Effectiveness and safety of second-line tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC) for whom first-line immuno-oncology (I-O) combination therapy was discontinued because of adverse events (AEs) remain to be determined.

Clinicopathological data were retrospectively collected from 34 institutions between August 2018 and January 2022 for 243 patients with mRCC who received second-line TKIs after first-line I-O combination therapy. Two patients who requested discontinuation of first-line I-O combination therapy were excluded. Oncological outcomes and safety were compared between patients who discontinued first-line I-O combination therapy because of progressive disease (Group PD) and AEs (Group AE). First- and second-line overall survival (OS) were defined as the time from the start of first- and second-line therapy to death, respectively. Propensity score matching was applied to adjust prognostic factors between the 2 groups.

There were 179 patients in Group PD and 62 patients in Group AE. Objective response rate and disease control rate were similar between the 2 groups. Progression-free survival (PFS), second-line OS, and first-line OS were significantly longer in Group AE than in Group PD (median 13.6 months vs. 8.5 months, P = 0.005; median not reached [NR] vs. 19.5 months, P = .005; median NR vs. 30.8 months, P = .012, respectively). After propensity score matching, PFS and second-line OS were still significantly longer and first-line OS tended to be longer in Group AE than in Group PD. There were no significant differences in the occurrence of AEs of any grade, including severe grades of 3 or greater, between the 2 groups.

Second-line TKIs are safe and at least as effective in patients with mRCC who discontinued first-line I-O combination therapy because of AEs as they are in patients who discontinued because of PD.

Immune evasion is a hallmark of cancer progression but the role of steroid hormones in this evasion has long been underrated. This oversight is particularly notable for glucocorticoids given that exogenous glucocorticoids remain a cornerstone therapy in various oncological treatment regimens, supportive care and treatment of immune-related adverse events caused by immune-checkpoint inhibitors. Cortisol, the main endogenous glucocorticoid in humans, is secreted by the adrenal cortex in response to stress. Additionally, cortisol and its inactive metabolite cortisone can be interconverted to further modulate tissue-dependent glucocorticoid action. In the past 5 years, intratumoural production of glucocorticoids, by both immune and tumour cells, has been shown to support tumour immune evasion. Here, we summarize current progress at the crossroads of endocrinology and immuno-oncology. We outline the known effects of steroid hormones on different immune cell types with a focus on glucocorticoids and androgens. We conclude with options for pharmaceutical intervention, including the engineering of cell-based therapies that resist the immunosuppressive action of steroid hormones. Overall, local steroid production and metabolism are emerging elements of tumour immune suppression that are potentially amenable to therapeutic intervention. Targeting steroid hormones to enhance anticancer therapies could increase their efficacy but will require expertise in endocrine care.

Immune checkpoint inhibitor (ICI)-related myocarditis has a low incidence but an extremely high mortality rate, and malignant arrhythmia caused by ICI therapy is even rarer. We report our experience of two patients with myocarditis with conduction system involvement after ICI therapy. Both patients developed myocarditis within a short period after the first ICI dose and they predominantly had conduction bundle involvement with minimal myocardial damage. One patient rapidly progressed from sinus rhythm to complete atrioventricular block, and the patient's symptoms improved only after pacemaker implantation. The other patient experienced paroxysmal ventricular tachycardia, which was controlled by synchronous corticosteroid therapy. Despite the strong immune side effects caused by ICIs, both patients achieved good clinical outcomes. We also conducted a literature search to explore the pathological mechanisms underpining immune-related myocarditis, as well as discussing the treatment strategies for immune-related myocarditis with conduction system involvement.

More promising, effective, and less-invasive biomarkers for PD(L)-1 targeted responses, immune-related adverse events (irAEs), and prognosis are being explored. We conducted a single-center retrospective study in pan-cancer patients with anti-PD(L)-1 monotherapy. Observational endpoints included treatment response, prognosis, and irAEs. Peripheral blood immunophenotypes were analyzed by Flow Cytometry. 104 patients were enrolled. Higher pretreatment percentages of CD3+CD4+ Th cells were associated with both responses (HR: 6.170, P = 0.034) and prognosis (HR: 1.930, P = 0.022). The higher baseline percentage of CD16+CD56+ NK cells was positively correlated with response (HR: 3.730, P = 0.050) and negatively related to irAEs (HR: 0.460, P = 0.012). Decreased pretreatment CD3+ T cell counts were related to more irAEs (HR: 0.970, P = 0.026), while the percentage of CD3+ T cells was negatively associated with prognosis (HR: 1.930, P = 0.022). The higher baseline cell counts of CD3+CD8+ CTL, CD19+ B, and the percentage of CD19+ B cells might be related to more irAEs (P < 0.05). Significant correlation between duration of treatment (DOT) and prognosis, irAE and outcome was also confirmed (P < 0.0001). Our findings confirmed multiple baseline circulating immunophenotype characteristics were related to PD(L)-1 targeted response, irAE onset, and prognosis.

