Immune-related Myocarditis Research Articles

Fatal Case of Immune-Related Myocarditis and Myositis Due to Treatment with Immune Checkpoint and Tyrosine Kinase Inhibitors.

Immune checkpoint inhibitor and tyrosine kinase inhibitor combinations have become the new standard of care in the first-line treatment of metastatic clear cell renal cell carcinoma. However, there is a growing concern regarding severe immune-related adverse events. A 78-year-old man with metastatic clear cell renal cell carcinoma, treated with pembrolizumab and axitinib, was admitted to the emergency department 30 days after initiating treatment due to rapidly progressive myositis. Myocarditis with severe ventricular dysfunction was identified. Muscular biopsy findings were compatible with inflammatory myopathy associated with immune checkpoint inhibitors. Initial treatment with high-dose corticosteroids showed an insufficient response. Therapeutic escalation on the third day with methylprednisolone, immunoglobulin, and abatacept resulted in clinical improvement. On the eleventh day, a sudden malignant arrhythmia occurred, followed by cardiac arrest. This represents one of the first case reports describing myocarditis and myositis during treatment with pembrolizumab-axitinib. While immune checkpoint inhibitor may play a major role, it is also possible that the tyrosine kinase inhibitor, while attempting to promote immune modulation, also increases severe toxicities.

Sintilimab combined with bevacizumab in relapsed or persistent ovarian clear cell carcinoma (INOVA): a multicentre, single-arm, phase 2 trial

Ovarian clear cell carcinoma rarely responds to second-line chemotherapy, the recommended treatment for relapsed epithelial ovarian cancer. Here, we report the activity and safety of sintilimab in combination with bevacizumab in patients with relapsed or persistent ovarian clear cell carcinoma. In the prospective, multicentre, single-arm, phase 2 INOVA trial, patients aged 18-75 years with histologically confirmed relapsed or persistent ovarian clear cell carcinoma were enrolled from eight tertiary hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group performance status score of 0-2 and previous exposure to at least one cycle of platinum-containing chemotherapy. Enrolled patients received sintilimab (200 mg) and bevacizumab (15 mg/kg) intravenously every 3 weeks until disease progression. The primary endpoint was objective response rate assessed by independent central review based on Response Evaluation Criteria in Solid Tumours version 1.1. Eligible enrolled patients who received at least one cycle of treatment and had at least one tumour response assessment following the baseline assessment per protocol were included in the activity analysis. Patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04735861) and is ongoing. Between April 8, 2021, and July 3, 2023, 51 patients were screened and 41 patients received at least one dose of sintilimab in combination with bevacizumab. Response evaluation was completed in 37 patients. Objective responses were observed in 15 patients (objective response rate 40·5%; 95% CI 24·8-57·9), of which five (14%) were complete responses and ten (27%) were partial responses. At data cutoff (Jan 29, 2024), the median follow-up was 16·9 months (IQR 7·5-23·4). Three (7%) patients developed grade 3 treatment-related adverse events including one patient with proteinuria, one patient with myocarditis, and one patient with rash. No treatment-related adverse events of worse than grade 3 severity were recorded. Treatment-related serious adverse events occurred in two (5%) patients including one patient with immune-related myocarditis and another with hypertension and renal dysfunction. No treatment-related deaths occurred. Sintilimab in combination with bevacizumab showed promising anti-tumour activity and manageable safety in patients with relapsed or persistent ovarian clear cell carcinoma. Larger, randomised trials are warranted to compare this low-toxicity, chemotherapy-free combinatorial regimen with standard chemotherapy. National Key Technology Research and Development Program of China, National Natural Science Foundation of China, Beijing Xisike Clinical Oncology Research Foundation, and Innovent Biologics. For the Chinese translation of the abstract see Supplementary Materials section.

Peripheral nervous system immune-related adverse events due to checkpoint inhibition.

Immune checkpoint inhibitors have revolutionized cancer therapy and are increasingly used to treat a wide range of oncological conditions, with dramatic benefits for many patients. Unfortunately, the resulting increase in T cell effector function often results in immune-related adverse events (irAEs), which can involve any organ system, including the central nervous system (CNS) and peripheral nervous system (PNS). Neurological irAEs involve the PNS in two-thirds of affected patients. Muscle involvement (immune-related myopathy) is the most common PNS irAE and can be associated with neuromuscular junction involvement. Immune-related peripheral neuropathy most commonly takes the form of polyradiculoneuropathy or cranial neuropathies. Immune-related myopathy (with or without neuromuscular junction involvement) often occurs along with immune-related myocarditis, and this overlap syndrome is associated with substantially increased mortality. This Review focuses on PNS adverse events associated with immune checkpoint inhibition. Underlying pathophysiological mechanisms are discussed, including antigen homology between self and tumour, epitope spreading and activation of pre-existing autoreactive T cells. An overview of current approaches to clinical management is provided, including cytokine-directed therapies that aim to decouple anticancer immunity from autoimmunity and emerging treatments for patients with severe (life-threatening) presentations.

