Immune-related Adverse Events Research Articles

Immune-related adverse events in metastatic/recurrent cervical and vulvar cancer associated with a significant survival advantage

Immune-related adverse events in metastatic/recurrent cervical and vulvar cancer associated with a significant survival advantage

Chronic immune-related adverse events following immunotherapy administration in a gynecologic cancer patient population

Chronic immune-related adverse events following immunotherapy administration in a gynecologic cancer patient population

Perioperative sintilimab and neoadjuvant anlotinib plus chemotherapy for resectable non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 2 trial (TD-NeoFOUR trial)

This open-label, single-arm, phase 2 trial evaluated the efficacy and safety of neoadjuvant sintilimab combined with anlotinib and chemotherapy, followed by adjuvant sintilimab, for resectable NSCLC. Forty-five patients received anlotinib (10 mg, QD, PO, days 1–14), sintilimab (200 mg, day 1), and platinum-based chemotherapy of each three-week cycle for 3 cycles, followed by surgery within 4–6 weeks. Adjuvant sintilimab (200 mg) was administered every 3 weeks. The primary endpoint was achieving a pathological complete response (pCR). From June 10, 2021 through October 10, 2023, 45 patients were enrolled and composed the intention-to-treat population. Twenty-six patients (57.8%) achieved pCR, and 30 (66.7%) achieved major pathological response (MPR). Forty-one patients underwent surgery. In the per-protocol set (PP set), 63.4% (26/41) achieved pCR, and 73.2% achieved MPR. The median event-free survival was not attained (95% CI, 25.1-NE). During the neoadjuvant treatment phase, grade 3 or 4 treatment-related adverse events were observed in 25 patients (55.6%), while immune-related adverse events were reported in 7 patients (15.6%). We assessed vascular normalization and infiltration of immune-related cells by detecting the expression of relevant cell markers in NSCLC tissues with mIHC. Significant tumor microenvironment changes were observed in pCR patients, including reduced VEGF+ cells and CD4+Foxp3+ Treg cells, and increased perivascular CD4+ T cells, CD39+CD8+ T cells, and M1 macrophages. In conclusion, perioperative sintilimab and neoadjuvant anlotinib plus chemotherapy achieved pCR in a notable proportion of patients with resectable NSCLC and were associated with profound changes in the tumour microenvironment (ClinicalTrials.gov NCT05400070).

Prospective screening and proposed treatment algorithm for immune checkpoint inhibitor induced myositis in neoadjuvant-treated rectal cancer patients: data from the phase II CHINOREC trial

Abstract Background Myositis is an infrequent (<1%) but potentially life-threatening (case fatality rate 40-50%) immune-related adverse event (irAEs) of immune checkpoint inhibitors (ICI), such as ipilimumab (IPI) and nivolumab (NIVO). The true incidence is likely to be underestimated and may not be representative for curative neoadjuvant treatment approaches in gastrointestinal (GI) cancers, especially in combination with chemoradiotherapy (CRT). Currently, the summary of product characteristics (SmPC) does not suggest any pre-emptive screening or surveillance. Methods The CHINOREC study is an ongoing prospective, randomized, open-label, multicenter, phase II investigator-initiated trial (IIT). Patients with intermediate to locally advanced rectal cancer (LARC) receive either neoadjuvant CRT alone or in combination with a single dose of IPI and 3 cycles of NIVO, following surgical resection. Patients are monitored at baseline and throughout the whole study period for myotoxicity biomarkers, including cardiac troponin T (cTnT) and cardiac troponin I (cTnI). Findings From 06/2020 to 11/2023, 80 patients have been enrolled of whom 50 patients were randomized to the CRT+IPI/NIVO arm. Six patients (12%) developed biopsy-verified myositis. Myositis treatment was promptly implemented using a pragmatic step-up approach. Patients received glucocorticoids (GC) with concomitant intravenous immunoglobulin (IVIG). If myotoxicity biomarkers did not improve, patients received infliximab (INFLIXI) and/or plasma exchange (PLEX). Although all patients had strikingly elevated cTnT (median peak 284 ng/L, 95% CI 39-3097), cTnI levels remained largely normal, correlating with a negative cardiac magnetic resonance (CMR). All patients underwent successful tumor surgery without any major surgical complication. As of today, all patients' creatine kinase (CK) and myoglobin (MB) levels have normalized and they are tumor free without any major sequela. Interpretation Longitudinal biomarker screening (cTnT/cTnI) for ICI-induced myotoxicities is pivotal in curative neoadjuvant-treated cancer patients to initiate an early counter treatment in a holistic step-up approach, without compromising oncological principles.

