2021. Clinical characteristics, treatment regimens, immune-related adverse events (irAEs), and hematological data were collected and analyzed. Results Patients receiving combined RT + ICI treatment had a higher risk of developing pneumonitis than those receiving ICI treatment alone (26.9 vs. 6.7 %, p<0.001). The multivariate logistic analysis identified the following independent risk factors for pneumonitis in patients undergoing combined RT + ICI treatment: history of lung disease (p=0.032), first-line ICI treatment (p=0.001), anti-PD-L1 instead of anti-PD-1 treatment (p=0.035), and the development of immunotherapy-related thyroid dysfunction (p=0.019). The independent risk factors were incorporated into a nomogram to predict the incidence of pneumonitis. The area under the receiver operating characteristic curve is 0.727, suggesting an acceptable predictive efficacy. Conclusions Compared to ICI monotherapy, NSCLC patients receiving the combination of thoracic radiotherapy and ICI treatment are at higher risk of developing pneumonitis. The nomogram holds promise for facilitating the risk assessment and early identification of pneumonitis in NSCLC patients receiving combined RT + ICI treatment.

Surgical resection following chemoradiotherapy for thoracic SMARCA4-deficient undifferentiated tumor: a report of two cases

BackgroundThoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a high-grade malignant neoplasm with a poor prognosis. Most cases of SMARCA4-UT have extensive chest wall and mediastinum involvement. The efficacy of surgical resection has not been clearly established. Here, we report two surgical cases of SMARCA4-UT with chest wall invasion after chemoradiotherapy.Case presentationThe first patient was a 40-year-old man with back pain. Computed tomography revealed a 6.8 cm mass in contact with the thoracic vertebrae near the intervertebral foramen, which was suspected to involve the third to fifth ribs. The patient was diagnosed with SMARCA4-UT with clinical T3N0M0 stage IIB. The tumor shrank after chemoradiotherapy, and conversion surgery combined with partial vertebrectomy was performed. Histopathological findings revealed 30% residual tumor in the tumor bed. Thirty-six days after surgery, the patient developed multiple liver metastases and peritoneal dissemination. Chemotherapy combined with immune checkpoint inhibitor treatment was performed, resulting in tumor shrinkage. However, peritoneal dissemination recurred within a short interval. The patient died 5 months postoperatively. The second patient was a 74-year-old man with chest pain. Computed tomography revealed a 7.4-cm mass in the left upper lobe with invasion of the third and fourth ribs. The patient was initially diagnosed with non-small cell lung cancer with clinical T4N1M0 stage IIIA. The tumor shrank after induction chemoradiotherapy, and a left upper lobectomy combined with the chest wall resection was performed. Based on histopathological findings, the patient was diagnosed with SMARCA4-UT. The residual tumor percentage was 3%. The patient was followed up for 12 months postoperatively without recurrence.ConclusionsWe performed the complete resection of SMARCA4-UT following chemoradiotherapy. The two surgical cases had different postoperative courses. Radical surgery after chemoradiotherapy is effective for local control. However, its long-term prognostic efficacy remains unclear. Multidisciplinary approaches and further investigations of novel therapeutic options are required.

Successful management of complete heart block in checkpoint inhibitor induced myocarditis by left bundle branch area pacing: a case report

Abstract Background Optimal management of checkpoint inhibitor-induced complete heart block is unknown. Previous reports showed relatively high incidence of pacing failure due to the co-existing myocarditis. Case summary A 71-year-old male with a prior history of stage IV metastatic squamous cell lung cancer presents was admitted for dyspnoea and hypotension 10 days after checkpoint inhibitor treatment using pembrolizumab. He was found to have myocarditis, third-degree AV block, severe left ventricular systolic dysfunction with EF 35%, and required pressure support. A dual chamber pacemaker using left bundle branch area pacing (LBBAP) was urgently placed that immediately improved his haemodynamics. Both the cathode and anode were able to capture the ventricle at different pacing outputs. The patient was taken off all intravenous pressors and successfully transferred to a larger centre for further management of the myocarditis with no further arrhythmia or hypotension. Discussion In conclusion, because of the unique ability to capture a large amount of myocardium from both the tip and ring electrodes as well as the ability to deliver cardiac resynchronization therapy, LBBAP may be the preferred pacing strategy in patients who develop complete heart block due to checkpoint inhibitor-induced myocarditis.