A tumor-responsive nanostrategy for reducing the risk of immunotherapy-related myocarditis

Immune checkpoint blockade (ICB) therapy using anti-programmed cell death 1 (PD1) and cytotoxic T lymphocyte antigen 4 (CTLA4), either individual or in combination, has emerged as a pioneer in clinical immunotherapy for various human cancers. However, immune-related adverse effects (irAEs) remain the significant hindrances to their clinical development. In particular, immune-related myocarditis has emerged as a fatal adverse event with the highest fatality rate. For this purpose, we report herein the first example of uncoupling efficacy and myocarditis toxicity in checkpoint blockade cancer therapy. This efficient, yet highly safe access to ICB therapy was achieved by a simple nanoplatform that masked anti-PD1/CTLA4 antibodies to albumin via a ROS-cleavable linker. An in-depth investigation of the experimental autoimmune myocarditis (EAM) mouse model revealed the avoiding exacerbation of myocarditis of our nanomedicine. Notably, the on-demand release of antibodies at the tumor sites enables the combined checkpoint antibody activity. The present study uncouples the ICB efficacy and toxicity, and highlights the irresistible charm of TME-responsive nanoantibodies in clinical cancer immunotherapy, offering solutions to challenges in the advancement of TME-responsive drug delivery toward clinical application.

Integrated analysis of single-cell data on role of NKG7high CD8+ Teff cells in driving immune-related adverse events.

e24114 Background: Immune-related adverse events (irAEs) frequently occur during immunotherapy and can impact various organ systems, which dampen the clinical outcomes of immune checkpoint inhibitors (ICIs). However, the precise immune hallmarks associated with irAEs remain further explored. Methods: We collected public (Bukhari et al., Zhu et al., Su et al., and Ma et al.) and our own scRNA-seq data across patients with different irAE types or without irAEs. By comparing T cell compositions between irAE and no-irAE patients, the subcluster correlated with the occurrence of irAE was identified. Subsequently, the integrated analyses were performed to explore its mechanisms in driving irAEs in both peripheral blood and local tissues. Results: Compared to no-irAE patients, a subcluster of effector T (Teff) cells was observed to increase notably in the peripheral blood of irAE patients during immunotherapy. This specific subcluster, named "NKG7high CD8+ Teff cells," was characterized by the significant expression of effector genes such as GZMH, CCL5, and especially NKG7. In contrast to other CD8+ T cells, the NKG7high CD8+ Teff cells exhibited stronger cytotoxicity functions, increased exosome secretion, and enhanced MIF-CD74 interaction with monocytes, which suggests the mechanistic link between its increased infiltration and the development of irAEs. Further investigation showed these characteristics were more remarkable in NKG7high CD8+ Teff from irAE patients than no-irAE patients. Subsequently, the increase of NKG7high CD8+ Teff during immunotherapy was validated in our own scRNA from immune thyroiditis patients, which was not observed in no-irAE patients. Across various irAE types, NKG7high CD8+ Teff subsets, along with their NKG7 expression, demonstrated heightened infiltration and expression in immune-related arthritis and myocarditis samples. After investigating the role of NKG7high CD8+ Teff in peripheral blood, we focused on its distribution and roles in local irAE tissue. NKG7high CD8+ Teff cells accumulated in immune-related thyroiditis tissues, and recruited macrophages through the IFNG and CSF1 signaling pathways, thereby inducing an immune overreaction. Meanwhile, in immune-related myocarditis mice heart tissues, NKG7high CD8+ Teff cells could interact with macrophages via the SPP1 signaling pathway and cause endothelial cell damage through the FASL-FAS pathway. Conclusions: This comprehensive study revealed the intricate mechanisms of NKG7high CD8+ Teff in inducing irAEs, providing valuable insights into their roles and potential implications in irAE treatment.

Phase II multi-center study of adjuvant nivolumab in combination with ipilimumab in patients with high-risk uveal melanoma (HCRN MEL17-309).