Cardiotoxicity in cancer immunotherapy: challenges in diagnosing and managing ICI-associated myocarditis

Immunotherapy has revolutionized cancer treatment, particularly through immune checkpoint inhibitors (ICIs), which enhance the body's immune response against tumors. However, these therapies can also trigger immune-related adverse events (irAEs), with myocarditis being one of the most severe but rare complications. This article reviews the pathophysiology, clinical manifestations, and current management strategies for ICI-induced myocarditis. While significant advancements have been made, the early diagnosis of this condition remains a challenge due to nonspecific symptoms. Current treatment relies heavily on the discontinuation of ICIs and the use of corticosteroids, but there is an urgent need for standardized diagnostic criteria and optimized therapeutic protocols. This review highlights the gaps in existing knowledge and emphasizes the importance of further research to improve patient outcomes. Understanding these complexities is crucial for ensuring that the benefits of immunotherapy outweigh the risks, ultimately improving the safety and efficacy of cancer treatments, as these treatments are essential for sustaining individual life.

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

Immune-checkpoint myocarditis phenotype when using systematic troponin surveillance in cancer patients.

Abstract Background ICI myocarditis, often described as potentially fulminant in registries from specialized centers, lacks sufficient data on its subclinical forms. ESC 2022 guidelines advocate systematic troponin measurements for early detection, resulting in numerous suspected cases of ICI myocarditis. Additionally, many patients receive other potentially cardiotoxic cancer drugs (e.g.,anthracyclines), adding complexity to the management. Purpose To identify factors associated with ICI-myocarditis diagnosis in a single-center unselected cohort referred for suspicion of CV immune-related adverse events(irAEs). Patients underwent standardized evaluation, including serum testing, ECG, echocardiogram, cardiac MRI(CMRi) and multidisciplinary team assessment including cardiology and internal medicine specialists. Coronary imaging and myocardial biopsy (EMB) were performed as needed. ICI-myocarditis diagnosis was adjudicated by expert panel (FC, MM, SH) based on Dallas, ESC, and IC-OS criteria. Results We enrolled 175 consecutive patients from March 2022 to October 2023; 40 (22.89%) were male, with a median age of 61 (IQR 48.0-72.0) years. 92(52.57%) were referred for lone asymptomatic troponin raise, 101 (57.7%) had breast cancer; 142 (81.11%) received other cardiotoxic drugs. We identified 95 (61.71%) patients with CV irAEs at referral (8 had >=2 CV irAEs) with a total of 108 CV irAEs after follow up, including 72 (41.14%) with ICI-myocarditis at referall. No CV deaths occurred within 30 days from referall. Characteristics and univariate analysis are depicted in the Table1. Reasons for referral in the ICI-myocarditis population are depicted in the Figure1. On multivariate regression analysis, prior CV disease history (OR 6.232 [CI 1.204-32.260], p=0.029), EMB (OR 24.969 [5.139-121.32], p=<.0001), IC-OS criteria fulfilled (OR 43.108 [9.222-201.510], p=<.0001), and positive Lake Louise criteria on CMRi (OR 6.583[1.416-30.610], p=0.0163) were associated with myocarditis. In a sub-analysis group of breast cancer patients (largely receiving anthracyclines), ICI-myocarditis was associated on multivariate regression with abnormal ECG (OR 14.227 [CI 1.632-124.040], p=< 0.0163) and EMB (OR 8.508 [CI 2.718-26.638], p=0.0002). The same characteristics were significantly associated with other CV irAEs in the group of breast cancer patients. In the group of patients with cancers other than breast, factors significantly associated with ICI myocarditis diagnosis were: EMB (OR 70.656 [CI 5.970-836.161], 0.0007), and no arterial hypertension (OR 9.554 [CI 1.792-50.940], p= 0.0082). Conclusions The FAST TRACK study highlights the high proportion of patients fulfilling ICI-myocarditis criteria despite no or mild symptoms, mainly referred for troponin elevation. However, subclinical ICI-myocarditis appears to bear good prognosis. Endomyocardial biopsy is key to increase the diagnosis rate of ICI-myocarditis across different cancer populations when mildly symptomatic.Table 1Figure 1