Real-world use of immune checkpoint inhibitors in advanced or recurrent endometrial cancer

ObjectiveThe aim of this study was to describe real-world use of immune checkpoint inhibitors for women with advanced or recurrent endometrial cancer.MethodsAdult women with advanced or recurrent endometrial cancer who...

The safety of standardized management of suspected cardiovascular immune-related events in patients treated by immunecheckpoints inhibitors

Abstract Background Immune checkpoint inhibitors (ICIs) treatment carries a risk of immune-related adverse events (irAEs), including cardiovascular (CV) events. Current guidelines recommend troponin testing to detect early CV irAEs, especially myocarditis, prompting hospital admission. However, high volumes might hinder hospital admission for all suspected CV irAEs patients. Purpose To assess the safety of standardized management in outpatients with suspected irAEs. Methods A prospective single-center cohort study was conducted, including all adults referred to our unit for suspected CV irAEs. Patients exhibiting CV symptoms, receiving double ICIs, or showing ECG changes were referred to cardiology or intensive care based on severity. Patients with no CV symptoms or ECG changes, on single ICI therapy, and no other immune disorder were assessed in a day stay within 8 working days. Patients underwent serial serum testing, ECG, transthoracic echocardiogram, and cardiac magnetic resonance imaging (cMRI) and were assessed by a multidisciplinary team (MDT) including cardiology and internal medicine specialists. Coronary artery imaging and endomyocardial biopsy were performed when deemed necessary (Figure 1). The primary endpoint was CV mortality at 30 days after referral. Secondary endpoints included identifying factors associated with the diagnosis of CV irAEs at referral. Events were adjudicated by a panel of experts (FC, MM, SH) who reviewed the MDT's weekly meeting conclusions. Results 175 patients were enrolled from March 2022 to October 2023; 40 (22.89%) were male, median age 61 (IQR 48.0-72.0) years. 146 (83.4%) were seen in the outpatient clinic. No CV deaths occurred within the initial 30 days. 95 patients (54.1%) had CV irAEs at referral, including 72 (41.1%) with myocarditis; 10 (5.7%) with acute coronary syndromes; 9 (5.1%) with pericarditis; 7 (4.0%) with heart failure; 4 (2.3%) with high-degree conduction or ventricular arrhythmias; and 1 (0.6%) with Tako-Tsubo. 8 (4.6%) had a combination of CV irAEs. The majority of patients admitted to the hospital had CV irAEs (24, 82.7%). On multivariable regression analysis(Figure 2), CV or muscle symptoms(OR 2.677 [CI 1.207-5.937], p=0.015), prior CV disease history(OR 3.668 [CI 1.486-9.057], p=0.0048), and abnormal ECG (OR 2.855 [CI 1.074-7.589], p=0.035) remained associated with CV irAEs at referral. Including global longitudinal strain (GLS) in the model, we identified prior CV disease history. (OR 7.011 [CI 2.217-22.167], p=0.0009) and GLS <16% (OR 2.774 [CI 1.07-7.17], p=0.035) as significant. Conclusions We demonstrate the safety of a standardized outpatient management approach for most patients referred for suspected CV irAEs, mainly triggered by asymptomatic elevation of troponin. No patient experienced CV death at 30 days. When suspecting a CV irAEs, CV or muscle symptoms, previous history of CV disease, and abnormal ECG should prompt speedy assessment given the higher likelihood of CV irAEsFigure 1

Relationship of Immune-Related Adverse Events with Tumor Response and Prognosis in Esophageal Squamous Cell Carcinoma Following Nivolumab Monotherapy.