9509 Background: High-risk uveal melanomas (UM) recur distantly in over 50% by 3 years (median distant metastatic-free survival (DMFS) 32 months). No effective treatment currently exists to reduce the risk of metastatic disease and patients (pts) with metastasis have a very poor prognosis with few therapeutic options. The combination of Nivolumab/Ipilimumab (Nivo/Ipi) has shown limited efficacy in pts with metastatic UM. However, preclinical data suggest differential biology between local vs metastatic UM. We performed a prospective multi-center phase II study of adjuvant Nivo/Ipi in pts high-risk UM patients to compare DMFS to a cohort of UM with the same tumor characteristics. Methods: This investigator-initiated study enrolled pts with high-risk UM, defined as a predicted 3-year distant relapse-free survival (DMFS) of approximately 50% (based on gene expression profiling (GEP) (DecisionDx-UM) class 2 with tumor largest basal diameter (LBD) of 12mm or higher). Pts received Nivo 240mg iv every 2 weeks and Ipi 1mg/kg every 6 weeks for up to 48 weeks. The target sample size was 50 evaluable pts. The primary endpoint was 3-year DMFS. Secondary endpoints were median DMFS, overall survival (OS), and toxicity (AE). In addition, a propensity score method (double robust estimate in R adjusted curves) is used to estimate the average DMFS and compare the nonrandomized treatment (tx) and the control patients. 119 pts from the Cooperative Ocular Oncology Group (COOG) database were defined as high risk, matched for tumor characteristics (GEP class 2, LBD≧12mm) and were used as a control cohort. Results: Fifty-two pts were enrolled and 50 were treated from 12/18/2018-9/29/2021. As of 11/6/2023, with a median follow-up of 36 months, the 3-year DMFS rate vs COOG control, was 69.1% vs 45.1% (two-sided p = 0.012) without any adjustment; and 70.4% vs 43.4% (two-sided p = 0.018) with the propensity score method. The median DMFS was not reached (NR) in the tx cohort vs 33.8 months. There was a reduction in the risk of distant recurrence with Nivo/Ipi vs control cohort (RR 0.52, 95%CI, 0.309-0.888). Median OS has not been reached with only 7 deaths from UM in the tx cohort so far. Grade ≥3 any-cause AE occurred in 27 pts (54%). Grade ≥3 treatment-related (TR) AE occurred in 48%. 22 pts (44%) discontinued the treatment due to toxicity. One pt died due to immune-related myocarditis. Conclusions: This phase II study of adjuvant Nivo/Ipi resulted in clinically meaningful and statistically significant improvement in 3-year DMFS of 70.4% vs 43.4% in control for pts with high-risk UM from the COOG database matched for tumor characteristics. Further investigation of this regimen as adjuvant therapy of high-risk UM is warranted. Clinical trial information: NCT03528408 .

Use of Infliximab in the Treatment of Immune Checkpoint Inhibitors-Related Myocarditis: A Systematic Review of Case Reports

Immune-mediated myocarditis is uncommon, progresses rapidly and has high mortality rate. Infliximab has been used in practice, particularly in steroid refractory cases, but evidence supporting the use is still lacking. This review aims to provide an overview of infliximab use in managing immune-related myocarditis. A systematic search was conducted using the PubMed and Cochrane Library databases as well as manual searching of bibliographies, from inception to 1 October 2021. Eligible studies were selected by the inclusion criteria. All the included studies were assessed for methodological quality using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports. There were 13 articles with total 14 reported cases of immune-related myocarditis treated with infliximab. Most patients developed myocarditis with high severity grade, concurrent immune-related adverse events (irAEs), particularly neuromuscular irAEs and multiple potentially fatal complications. Most patients received single dose of infliximab, whereas few received multiple doses. Four patients improved clinically or biochemically, but 10 patients did not improve or deteriorated clinically with the addition of infliximab. Half of the reported cases did not survive due to myocarditis and its complications. Conflicting results were observed when infliximab was used in patients with heart failure and higher dose did not appear to be beneficial in these patients. Concomitant irAEs, high severity grade and occurrence of potentially fatal complications indicate the need to escalate the treatment by using additional immunosuppressive agents such as infliximab. However, there is no standardisation on the infliximab treatment regimen, outcomes have been inconsistent and safety data is limited.

Molecular Pathways and Cellular Subsets Associated with Adverse Clinical Outcomes in Overlapping Immune-Related Myocarditis and Myositis.