The predictive value of coronary artery calcium deposit for cardiovascular events in patients treated with immune checkpoint inhibitor therapy

Abstract Background Immune checkpoint inhibitors (ICIs) are now a standard of care for the treatment of wide variety of cancers, due to their dramatically improved patient's outcomes. Nevertheless, their use may lead to significant cardiovascular immune-related adverse events (CV irAEs). Objectives We aimed to assess whether pre-treatment coronary artery calcium (CAC) deposit may play as a risk factor for CV irAEs development in patients treated with ICIs therapy. Methods A retrospective single center cohort of patients treated with ICIs therapy, who performed pre-treatment chest computed tomography. Visual CAC assessment was performed, categorized to positive or negative calcium deposit in the coronary arteries. Patients with pre-existing ischemic heart disease were excluded. The primary endpoint was to evaluate the association between positive CAC deposit and the composite CV irAEs, including myocarditis, acute coronary syndrome, heart failure, and arrhythmias. The secondary endpoint was to evaluate its association to all-cause mortality. Results The cohort included 238 patients, with mean age 65±13 years and 53% male representative. The most prevalent type of cancer was lung (36%) and the prominent ICIs regimen was pembrolizumab (54%). High incidence of cardiac risk factors was observed, including hypertension (39%), hyperlipidemia (35%) and diabetes (23%). Overall, 145 (61%) patients were included in the positive CAC deposit group. No significant differences were observed between the positive and negative groups regarding cancer type, ICIs therapy and baseline cardiac risk factors or medical therapy. Over a 12-months follow-up period, positive CAC deposit was not associated with the development of CV irAEs (p=0.139), or increased all-cause mortality (p=0.884). Conclusion The presence of pre-treatment positive CAC deposit did not demonstrate a predictive role in assessing the risk of CV irAEs or all-cause mortality in patients treated with ICIs.

Prognostic value of neutrophil-to-lymphocyte ratio and cardiac troponin I in patients with immune checkpoint inhibitors-related myocarditis

Abstract Background Over the past decade, immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment. However, ICIs inevitably may cause a spectrum of immune-related adverse events, among which cardiovascular toxicity, particularly myocarditis, while infrequent, has garnered increasing attention due to its high fatality rate. Purpose We executed a multicenter study aimed at characterizing ICI-related myocarditis and risk factors influencing its prognosis. Methods The study included patients with ICIs-associated myocarditis at four medical centers in China from January 28, 2019 to June 15, 2023. Logistic regression was performed to explore the risk factors for the development of severe myocarditis. Receiver operating characteristic curves were conducted to assess the diagnostic abilities of biomarkers to distinguish severe myocarditis, and the performance and calibration were evaluated using Hosmer-Lemeshow test. Cox regression analysis was employed to investigate the influential risk factors affecting the prognosis of ICI-related myocarditis. Kaplan-Meier survival curve analyses were conducted to assess the differences in survival times among different myocarditis groups. Results 35 ICIs-associated myocarditis patients were identified. 21 patients (60%) were classified as severe myocarditis, and they presented higher cardiac troponin I (cTnI) levels (P=0.013), higher N-terminal pro-B-type natriuretic peptide levels (P=0.031), higher creatine kinase (CK) levels (P=0.018), higher CK-MB levels (P=0.026), and higher neutrophil to lymphocyte ratio (NLR) levels (P=0.016) compared to non-severe myocarditis patients. Multivariate logistic regression showed that cTnI (adjusted odds ratio: 1.021, 95% confidence interval (CI): 1.002-1.039, P=0.03) and NLR (adjusted odds ratio: 1.890, 95% CI: 1.026-3.483, P=0.041) were the independent risk factors of ICI-associated severe myocarditis. The receiver operating characteristic curve showed an area under curve of 0.765 (95% CI: 0.601 to 0.929, P=0.013) for cTnI, and 0.773 for NLR (95% CI: 0.597 to 0.948, P=0.016). Multivariate COX regression showed that NLR (adjusted hazard ratio: 1.189, 95% CI: 1.028-1.376, P=0.020) and pneumonitis (adjusted hazard ratio: 8.142, 95% CI: 1.191-55.651, P=0.032) were the independent prognostic risk factor associated ICI- related myocarditis. Further Kaplan-Meier survival curve analysis showed that the survival rate among patients without pneumonitis and with low level of NLR significantly outstripped that of patients with pneumonitis (P=0.015) and high level of NLR (P=0.024). Conclusions As independent risk factors for the development of ICI-associated severe myocarditis, cTnI and NLR demonstrated a promising predictive utility for the identification of ICI-associated severe myocarditis. NLR and the presence of pneumonitis were identified as independent risk factors that significantly impacted the prognosis of ICI-related myocarditis.