Patients across various cancers who develop immune-related adverse events (irAEs) post-immune checkpoint inhibitor (ICI) treatment tend to experience better tumor response and survival than those who do not. However, studies regarding this association in patients with esophageal squamous cell carcinoma (ESCC) are limited. We assessed the relationship of irAEs with tumor response and survival in 82 consecutive patients with unresectable advanced or recurrent ESCC treated with second- or later-line nivolumab, an anti-PD-1 antibody, monotherapy. We observed irAEs in 24 (29.3%) patients, with the overall response and disease control rates in the irAE-positive group being significantly better than those in the irAE-negative group (both p < 0.0001). During the entire period and within 8 weeks of nivolumab initiation, progression-free and overall survivals (PFS and OS, respectively) were significantly better in patients with grade1/2 irAEs than in those without. Univariate and multivariate analyses indicated grade1/2 irAEs during the entire period and within 8 weeks as independent covariates for PFS (entire period: hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.16-0.49, p < 0.001; within 8 weeks: HR 0.46, 95% CI 0.23-0.93, p = 0.03) and OS (entire period: HR 0.24, 95% CI 0.13-0.44, p < 0.001; within 8 weeks: HR 0.41, 95% CI 0.18-0.92, p = 0.03). Grade1/2 irAEs during the entire treatment period and within 8 weeks of nivolumab initiation were significantly associated with improved tumor response and survival in patients with advanced ESCC treated with nivolumab monotherapy. Therefore, mild irAEs may be predictive markers for the response and prognosis of ESCC following ICI treatment.

Exosomes from human bone marrow MSCs alleviate PD-1/PD-L1 inhibitor-induced myocardial injury in melanoma mice by regulating macrophage polarization and pyroptosis

Myocarditis, which can be triggered by immune checkpoint inhibitor (ICI) treatment, represents a critical and severe adverse effect observed in cancer therapy. Thus, elucidating the underlying mechanism and developing effective strategies to mitigate its harmful impact is of utmost importance. The objective of this study is to investigate the potential role and regulatory mechanism of exosomes derived from human bone marrow mesenchymal stem cells (hBMSC-Exos) in providing protection against myocardial injury induced by ICIs. We observed that the administration of programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitor BMS-1 in tumor-bearing mice led to evident cardiac dysfunction and myocardial injury, which were closely associated with M1 macrophage polarization and cardiac pyroptosis. Remarkably, these adverse effects were significantly alleviated through tail-vein injection of hBMSC-Exos. Moreover, either BMS-1 or hBMSC-Exos alone demonstrated the ability to reduce tumor size, while the combination of hBMSC-Exos with BMS-1 treatment not only effectively improved the probability of tumor inhibition but also alleviated cardiac anomalies induced by BMS-1.