Immune checkpoint therapies (ICT) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we performed single-cell RNA sequencing of heart and skeletal muscle biopsies obtained from living patients with cancers treated with ICTs and admitted to the hospital with myocarditis and/or myositis (overlapping myocarditis plus myositis, n = 10; myocarditis-only, n = 1) or ICT-exposed patients ruled out for toxicity utilized as controls (n = 9). All biopsies were obtained within 96 hours of clinical presentation. Analyses of 58,523 cells revealed CD8+ T cells with a cytotoxic phenotype expressing activation/exhaustion markers in both myocarditis and myositis. Furthermore, the analyses identified a population of myeloid cells expressing tissue-resident signatures and FcγRIIIa (CD16a), which is known to bind IgG and regulate complement activation. Immunohistochemistry of affected cardiac and skeletal muscle tissues revealed protein expression of pan-IgG and complement product C4d, which were associated with the presence of high-titer serum autoantibodies against muscle antigens in a subset of patients. We further identified a population of inflammatory IL1B+TNF+ myeloid cells specifically enriched in myocarditis and associated with greater toxicity severity and poorer clinical outcomes. These results provide insight into the myeloid subsets present in human immune-related myocarditis and myositis tissues and nominate new targets for investigation into rational treatments to overcome these high-mortality toxicities. See related Spotlight by Fankhauser et al., p. 954.

Anlotinib plus TQB2450 as adjuvant therapy in patients with esophageal squamous cell carcinoma: A phase II study (ALTER-E005).

347 Background: There is currently a limited range of therapeutic options available for postoperative patients (pts) with esophageal squamous cell carcinoma (ESCC), emphasizing the urgent requirement to investigate more efficient and safer postoperative treatment regimens for resectable ESCC. TQB2450, a novel PD-L1 blockade, has shown promising activity when combined with anlotinib, an antiangiogenic agent, in the treatment of various tumors, including advanced ESCC,1 and biliary tract cancer.2 The ALTER-E005 study aimed to evaluate the efficacy and safety of combining anlotinib with TQB2450 as adjuvant therapy in pts with ESCC. Methods: This was a single-arm, multi-center phase II clinical trial. 30 pts (≥18 years) with histologically confirmed T1-2N1-3M0 or T3-4NanyM0 ESCC who had undergone radical (R0) resection with no recurrence 6 to 12 weeks after surgery and ECOG PS ≤ 1 would been rolled. Enrolled pts received oral anlotinib 12 mg on days 1-14 and intravenous TQB2450 1200 mg on day 1every 3 weeks for up to 16 cycles, until disease recurrence. The primary endpoint was disease recurrence free (DFS). The secondary endpoints included safety, 1-year DFS rate, 3-year DFS rate, 1-year overall survival (OS) rate, and 3-year OS rate. Results: Between August 18, 2022, and August 25, 2023, a total of 12 patients were enrolled. Out of the 12 surgically resected cases of ESCC, 11 (91.7%) had an ECOG score of 1, 10 (83.3%) were male, and 6 (50%) were under the age of 65. According to the eighth edition of the AJCC Cancer Staging Manual, 7 (58.3%) were classified as stage II, and 5 (41.7%) were classified as stage III. As of the data cut-off date (August 25, 2023), the median follow-up time was 5.1 months (95% CI: 3.4-6.8). 2 pts experienced disease recurrence, and the median duration of DFS has not yet been reached. Currently, 9 pts are still undergoing therapy, with treatment durations ranging from 0.3 months to 9.6 months. 2 pts discontinued therapy due to adverse events (AE), which subsequently improved after treatment. One patient experienced immune-related myocarditis, while the other patient had mouth ulcers and hand-foot syndrome. Additionally, one patient voluntarily withdrew from the study. Out of the total 12 patients, 3 (25%) experienced grade 3 treatment-emergent adverse events (TEAEs). There was no grade 4 or higher TEAEs reported. The grade 3 TEAEs included hand-foot syndrome (16.7%), abnormal liver function (8.3%), and immune-related hepatitis (8.3%). Conclusions: The study demonstrated the preliminary efficacy and safety of combining anlotinib with TQB2450 as adjuvant therapy in patients with ESCC who had undergone radical (R0) resection and showed no recurrence 6 to 12 weeks after surgery. 1. Zhi-Ye Zhang, et al. poster 4041: ASCO 2023. 2. Zhou J, et al. Hepatology 2022. Clinical trial information: NCT05252078 .

The role of circulating biomarkers in predicting the 30-day mortality of immune checkpoint inhibitors-related myocarditis: a retrospective cohort study.