Immune checkpoint inhibitor-associated bullous pemphigoid: Aretrospective and real-world study based on the United States Food and Drug Administration adverse event reporting system.

This study aimed to describe bullous pemphigoid (BP) associated with immune checkpoint inhibitors (ICIs) reported in the United States Food and Drug Administration adverse event reporting system (FAERS). We obtained reports of ICI-associated BP from the first quarter of 2011 to the first quarter of 2024 in the FAERS database. The reporting odds ratio (ROR) method of the disproportionality analysis was performed to assess the potential risk for ICI-associated BP. We also described the clinical characteristics of ICI-associated BP and evaluated the time to onset (TTO) of BP developed after treatment with ICIs. Eight hundred and six cases of ICI-associated BP were gathered, in which 56.58% of the patients were aged 65 years or older. The majority of patients were male, accounting for 68.49% of all cases. The prevalent potential cancer type was skin cancer (31.64%). The results of the disproportionality analysis showed that males (ROR = 2.10 [1.78-2.49]), patients aged 65 or older (ROR = 2.13 [1.79-2.55]), and patients with skin cancer (ROR = 2.08 [1.80-2.43]) were more likely to develop ICI-associated BP. In comparison to cytotoxic T-lymphocyte-associated antigen 4 inhibitor and programmed cell death ligand 1 inhibitor, programmed cell death 1 inhibitor-associated BP has a higher risk of development (ROR = 24.45 [22.52-26.56]). ICI-associated BP had a median TTO of 204 days (interquartile range 57-426 days). ICI-associated BP is a rare but important immune-related adverse event. Our study provided helpful information to help medical professionals further understand ICI-associated BP.

Therapeutic advances in hepatocellular carcinoma: an update from the 2024 ASCO annual meeting

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide. Recent advances in immunotherapies, targeted therapies, and combination treatments have significantly improved outcomes for many patients with HCC. This review summarizes key findings from the 2024 ASCO Annual Meeting, focusing on emerging therapies, including immune checkpoint inhibitors (ICIs), CAR-T cell therapies, oncolytic viruses, and locoregional treatments like transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC). ICIs, particularly when combined with other agents, have shown promising efficacy, though challenges such as immune-related adverse events and resistance mechanisms remain. CAR-T cell therapies and oncolytic viruses offer novel therapeutic avenues for advanced HCC, but their long-term efficacy in solid tumors is still under investigation. Locoregional therapies, especially in combination with systemic treatments, continue to play a critical role in managing unresectable HCC and improving conversion rates to surgical resection. Additionally, the potential of biomarkers, such as hypoxia scores and CTNNB1 mutations, is being explored to better personalize treatment and predict patient responses. These biomarkers could pave the way for more targeted and effective therapeutic strategies. Overall, the recent studies presented at the ASCO meeting highlight progress in HCC treatment, underscoring the importance of continued innovation. Future research should focus on overcoming resistance mechanisms, optimizing combination therapies, and integrating biomarker-driven approaches to improve patient outcomes and enhance personalized treatment strategies.

Efficacy, Safety, and Influence on Tumor Microenvironment of Neoadjuvant Pembrolizumab plus Ramucirumab for PD-L1 Positive NSCLC: A Phase 2 Trial (EAST ENERGY).