6779 The Diversity of Immune Checkpoint Inhibitor Associated Diabetes

Abstract Disclosure: V.A. Mendpara: None. M. Lansang: None. M. Caromori: None. L. Kennedy: None. K. Zhou: None. Immune checkpoint inhibitor (ICI) treatment has become a first-line therapy for a variety of cancers, including use of nivolumab (a programmed death 1 [PD-1] inhibitor) for metastatic melanoma. Though able to prolong survival, ICIs cause immune-related adverse events (irAE) through down-regulation of immune control pathways. One irAE is diabetes mellitus (DM), referred to as ICI-induced DM. Despite its low incidence (2%), ICI-induced DM carries with it high morbidity, with need for hospitalization in up to 25% of patients, and burden as patients are typically committed to multiple daily insulin injections (MDII). Here we report diverse presentations of four patients treated with ICI for metastatic melanoma who developed ICI-induced DM. The median age at DM presentation was 60.5 years (range 59-78 years). All patients received nivolumab and one patient was also treated with ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 inhibitor). The median time from start of ICI to development of ICI-induced DM was 32.5 wks, ranging from 27-46 wks. Three of the 4 patients previously developed hypothyroidism at median of 15 wks from starting ICI. Two patients presented in DKA and the other 2 with severe hyperglycemia (glucose &amp;gt;300 mg/dL). Median HbA1c was 7.05% (range 6.4%-7.4%) at presentation. GAD Ab was negative in 3 of 4 patients, including one who had DKA. C-peptide was undetectable (&amp;lt;0.2 ng/mL) in the 2 patients with DKA, 0.4 ng/mL in one other patient, and not measured in the fourth. All patients were immediately started on MDII. However, the two patients without DKA on presentation were eventually initiated on non-insulin agents. One of them was started on a DPP-4 inhibitor and discontinued fast-acting insulin, and the other started a GLP-1 receptor agonist and reduced their fast-acting insulin requirement. The heterogeneity of DM presentation and its clinical course reported here highlights a few important points. The first is that the onset of ICI-induced DM is often much later than that of the most common endocrine irAE, hypothyroidism, which has an onset around 10 weeks in average. Second, DM often presents as severe hyperglycemia incidentally detected on blood work. GAD Ab positivity is relatively less common, suggesting a different underlying etiology than classic type 1 DM. Onset of severe hyperglycemia can occur over many weeks (as indicated by higher HbA1c), making it important to monitor for hyperglycemia in those with no previous history of prediabetes or DM. Finally, it may be possible to use a combination of non-insulin antihyperglycemic agents to provide better glycemic management. No widely validated strategies for the surveillance of irAEs are currently available, and a better understanding in the propensity of patients to develop irAEs is clearly required. Importantly, optimal management of irAEs relies on early recognition and frequently demands a multidisciplinary approach. Presentation: 6/2/2024

7596 Thyroid Function Tests in Breast Cancer Patients Following Immune Checkpoint Inhibitor Treatment: What Happened in a Population with Preexisting Thyroid Dysfunction?

Abstract Disclosure: M. Villanova: None. L. Min: None. Introduction: Thyroid dysfunction occurs commonly following immune checkpoint inhibition, but the etiology remains unclear. Immune checkpoint inhibitor (ICI) is not contraindicated in patients with a preexisting thyroid dysfunction, but little is known about the impact of ICI on thyroid function tests (TFTs) in this setting. This study sought to define TFTs abnormalities following ICI treatment in patients with previous thyroid dysfunction. Methods: We performed a retrospective cohort study of thyroid dysfunction in patients with breast cancer undergoing anti-programmed cell death protein-1/ligand-1 therapy from May 2016 to Dec 2023. Results: A total of 30 patients were included with a mean follow-up of 18 ± 12 months. Two patients (7%) had a history of Graves’ disease, 4 patients (13%) had a post ablative hypothyroidism, and 3 patients (10%) had a post-surgical hypothyroidism. The etiology of the hypothyroidism was not further specified in the remain cases (70%). Twenty-three patients (77%) were treated with levothyroxine at baseline at the mean dose of 1.31 ± 0.68 mcg/kg. Baseline TFTs were available in 27 patients (90%). Twenty-four patients (80%) had at least one TFTs abnormality after initiating ICI treatment. Subclinical hypothyroidism (n = 11) was the most common abnormality, followed by overt thyrotoxicosis (n = 10), subclinical thyrotoxicosis (n =7), and overt hypothyroidism (n = 7). Thirteen out of 16 patients with normal baseline TFTs developed at least one TFTs abnormality after initiating ICI treatment. Subclinical hypothyroidism (n = 6) and overt thyrotoxicosis (n =6) were the most common alterations, followed by subclinical thyrotoxicosis (n = 5), and overt hypothyroidism (n = 3). Three patients with post-ablative hypothyroidism had normal baseline TFTs. Among these, one patient developed an overt thyrotoxicosis, one patient developed a subclinical hypothyroidism followed by overt thyrotoxicosis and one patient had no TFTs alterations. One post-operative hypothyroid patient had a normal baseline TFT and developed a subclinical hypothyroidism followed by overt thyrotoxicosis. Twenty-five patients (83%) were on levothyroxine at the last follow-up at the mean dose of 1.41 ± 0.60 mcg/kg. The dose was higher than that at baseline but did not reach statistical difference (Student T test, P = 0.059). Levothyroxine dosage was adjusted in 16 patients (53%) and 25 patients (83%) achieved normal TFTs at the last follow-up. Conclusion: ICI treatment related TFTs abnormalities were common in patients with preexisting thyroid dysfunction. There were multiple distinct phenotypes. The mechanisms underlying the TFTs abnormalities is not clear. Destructive thyroiditis, medication adherence, or interference with TFT assay by ICI are among the possible etiologies. ICI is not contraindicated in this group of patients but their TFTs should be monitored closely. Presentation: 6/1/2024