Immune checkpoint inhibitors-related myocarditis (ICIs-M) is a rare and highly lethal immune-related adverse events (irAEs) in common irAEs. This study aims to find circulating biomarkers that can reflect disease state and prognosis accurately. 48 patients with ICIs-M were enrolled according to the diagnostic criteria for ICIs-related myocarditis. For all enrolled patients, valuable information was extracted retrospectively from the medical system, mainly including demographic information, tumor information and laboratory examination. The follow-up period was defined as 30days after the first diagnosis of ICIs-M. In this study, the 30-day mortality rate of ICIs-M was 24.4%. After adjusting for potential confounding factors using multivariate analysis tools, we demonstrated the excellent performance of biomarkers in predicting 30-day mortality in patients with ICIs-M, including PLT (hazard ratio (HR),1.07; 95% confidence interval (95%CI),1.01-1.14; p = 0.028), ALT (HR, 1.23; 95%CI, 1.06-1.41; p = 0.005), AST(HR,1.06; 95%CI,1.01-1.10; p = 0.015), LDH (HR,1.15; 95%CI, 1.04-1.26; p = 0.004), troponin I(HR, 1.44; 95%CI, 1.09-1.89; p = 0.009), PLR (blood plate/lymphocyte) (HR, 1.04; 95% CI,1.01-1.07; p = 0.024), LAR (lactate dehydrogenase/albumin) (HR, 1.05; 95%CI,1.01-1.09; p = 0.012), and AAR (aspartate transaminase/albumin) (HR, 1.18; 95%CI, 1.00-1.39; p = 0.048). The analysis of the receiver operating characteristic showed that biomarkers with area under curve (AUC) greater than or equal to 0.80 were LDH (cutoff value,724.5; AUC, 0.86;95%CI, 0.75-0.97), LAR (cutoff value,18.11; AUC, 0.87;95%CI, 0.76-0.97), troponin I (cutoff value,0.87; AUC, 0.80;95%CI, 0.62-0.99), and AAR(cutoff value,1.52; AUC, 0.80;95%CI, 0.61-0.98). LDH, LAR, troponin I, and AAR are a group of promising biomarkers that demonstrate excellent predictive ability in predicting the 30-day mortality rate of immune-related myocarditis.

A retrospective pilot study of transarterial chemoembolisation using camrelizumab-eluting Callisphere beads for unresectable hepatocellular carcinoma

BackgroundOur objective was to assess the efficacy and safety of initial hepatic arterial infusion of chemotherapy combined with transarterial chemoembolisation using camrelizumab-eluting Callisphere beads (camrelizumab-DEB-TACE) for treating unresectable hepatocellular carcinoma (HCC).MethodsEnrolment included patients with unresectable HCC who underwent camrelizumab-DEB-TACE treatment from September 2021 to February 2023. The assessment included the examination of tumour response, overall survival (OS), progression-free survival (PFS), and the monitoring of adverse events (AEs).ResultsTwenty-one patients were included in the study. The objective response rates (ORR) and disease control rates (DCR) were 55.0% and 90.0% at 1 month and 57.9% and 78.9% at 3 months, respectively. The median PFS and OS were 7.4 and 15.5 months months, respectively. Among the 21 patients, 4 underwent more than 2 procedures of camrelizumab-DEB-TACE, with a mean of 1.9 ± 1.1 procedures (range: 1–4) per patient. No severe complications or treatment-related mortalities were observed. In addition, no patient developed severe AEs related to camrelizumab, such as reactive cutaneous capillary endothelial proliferation, immune-related pneumonia, or immune-related myocarditis. Nineteen patients experienced at least one type of AEs related to DEB-TACE, with abdominal pain (n = 16, 76.2%) being the most prevalent AE.ConclusionCamrelizumab-DEB-TACE demonstrated effectiveness and safety as a treatment for unresectable HCC, with no occurrence of severe camrelizumab-related AEs.

Atrial and ventricular arrhythmias with immune checkpoint inhibitor therapy in patients without evidence of myocarditis