Angiogenesis inhibitors are known to modify tumor immunity. Combination of angiogenesis inhibitors with immune checkpoint inhibitors (ICIs) has shown efficacy against many types of cancers, including non-small cell lung cancer (NSCLC). We investigated the feasibility of neoadjuvant therapy with pembrolizumab and ramucirumab, a vascular endothelial growth factor (VEGF) receptor-2 antagonist for patients with PD-L1-positive NSCLC and its influence on the tumor microenvironment (TME). Patients with pathologically proven NSCLC with PD-L1-positive, clinical stage IB-IIIA were eligible. Patients received two cycles of pembrolizumab (200 mg/body) and ramucirumab (10 mg/kg) every three weeks. Surgery was scheduled 4 to 8 weeks after the last dose. The primary endpoint was the major pathologic response (MPR) rate by a blinded independent pathology review. The sample size was 24 patients. Exploratory endpoints were evaluated to elucidate the effects of neoadjuvant therapy on TME. The 24 eligible patients were enrolled between July 2019 and April 2022. The MPR rate was 50.0% (90% confidence interval, 31.9-68.1%). Six patients showed pathological complete response. Grade 3 adverse events (AEs) occurred in 9 patients (37.5%), including 3 immune-related AEs (acute tubulointerstitial nephritis in 2 cases and polymyalgia rheumatica in one). There were no grade 4 or 5 AEs. The transcriptome and multiplexed immunohistochemistry results suggested that tumors with greater CD8+ T-cell infiltration and higher expression of effector molecules at the baseline could show better sensitivity to treatment. This new neoadjuvant combination of pembrolizumab plus ramucirumab was feasible and anti-VEGF agents may enhance the effects of ICIs.

Immunohistochemical Expression of Immune Regulatory Proteins in Interface Dermatoses.

Cutaneous immune-related adverse events (irAEs) of immunotherapies, such as anti-programmed cell death protein-1 (PD-1), suggest that immune checkpoint factors may contribute to the pathobiology of lichenoid interface dermatitis in immunotherapy-naïve patients. Our study aimed to describe innate and adaptive immune markers via immunohistochemical (IHC) staining of lichenoid interface dermatoses. We studied the staining patterns of PD-L1, STING, IL-36 gamma, CD8, PD-1, and LAG-3 in five interface dermatoses: oral lichen planus (LP) (n = 10), cutaneous LP (n = 10), chronic cutaneous lupus erythematosus (CLE) (n = 11), erythema multiforme (EM) (n = 11), and toxic epidermal necrolysis (TEN) (n = 13), by immunohistochemistry (IHC) analysis. Expression was evaluated semi-quantitively according to the percentage of keratinocytes and dermal lymphocytes stained compared to keratinocytes and resident pericapillary lymphocytes in normal human skin. All interface dermatoses evaluated showed increased expression of PD-L1 on keratinocytes and LAG-3 in lymphocytes. STING was increased on the keratinocytes of most specimens. Expression of IL-36 gamma, in basal layer keratinocytes was more extensive in oral LP and cutaneous LP and varied in CLE, EM, and TEN. Lymphocytic infiltration expressing PD-1 was elevated in oral LP, cutaneous LP, and CLE. Current thinking is that interface dermatitis is the result of a cell-mediated immune reaction involving cytotoxic CD8+ T-cell-mediated apoptosis of keratinocytes. The findings of this study suggest that in addition to cell-mediated immunity, innate immune factors may contribute to pathobiology.

Development of an Educational Website for Patients With Cancer and Preexisting Autoimmune Diseases Considering Immune Checkpoint Blockers: Usability and Acceptability Study.