Regulatory Role of IL6 in Immune-Related Adverse Events during Checkpoint Inhibitor Treatment in Melanoma

The landscape of clinical management for metastatic melanoma (MM) and other solid tumors has been modernized by the advent of immune checkpoint inhibitors (ICI), including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. While these agents demonstrate efficacy in suppressing tumor growth, they also lead to immune-related adverse events (irAEs), resulting in the exacerbation of autoimmune diseases such as rheumatoid arthritis (RA), ulcerative colitis (UC), and Crohn’s disease (CD). The immune checkpoint inhibitors offer promising advancements in the treatment of melanoma and other cancers, but they also present significant challenges related to irAEs and autoimmune diseases. Ongoing research is crucial to better understand these challenges and develop strategies for mitigating adverse effects while maximizing therapeutic benefits. In this manuscript, we addressed this challenge using network-based approaches by constructing and analyzing the molecular and signaling networks associated with tumor-immune crosstalk. Our analysis revealed that IL6 is the key regulator responsible for irAEs during ICI therapies. Furthermore, we conducted an integrative network and molecular-level analysis, including virtual screening, of drug libraries, such as the Collection of Open Natural Products (COCONUT) and the Zinc15 FDA-approved library, to identify potential IL6 inhibitors. Subsequently, the compound amprenavir was identified as the best molecule that may disrupt essential interactions between IL6 and IL6R, which are responsible for initiating the signaling cascades underlying irAEs in ICI therapies.

Dose-Volume Constraints Parameters for Lung Tissue in Thoracic Radiotherapy Following Immune Checkpoint Inhibitor Treatment.

This study aims to identify risk factors associated with symptomatic radiation pneumonitis (RP, Grade ≥ 2) following immunotherapy preceding thoracic radiotherapy (ICI-TRT) and establish safe dose constraints. This retrospective study enrolled patients diagnosed with non-small-cell lung cancer (NSCLC) who underwent thoracic radiotherapy (TRT) following immune checkpoint inhibitors (ICIs) treatment. The primary endpoint was the occurrence of symptomatic RP (Grade ≥ 2), as defined by the Common Terminology Criteria for Adverse Events version 5.0. Clinical and lung dosimetric parameters were analyzed to determine their associations with symptomatic RP. Dosimetric parameters included mean lung dose (MLD) and the percentage of lung volume receiving ≥10 Gy (V10), ≥20 Gy (V20), ≥30 Gy (V30), and ≥40 Gy (V40). Receiver operating characteristic curves were used to predict the risk of developing symptomatic RP to establish optimal threshold values for each dosimetric predictor. Among the 118 patients included, the incidence of symptomatic RP was 25.4%. Tumor locations, intervals between immunotherapy and radiotherapy, and MLD, V10, V20, V30, and V40 were identified as independent risk factors for symptomatic RP. The area under the curve (AUC) values for MLD, V10, V20, V30, and V40 were 0.788 (95% confidence interval [CI] 0.704-0.873), 0.789 (95% CI 0.705-0.874), 0.791 (95% CI 0.706-0.876), 0.784 (95% CI 0.697-0.871), and 0.749 (95% CI 0.656-0.842), respectively. The optimal threshold values for MLD, V10, V20, V30, and V40 were 9.7 Gy, 26.3%, 15.9%, 13.3%, and 8.6%, respectively. These thresholds are lower than current guideline recommendations, and maintaining dosimetric parameters below these values resulted in a cumulative symptomatic RP incidence of <12%. The recommended dose thresholds for MLD, V10, V20, V30, and V40 are lower than the current guidelines, underscoring the importance of radiotherapy planning to minimize symptomatic RP occurrence in patients receiving ICI-TRT.