Abstract Background Immune checkpoint inhibitor (ICI) therapy has improved the prognosis of many cancer types. Immune-related adverse events (irAEs) are common and recent studies suggest ICI therapy may be associated with an increased risk of arrhythmias. However, data on arrhythmias after ICI therapy has been limited by small sample sizes, the inclusion of patients with ICI myocarditis, or an incomplete characterization of the factors that drive arrhythmias with an ICI. Purpose This study aimed to characterize the association between ICIs and arrhythmias in patients without evidence of myocarditis. Methods We conducted a hospital network-wide retrospective cohort study on all patients treated with ICI who were free from arrhythmias at the start of ICI therapy, and had no evidence of immune-related myocarditis. We used a historical pre-ICI therapy era cohort of cancer patients of similar age and tumor types, diagnosed between 2008-2012. The main study outcome was the incidence of atrial fibrillation, atrial flutter, supraventricular tachycardia, and ventricular tachycardia after ICI therapy. International Classification of Diseases 9th and 10th edition codes were used to ascertain baseline characteristics and to detect the study outcomes. Myocarditis cases were identified through the application of natural language processing techniques to electronic health records. Patients on ICI therapy and controls were followed from the start of ICI therapy, and from the first visit after 2008, respectively, up to three years after the index date. Results The study population consisted of 7441 patients on ICI therapy and 2311 controls. Patients on ICI therapy were older (65±13 vs. 63±13 years, p<0.001) and more frequently had arterial hypertension (52% vs. 47%, p<0.001), but had lower rates of prior congestive heart failure (6% vs. 11%, p<0.001). Over a median follow-up period of 36 months, 9.8% on ICI therapy were diagnosed with any incident atrial or ventricular arrhythmia, compared to 7.1% in the control group (p<0.001) with corresponding incidence rates of 4.4 and 2.3 cases per 100 person-years, respectively (Fig. 1). When correcting for age, sex, cancer type, prior congestive heart failure, and cardiovascular risk factors, patients on ICI therapy had a higher risk of a composite outcome of any arrhythmia (hazard ratio [HR] 1.68, 95% confidence interval [CI]: 1.39-2.04, p<0.001), atrial fibrillation (HR 1.29, 95%CI: 1.02-1.63, p=0.034) and ventricular tachycardia (HR 2.01, 95%CI: 1.34-3.04, p<0.001). In a multivariable logistic regression model, the occurrence of a non-cardiovascular irAE was a predictor of an incident arrhythmia (odds ratio 1.81, 95%CI: 1.56-2.23, p<0.001). Conclusion This study, to the best of our knowledge, is the largest to report on ICI therapy-related arrhythmias and the first to show the occurrence of non-cardiovascular irAEs as a predictor of arrhythmia risk in patients on ICI therapy without evidence of myocarditis.Fig. 1

Mediators and mechanisms of immune checkpoint inhibitor-associated myocarditis: Insights from mouse and human.

The broad application of immune checkpoint inhibitors (ICIs) has led to significant gains in cancer outcomes. By abrogating inhibitory signals, ICIs promote T cell targeting of cancer cells but can frequently trigger autoimmune manifestations, termed immune-related adverse events (irAEs), affecting essentially any organ system. Among cardiovascular irAEs, immune-related myocarditis (irMyocarditis) is the most described and carries the highest morbidity. The currently recommended treatment for irMyocarditis is potent immunosuppression with corticosteroids and other agents, but this has limited evidence basis. The cellular pathophysiology of irMyocarditis remains poorly understood, though mouse models and human data have both implicated effector CD8+ T cells, some of which are specific for the cardiomyocyte protein α-myosin. While the driving molecular signals and transcriptional programs are not well defined, the involvement of chemokine receptors such as CCR5 and CXCR3 has been proposed. Fundamental questions regarding why only approximately 1% of ICI recipients develop irMyocarditis and why irMyocarditis carries a much worse prognosis than other forms of lymphocytic myocarditis remain unanswered. Further work in both murine systems and with human samples are needed to identify better tools for diagnosis, risk-stratification, and treatment.

Phase 2 multicenter trial of rucaparib and nivolumab as maintenance therapy following first-line platinum-based chemotherapy in patients with advanced biliary tract cancer (BTC): BilT-02.

4113 Background: Gemcitabine, cisplatin and durvalumab followed by maintenance durvalumab is standard of care first-line (1L) therapy for patients (pts) with advanced BTC. In this trial, we investigated the combination of a PARP inhibitor with anti-PD1 antibody in absence of progression after at least 4 months of standard 1L platinum-based chemotherapy. Methods: Pts with advanced BTC, ECOG PS 0-1 and absence of progression on 1L platinum-based therapy were enrolled on a phase 2 trial to receive rucaparib 600 mg PO BID in combination with nivolumab 240 mg IV Q2 weeks every 28 days for up to 2 years. The primary endpoint was 4-month progression-free survival (PFS) rate from the date of first study treatment with an alternative hypothesis of 85%. Secondary endpoints included median PFS and overall survival (OS) from first study treatment (PFS1, OS1) as well as from start date of first-line chemotherapy (PFS2, OS2), best overall response, and safety. Results: 31 pts were enrolled of which 14 (45%) were women, 25 (80.6%) Caucasian and 24 (77.64%) with ECOG 1. Primary disease site was intrahepatic, extrahepatic hilar and distal, and gallbladder cancer in 21 (67.7%), 4 (12.9%), 1 (3.2%) and 4 (12.9%), respectively. 1L platinum-based treatment included gemcitabine/cisplatin based in 26 (83.9%), FOLFOX in 3 (9.7%) and carboplatin/paclitaxel in 1 (3.2%) pts. Mean (range) cycles of rucaparib and nivolumab were 6.75 (1-24) and 5.9 (1-24). The median follow-up time is 28.7 months using reverse censoring methodology. PFS rate at 4 months was 54.8% (95% CI, 36-70.3), comparable to the 63% null estimate based on ABC-02 trial. Median PFS1 and OS1 are estimated to be 4.6 months (95% CI, 3.7-6.2) and 15.9 months (95% CI, 9.8-24.1). Median PFS2 and OS2 calculated from date of 1L chemotherapy are estimated as 9.9 months (95% CI, 8.3-11.3) and 21.4 months (95% CI, 14.8-26.7). Two (6.4%) pts had partial response (with IDH R132G and KRAS G12D) as best response with stable disease in an additional 22 (71%) pts. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 15 (48.4%) pts, including 1 patient who died on therapy due to possibly-related immune-related myocarditis. The most common grade 2 or greater TRAEs included fatigue (9, 29.0%), anemia (7, 22.6%), neutropenia (6, 19.3%), elevated AST (5, 16.1%) and elevated ALT (4, 12.9%). Reasons for treatment discontinuation included death (2), progression (27), adverse event (1) while 1 patient completed 2 years of study treatment. Conclusions: The primary endpoint of PFS rate at 4 months was not met but the preliminary measures of PFS1 and OS1 are much longer than expected, and hypothesis generating for rational combination of PARP inhibitor with maintenance immunotherapy in this rare cancer. Exploratory endpoint of association of genomic analysis with efficacy is ongoing and will be discussed. Clinical trial information: NCT03639935 .