Patients with cancer and an underlying autoimmune disease who are considering immune checkpoint blockers (ICBs) need to know about the benefits and risks of severe immune-related adverse events and flares of the autoimmune condition. This study aims to develop and alpha test an educational website for patients with cancer. Learning topics, images, and website architecture (including flow and requirements) were developed and iteratively reviewed by members of a community scientist program, a patient advisory group, and content experts. Alpha testing was performed, measuring the site's usability using the Suitability Assessment of Materials and its acceptability using the Ottawa Acceptability Measure. The website included a home page; general information about ICBs; comprehensive modules on the benefits and risks of ICBs for patients with cancer and preexisting autoimmune diseases; general wellness information; and features such as a quiz, additional resources, and a glossary. For the alpha testing, 9 users assessed the newly developed website. Patient reviewers (n=5) had rheumatoid arthritis, Crohn disease, Sjogren syndrome, or vasculitis. Health care provider reviewers (n=4) were medical oncologists or rheumatologists. The median Suitability Assessment of Materials rating was 75 (IQR 70-79; range 0-100) for patients versus 66 (IQR 57-72; range 0-100) for providers (scores ≥70 indicate no substantial changes needed). Recommendations for improvement, mostly involving navigation and accessibility, were addressed. All participants expressed that the website was acceptable and balanced in terms of discussion of benefits and harms. Because half (2/4, 50%) of the providers suggested we increase the amount of information, we extended the content on the impact of having an autoimmune disease when considering ICB treatment, the probability of flares, and the management of flares in this context. The feedback led to minor revisions to enhance readability, navigation, and accessibility, ensuring the website's suitability as a decision-making aid. The newly developed website could become a supporting tool to facilitate patient-physician discussion regarding ICBs.

Cancer Therapy-Induced Encephalitis

Encephalitis associated with cancer therapies is a rare but serious complication that can significantly impact patients’ quality of life and it requires prompt identification and management. Over the past two decades, immunotherapy—particularly immune checkpoint inhibitors—has become a cornerstone of cancer treatment, with up to half of metastatic cancer patients in economically developed countries now receiving these therapies. The widespread adoption of immunotherapy has led to improved survival rates and long-term remissions, even in patients with advanced metastatic disease. However, as immune modulators, these therapies can trigger a range of immune-related adverse events, including a variety of novel neurological toxicities. Among these, encephalitis is of particular concern due to its potential severity, which can compromise treatment outcomes. This review aims to provide a comprehensive overview of the literature on this condition, highlighting optimal diagnostic strategies and management approaches to mitigate the risk of significant morbidity, while also comparing encephalitis induced by immunotherapy with that caused by traditional chemotherapies and targeted oncologic treatments.

PD-1 immunology in the kidneys: a growing relationship

In recent years, knowledge regarding immune regulation has expanded rapidly, and major advancements have been made in immunotherapy for immune-associated disorders, particularly cancer. The programmed cell death 1 (PD-1) pathway is a cornerstone in immune regulation. It comprises PD-1 and its ligands mediating immune tolerance mechanisms and immune homeostasis. Accumulating evidence demonstrates that the PD-1 axis has a crucial immunosuppressive role in the tumor microenvironment and autoimmune diseases. PD-1 receptors and ligands on immune cells and renal parenchymal cells aid in maintaining immunological homeostasis in the kidneys. Here, we present a comprehensive review of PD-1 immunology in various kidney disorders, including renal cell carcinoma, glomerulonephritis, kidney transplantation, renal aging, and renal immune-related adverse events secondary to PD-1 immunotherapy.

Prognostic Factors for Patients with Small-Cell Lung Cancer Treated with Chemoimmunotherapy: A Retrospective Multicenter Study

Background: This study aimed to investigate prognostic factors for predicting the survival of patients with extensive-disease-stage small-cell lung cancer treated with chemoimmunotherapy. Methods: Patients were classified according to overall survival (OS): favorable corresponded to an OS ≥ 24 months, moderate corresponded to an OS of 6–24 months, and poor corresponded to an OS < 6 months. Multivariate Cox regression analyses were used to evaluate prognostic factors. Results: Of 130 patients, the proportions of performance status decline and liver metastasis were significantly higher in the poor-prognosis group. With regard to the laboratory findings, neutrophil/lymphocyte ratios and albumin levels differed significantly among the groups. Multivariate analysis showed that the independent prognostic factors for OS were liver metastasis and decreased albumin levels (<3.5 mg/dL). After classifying the patients into three groups according to the quantities of these prognostic factors, the OS differed significantly among the groups (18.3 vs. 13.5 vs. 3.8 months; p < 0.001). The incidence of immune-related adverse events (irAEs) was higher in patients without these prognostic factors than in those with both (36% vs. 5%; p = 0.01). Conclusion: Liver metastasis and decreased albumin levels are independent unfavorable prognostic factors. Patients with both prognostic factors showed unfavorable OS; however, patients without these factors may have a favorable prognosis but be at greater risk of irAEs.