Absence of Survival Impact from Hepatitis During Immunotherapy in 193 Patients with Advanced Hepatocellular Carcinoma - An Observational Study from Taiwan.

Hepatitis often occurs after initiating immune checkpoint inhibitor (ICI) treatment. The time and grade of hepatitis after ICI starts and the prognostic role of immune-related hepatitis in patients with advanced hepatocellular carcinoma (aHCC) remain unclear. In this real-world analysis, we enrolled aHCC patients receiving ICIs, documented the highest level of liver enzymes during/after ICIs, and analyzed the survival impact of different hepatitis patterns. One hundred and ninety-three aHCC patients receiving ICIs were recruited. During ICIs, 88.6% of patients experienced aspartate transaminase (AST) elevations (Grade III/IV: 7.8%). For alanine transaminase (ALT), 81.3% had elevated levels (Grade III/IV: 3.6%), and 41.5% of patients had elevated bilirubin levels (Grade 3/4: 6.7%). The median AST, ALT, and total bilirubin values significantly increased after ICI treatment initiated (all p < 0.001) and, similarly, after excluding progressive disease (p = 0.014, p = 0.002, p < 0.001). The median time of hepatitis occurrence is from the 4.0th to 15.9th weeks. Multivariable analysis showed that patterns of liver enzyme change of AST and total bilirubin in patients receiving ICIs significantly correlate to overall survival (OS, p = 0.009 and 0.001, respectively). After ICI termination, patients with elevated bilirubin (p = 0.003) and AST (p = 0.005) would indicate poor survival, with adjustment of viral hepatitis and ICI responses. Hepatitis emerges between the 4th and 20th weeks post-ICI initiation. Changes in liver enzymes during ICI therapy do not directly affect OS, implying the safety of ICI use when corticosteroids are promptly administered if clinically indicated.

Toxicity of Cancer Immunotherapies in Older Patients: Does Age Make a Difference?

The use of immunotherapy agents especially immune checkpoint inhibitors is growing, and toxicities known as immune-related adverse events affecting any organ system may develop as a consequence of the treatment. With an ageing population, a considerable number of patients who will receive these therapies will be older adults. However, older patients who have highly heterogenous clinical characteristics, age-related changes in the immune system, a higher prevalence of comorbidities and frailty have been poorly represented in clinical trials, leaving gaps in understanding the safety of immune checkpoint inhibitor agents in this subgroup. Therefore, the safety of immune checkpoint inhibitors is a primary point of consideration when treating older patients with cancer. The available evidence is conflicting, but it generally suggests that the incidence of immune-related adverse events is not necessarily higher in older patients, but it may have a different profile. It is important to also note that the management of immune-related adverse events can be a challenge in these patients, owing to the risks associated with the use of corticosteroids and a reduced physiological reserve. A comprehensive characterisation of immune ageing, potential biomarkers to predict immune-related adverse events, the use of measures for frailty, enrolling older patients with cancer to clinical trials and analysis of real-world data are necessary to improve the evidence-based decision making for immune checkpoint inhibitor treatment in a geriatric oncology population.

Serum Inflammatory Dynamics as Novel Biomarkers for Immune Checkpoint Inhibitors in Non-small-cell Lung Cancer With Bone Metastases.