A case of subclinical immune checkpoint inhibitor-associated myocarditis in non-small cell lung cancer

BackgroundImmune checkpoint inhibitors (ICIs) have been widely used in the treatment of cancer. Moreover, immune-related adverse events (irAEs) have become a new clinical challenge. ICI-associated myocarditis is a rare but fatal condition among diverse organ injuries, and early recognition and effective interventions are critical for patients.Case presentationIn this report, we present the case of a healthy 60-year-old male who was diagnosed with lung squamous cell carcinomas following chemotherapy and received ICIs. The patient presented with asymptomatic cardiac biomarker elevation followed by immune-related myocarditis. Fortunately, the patient achieved a good clinical result after receiving high-dose steroids. The treatment with ICIs was discontinued because of recurrent increases in troponin T.ConclusionICI-mediated associated myocarditis is an uncommon but potentially life-threatening adverse event. The current data suggest that clinicians need to be cautious about reinitiation in low-grade patients; however, further study of the diagnosis and treatment is necessary.

Myasthenia Gravis Induced by Immune Checkpoint Inhibitors: An Emerging Neurotoxicity in Neuro-Oncology Practice: Case Series

Immunotherapy with immune checkpoint inhibitors (ICIs) have been reported to induce de novo or exacerbate pre-existing Myasthenia Gravis (MG). We present a single center case series of patients who developed an immune-related myasthenia gravis (irMG) related with ICIs. We performed a retrospective chart review of the electronic medical records between 1 September 2017 and 2022. We report the clinical features, presentation forms, diagnostic workflows, general management and outcomes of six patients who received ICIs for different solid organ malignancies and developed an irMG frequently overlapping with immune-related myocarditis and/or myositis. The aim of the article is to describe the clinical features, treatment and outcomes of this challenging and potentially life-threating syndrome, comparing our data with those described in the literature. Differences between irMG and classic MG are highlighted.

Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block.

Immune-related cardiotoxicities are uncommon but potentially fatal. The study aims to evaluate the value of pacemakers and methylprednisolone pulse therapy (MPPT) to patients with immune-related myocarditis concomitant with complete heart block (CHB). We first reviewed medical records of three patients with immune-related myocarditis concomitant with CHB. For the pooled analysis, we searched related cases with immune-related myocarditis in the PubMed database and screened the patients. Clinical characteristics, management, and outcomes were summarized. Our three patients developed immune-related myocarditis concomitant with CHB about 2 weeks after receiving pembrolizumab, and were successfully treated with pacemaker implantation and high-dose steroids (two received MPPT). In the pooled analysis, 21 cases were eligible with an overall fatality rate of 52%. Patients with pacemakers had a fatality rate of 38%, significantly lower than patients without them (38% vs 100%; p = 0.035), particularly the MPPT subgroup (25% vs 100%; p = 0.019). All five patients without pacemakers expired. Among patients with pacemakers, MPPT patients tended to have an inferior rate compared with non-MPPT patients. Timely pacemaker implantation played a crucial role in improving the outcomes of patients with immune-related myocarditis concomitant with CHB. Patients receiving MPPT appeared to have a better prognosis. Additionally, multidisciplinary consultation should be recommended for better management.

Analysis of the efficacy and safety of immunotherapy in advanced thymoma patients.