The Good (Tumor Killing) and the Bad (Cardiovascular Complications) of Immunologic Checkpoint Inhibitors.

This review details the significant advancement in knowledge of Immune-checkpoint inhibitor (ICI) and its potential deleterious cardiac immune-related adverse effects (irAE). We explore their mechanisms on the cardiac tissue, providing guidance on risk factors, clinical presentations, diagnostic strategies along with treatment. Recent findings have provided insights of cardiac irAEs that exist beyond the previously well-known ICI-induced myocarditis. We have a better understanding of the wide variety of cardiac irAEs pathologies both early and late onset. Moreover, there is more data on mechanisms of cardiotoxicity and patient and therapy-related risk factors, supporting closer routine cardiac monitoring with biomarkers and imaging for prevention and early detection. Diagnosing cardiac irAEs is a challenge given its broad clinical presentation. A high-level of suspicion in addition to early work-up is crucial to prevent serious cardiac events. A multi-disciplinary team including Cardiologists and Oncologists is essential for closely monitor patients' cardiac status on ICI therapy. There is a need of updated guidelines to establish clear recommendations in patients on ICIs.

Efficacy and safety of dual blockade of HER2 and PD-1 in patients with HER2-positive gastric cancer: a retrospective, multicentre study

Human epidermal growth factor receptor 2 (HER2) expression is one of the most important pathological characteristics of gastric cancer. The positive rate of HER2 expression in patients with gastric cancer is approximately 20%. The phase III Keynote-811 study revealed that anti-HER2 and anti-PD-1 therapy combined with chemotherapy could significantly improve the objective response rate as first-line treatment in patients with HER2-positive advanced gastric cancer. In the present study, we aimed to evaluate the efficacy of combination therapy with trastuzumab and PD-1 inhibitors in patients with advanced HER2-positive gastric cancer in a real-world setting. Seventy-two HER2-positive gastric cancer patients from three hospitals in China were retrospectively reviewed. These patients were treated with trastuzumab plus one anti-PD-1 agent with or without chemotherapy. The overall response rate, progression-free survival and overall survival were assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). From January 2018 to October 2021, 72 patients with HER2-positive gastric cancer received trastuzumab and a PD-1 inhibitor with or without chemotherapy as neoadjuvant chemotherapy, first-line therapy, second-line therapy or salvage therapy. The ORR was 54.2% for all patients and 79.4% for previously untreated patients. The median PFS and median OS were 10 months (95% CI: 8–13 months) and 26.1 months (95% CI: 18.5-NA months), respectively, for all patients. Grade 3 adverse effects occurred in approximately 25% of patients. Immune-related adverse effects occurred in approximately 12.5% of patients. Trastuzumab and PD-1 inhibitor combination therapy with or without chemotherapy achieved satisfactory survival outcomes in patients with HER2-positive gastric cancer with acceptable safety.

Emerging Strategies for Local Delivery of Immune Checkpoint Inhibitors to Potentiate Cancer Immunotherapy: Current Status and Future Prospects.

Cancer constitutes a significant threat to patients' lives worldwide. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) that boost antitumor immunity by targeting immune checkpoint components, has emerged as a promising strategy for its treatment in recent years. However, the objective response rates of the ICIs are unsatisfactory. As the primary route, systemic administration of ICIs is often accompanied by immune-related adverse events. Local delivery of ICIs serves as a potential therapeutic strategy that can improve the efficacy while simultaneously reducing side effects through precise drug release at the tumor site. Initial validation of direct local application of ICIs for tumors in clinical trials has indicated reduced side effects and improved efficacy, while low bioavailability remains a challenge. Furthermore, research on various carriers, including nanoparticles, microneedles, hydrogels, combined platforms, and implantable devices for local release of ICIs has exhibited applying potential in treating murine tumors, among which combined platforms such as combined hydrogel system hold the highest promise due to their encompassment of the advantages of multiple carriers. These carriers, by incorporating ICIs and other therapeutics, could manage cancers more potently, which needs to be confirmed in clinical trials after the refinement of their biocompatibility. This review summarizes the latest research advancements regarding local administration of ICIs, with a particular focus on the carriers for local delivery as well as the combination therapies, thus providing novel insights and research guidance for scholars to enhance the efficacy of locally delivered ICIs on managing multiple cancers in the future.