The aim of the study was to develop a novel predictive scoring system based on the dynamics of serum inflammatory indicators in immune checkpoint inhibitor (ICI) treatment on non-small-cell lung cancer (NSCLC) with bone metastases. Sixty patients with NSCLC and bone metastases treated with ICIs between January 2016 and March 2021 were included in the development cohort. Serum neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) levels were assessed before (pre-value) and 6 weeks after (post-value) ICI treatment, and a novel predictive score was developed: pre-value ≥ post-value, 0 points; pre-value < post-value, 1 point; total score: 0-2 points. The associations of these dynamics and the score with clinical outcomes, including overall survival (OS), progression-free survival (PFS), response rate (RR) of bone metastases, and disease control rate (DCR), were evaluated. Furthermore, cross-validation was performed with 23 patients after April 2021 using the same inclusion criteria. The patients with decreased serum inflammation levels had significantly better OS, PFS, and RR than those with increased levels. Applying the developed score to the development cohort, the patients with 0 points had significantly better OS, PFS, and RR than others. In multivariable analysis, the score independently predicted treatment response to ICI for bone metastasis and prognosis. Cross-validation showed that OS, PFS, and RR were significantly better in the patients in the 0-point group. The early NLR and CRP dynamics were associated with therapeutic responses to ICIs in NSCLC with bone metastases. Our novel scoring system based on these dynamics is simple and has a high predictive accuracy.

Relevance of surveillance manual for the early detection of immune checkpoint inhibitor-induced myocarditis: A case series

ObjectiveThe European Cardio-Oncology Guidelines recommend regular electrocardiography and troponin testing during immune checkpoint inhibitors (ICIs) treatment, but their efficacy for monitoring ICI treatment remains unclear. This study aimed to evaluate the effectiveness of a surveillance protocol for early detection of ICI-induced myocarditis. MethodsBetween May 2014 and May 2024, patients who began treatment with ICIs at our hospital and developed ICI-induced myocarditis were included in this study. We created a straightforward management flowchart for myocarditis. The protocol was based on monitoring troponin T levels. We confirmed the efficacy of our surveillance protocol using a case series of ICI-induced myocarditis. ResultsDuring the observation period, 3481 patients were newly started on ICIs at our hospital. Five patients were previously diagnosed with myocarditis, and five patients were diagnosed with myocarditis after the implementation of the surveillance protocol. The manual enabled the early detection of myocarditis, and the mortality rate for myocarditis at our hospital improved from 60% to 0%. The incidence of conduction system disorders significantly reduced from 100% to 0% (P < 0.01). After the surveillance protocol was initiated, there were no cases of myocarditis requiring immunosuppressive drugs beyond steroids. ConclusionsThis study confirmed the relevance of a troponin-based surveillance protocol for the early detection of ICI-induced myocarditis. The implementation of the surveillance protocol reduced mortality from myocarditis and significantly reduced serious complications of conduction system disorders. Although this study is a small case series of patients who developed myocarditis, we confirm the effectiveness of surveillance for myocarditis.

Comprehensive analysis of NOTCH pathway with tumor environment in pancreatic adenocarcinoma

Abstract Objectives Pancreatic adenocarcinoma (PAAD) ranks among the most prevalent malignant neoplasms, and multiple pathways are involved in its pathogenesis, including the NOTCH pathway. However, the variable biological functions of the pathway in PAAD are controversial. Methods RNA-seq data for PAAD was analyzed using data from The Cancer Genome Atlas and Genotype-Tissue Expression databases. Utilizing Kaplan-Meier survival curves and Cox regression analyses, we examined the prognostic significance. The tumor microenvironment and immunotherapy responses were investigated using ssGSEA, ESTIMATE, and TIDE models. Functional enrichment analysis was used to explore gene functions. Results We identified NOTCH2, JAG1, NOTCH4, and DLL3 as high-priority members of the NOTCH pathway that modulates PAAD. Elevated NOTCH2 and JAG1 levels were markedly linked to reduced overall survival (OS), while increased NOTCH4 and DLL3 levels were significantly related to extended OS. Immune analyses showed that NOTCH-based scores were closely related to the immune microenvironment. NOTCH scores were not only closely correlated with tumor-infiltrating immune cells, but also with immunologically activated and immune checkpoint gene expression. The high NOTCH score group had a higher proportion of tumor-infiltrating immune cells and had better responses to immune checkpoint inhibitor therapy. Conclusions These data indicate that NOTCH2, JAG1, NOTCH4, and DLL3 could function as efficient prognostic biomarkers and therapeutic targets in PAAD, and patients with a high NOTCH score may have a significant response to immune checkpoint inhibitor treatment.