Immunotherapy has exhibited efficacy in thymic carcinoma patients; however, there are insufficient data to confirm this efficacy in thymoma. The toxicity of immunotherapy also remains to be determined. The efficacy and safety of immunotherapy were analyzed in 11 thymoma patients who received PD-1 inhibitors according to a range of relevant indexes including the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and immunotherapy-related adverse events. The PFS and OS rates for all patients were 12.8 and 56.5 months, respectively. No difference in efficacy was detected between monotherapy and combination therapy (PFS: 12.8 vs 2.2 months, P = 0.787; OS: 73.8 vs 56.5 months, P = 0.367). The ORRs and DCRs for all patients were 27.3% and 90.9%, respectively. The incidence of adverse events was 45.5% among the 11 thymoma patients, including immune-related myocarditis (36.4%), immune-related liver damage (18.2%), and myasthenia gravis (18.2%). In the whole cohort of patients, the rate of adverse events of grade 3 or higher was 36.4%. The rates of adverse events of grade 3 or 4 in B3-type and non-B3-type thymoma patients were 0% and 62.5%, respectively. Immunotherapy elicited a response in thymoma patients; however, more attention should be paid to the immune-related adverse events.

Case Report: Treatment for steroid-refractory immune-related myocarditis with tofacitinib

IntroductionImmune therapy has ushered in a new era of tumor treatment, at the expense of immune-related adverse events, including rare but fatal adverse cardiovascular events, such as myocarditis. Steroids remain the cornerstone of therapy for immune-related myocarditis, with no clear consensus on additional immunosuppressive treatment for steroid-refractory cases yet.Case reportHere, we report a patient with stage IV nasopharyngeal carcinoma who developed immune-related myocarditis in the fourth course of therapy with immune checkpoint inhibitors. The patient presented with precordial discomfort with elevation of cardiac enzymes and interleukin-6, atypical electrocardiographic abnormalities, and reduced left ventricular ejection fraction. Coronary computed tomography angiography excluded the possibility of acute coronary syndrome. The therapy with tofacitinib targeting the Janus kinase-signal transducer and activator of transcription signal pathway was successfully conducted, since there was no significant improvement in troponin under high-dose steroid and intravenous immunoglobulin treatment. The patient recovered without major adverse cardiac events during hospitalization.DiscussionThe safety and efficacy of tofacitinib in a patient with steroid-refractory immune-related myocarditis were investigated, hoping to provide a basis for prospective therapeutic strategies. Tofacitinib led to remarkable remissions in primary autoimmune disease by blocking the inflammatory cascade, indicating its potential therapeutic use in immune-related adverse events.

Multi-organ Immune-Related Adverse Event Is a Risk Factor of Immune Checkpoint Inhibitor-Associated Myocarditis in Cancer Patients: A Multi-center Study.

Background and ObjectiveImmune checkpoint inhibitor (ICI)-associated myocarditis is a fatal immune-related adverse events (irAEs), which is prone to affecting multiple organ systems. Multi-organ irAEs have not been fully studied in ICI-associated myocarditis. Therefore, we aimed to explore the impact of multi-organ irAEs on ICI myocarditis in terms of clinical features, treatment, and prognosis.MethodsThis was a retrospective study. The clinical data of ICI myocarditis patients were collected from 6 hospitals in China. The risk factors and characteristics of pure myocarditis and multi-organ irAEs were analyzed. The overall survival (OS) after myocarditis was analyzed and univariate and multivariate regression analysis were performed.ResultsA total of 46 patients were analyzed in this study. Multi-organ irAEs were common (30/46, 65.2%) and prone to severe heart failure. The severe myocarditis was observed in 32 patients (69.6%). When myocarditis occurred, neutrophil to lymphocyte ratio, C-reactive protein, lactate dehydrogenase, interleukin (IL)-6, IL-10, creatine kinase, MB isoenzyme of creatine kinase, and brain natriuretic peptide increased from baseline, but absolute lymphocyte count decreased. Thymoma (B2/B3) was a risk factor for multi-organ irAEs. Heart failure and myocarditis were more severe in patients with multi-organ irAEs and require early corticosteroid therapy (<24 hours). Univariate analysis showed that age ≥ 60 years, myocarditis (grade 3-4), heart failure (grade 3-4), multi-organ irAEs, and severe myocarditis were associated with OS after myocarditis. After adjusting for other factors, heart failure (grade 3-4) was an independent risk factor for immune-related myocarditis (HR: 6.655, 95% CI: 1.539-28.770, p=0.011).ConclusionPatients with ICI-associated myocarditis had multi-organ irAEs with a high incidence of severe myocarditis, mortality, and poor prognosis. Thymoma was prone to those patients with multiple organs involvement. Patients could benefit from early corticosteroid intervention. Heart failure (grade 3-4) was an independent risk factor for OS after myocarditis.