Baseline eosinophil proportion is a useful predictor of immune-related adverse events following immune checkpoint inhibitor treatment for recurrent metastatic head and neck cancer

Background Immune checkpoint inhibitors (ICIs) occasionally cause immune-related adverse events (irAEs) in various organs. However, predictors of irAEs remain unidentified. Objectives We evaluated the predictors of irAEs and compared the outcomes of ICIs with and without irAEs in patients with recurrent/metastatic head and neck cancers (R/M HNCs). Materials and methods We retrospectively analyzed 157 patients with R/M HNCs who were administered an anti-PD-1 antibody between September 2014 and December 2022. We examined whether various pretreatment factors were associated with irAEs. The overall survival (OS) and progression-free survival (PFS) in patients with and without irAEs were analyzed. Results Overall, 44 patients (28.0%) developed irAEs. The survival curve estimated for patients with and without irAEs showed a significant difference in PFS (p = 0.018), but not in OS (p = 0.208). Multivariate analysis revealed significant differences in relative eosinophil counts (p < 0.001), TP (p = 0.014), and NLR (p = 0.002), which may be independent predictors of irAEs. Conclusion IrAEs may be associated with higher efficacy of ICIs and longer PFS. The relative eosinophil count may be predictors of irAEs and useful in routine medical practice. Using these biomarkers to predict irAEs will help predict ICI effects and manage irAEs.

Immune-related [18F]FDG PET findings in patients undergoing checkpoint inhibitors treatment: correlation with clinical adverse events and prognostic implications

BackgroundDirect comparisons between [18F]FDG PET/CT findings and clinical occurrence of immune-related adverse events (irAEs) based on independent assessments of clinical and imaging features in patients receiving immune checkpoint inhibitors (ICIs) are missing. Our aim was to estimate sites, frequency, and timing of immune-related PET findings during ICIs treatment in patients with melanoma and NSCLC, and to assess their correlation with clinical irAEs. Prognostic implications of immune-related events were also investigated.MethodsFifty-one patients with melanoma (47%) or NSCLC (53%) undergoing multiple PET examinations during anti-PD1/PDL1 treatment were retrospectively included. Clinical irAEs were graded according to CTCAE v.5.0. Abnormal PET findings suggestive of immune activation were described by two readers blinded to the clinical data. Progression-free survival (PFS) and overall survival (OS) were analyzed with the Kaplan-Meier method in patients stratified according to the presence of irAEs, immune-related PET findings or both.ResultsTwenty-one patients showed clinical irAEs only (n = 6), immune-related PET findings only (n = 6), or both (n = 9). In patients whose imaging findings corresponded to clinical irAEs (n = 7), a positive correlation between SUVmax and the severity of the clinical event was observed (rs=0.763, p = 0.046). Clinical irAEs occurred more frequently in patients without macroscopic disease than in metastatic patients (55% vs. 23%, p = 0.039). Patients who developed clinical irAEs had a significantly longer PFS than patients who remained clinically asymptomatic, both in the overall cohort (p = 0.011) and in the subgroup of (n = 35) patients with metastatic disease (p = 0.019). The occurrence of immune-related PET findings significantly stratified PFS in the overall cohort (p = 0.040), and slightly missed statistical significance in patients with metastatic disease (p = 0.08). The best stratification of PFS was achieved when all patients who developed immune-related events, either clinically relevant or detected by PET only, were grouped together both in the overall cohort (p = 0.002) and in patients with metastatic disease (p = 0.004). In the whole sample, OS was longer in patients who developed any immune-related events (p = 0.032).ConclusionPatients with melanoma or NSCLC under ICI treatment can develop clinical irAEs, immune-related PET findings, or both. The occurrence of immune-related events has a prognostic impact. Combining clinical information with PET assessment improved outcome stratification.