Immune checkpoint inhibitors (ICIs) have improved the survival of patients with different solid tumors and even resulted in cure of metastatic disease. Since the introduction of ICIs, an increasing number of patients is admitted to the ICU for severe and potentially life-threatening immune related adverse events (irAEs). The outcome of patients who are admitted to the ICU because of severe irAEs is still unknown. The aim of this systematic review is to collect evidence on the outcomes of patients with solid tumors who are admitted to the ICU because of irAEs.

Medline, Embase, Cochrane central register of controlled trials and Google Scholar were searched systematically from 1975 to 24 September 2024. Articles were only included when describing patients with solid tumors who were admitted to the ICU because of irAEs after treatment with ICIs. Two independent reviewers extracted the data and assessed the risk of bias.

A total of 183 articles were included: two prospective ICU population-based studies, four retrospective ICU population-based studies, 25 retrospective studies describing irAEs with incidental ICU admissions, one review of case reports, and 153 articles with a total of 177 case reports. The six ICU population-based studies contained a total of 169 patients who were admitted to the ICU due to irAEs. In these six studies, the most frequently reported irAEs were pneumonitis and neurological irAEs. Of these 169 patients, 26% of the patients died on the ICU and an additional 8% of patients in the three to six months thereafter due to irAEs or disease progression. In all 183 included articles, various irAEs were described and the reported mortality rate varied from 0 to 53%.

The potential favorable outcomes of both the solid tumors and irAEs will probably result in more need for ICU admissions. Prospective clinical trials are needed to optimize the treatment strategy of severe irAEs at the ICU. Based on the favourable outcomes after life-threatening irAEs, ICU admission should definitely be considered for patients with solid tumors who have life-threatening irAEs.

Purpose: To evaluate frequency and distribution of immune-related adverse events detected by 18F-FDG PET/CT in patients with metastatic melanoma undergoing immunotherapy. Materials and Methods: Retrospective observational cohort study evaluating 147 patients with metastatic melanoma treated with immunotherapy and referred for therapy response assessment with 18F-FDG PET/CT at our institution from January 2010 to August 2022. In total, 201 PET/CT scans performed at various time points were analyzed. IRAEs detected on PET/CT were compared against clinical reference standards, including physical examinations, laboratory tests, and biopsies. Diagnostic performance metrics (sensitivity, specificity, positive predictive value, negative predictive value), and diagnostic yields were calculated. Results: There were 36/147 patients (24.5%) with IRAEs recorded according to standard of reference, with 39 IRAEs in the entire cohort. At time point level, PET/CT identified 36/36 (100%) patients with IRAEs confirmed by the reference standard, while clinical suspicion identified 26/36 (72%) cases. At IRAE level, PET/CT identified 36/39 (92%) of IRAEs confirmed by the reference standard. Thirteen out of 39 (33.3%) cases identified on PET/CT were not suspected clinically but confirmed by the reference standard. The most frequent IRAEs, both suspected clinically and on PET/CT, corresponded to thyroiditis and colitis. Among the PET/CT positive cases, the majority corresponded to grade 2 severity. Conclusion: 18F-FDG PET/CT is highly effective in detecting IRAEs in patients with metastatic melanoma on immunotherapy, uncovering clinically unsuspected events in up to 33% of cases. These results highlight its important role in early detection, guiding timely interventions, and improving overall outcomes of immunotherapy-related toxicities.

This review discusses reprogramming the breast tumor immune microenvironment from an immunosuppressive cold state to an immunologically active hot state. A complex interplay is revealed, in which the accumulation of metabolic byproducts-such as lactate, reactive oxygen species (ROS), and ammonia-is shown to impair T-cell function and promote tumor immune escape. It is demonstrated that the tumor microenvironment (TME) is dominated by immunosuppressive cytokines, including interleukin-10 (IL-10), transforming growth factorβ (TGFβ), and IL-35. Notably, IL-35 is produced by regulatory T cells and breast cancer cells. The conversion of conventional T cells into IL-35-producing induced regulatory T cells, along with the inhibition of pro-inflammatory cytokine secretion, contributes to the suppression of anti-tumor immunity. It is further demonstrated that key immune checkpoint molecules-such as PD-1, PDL1, CTLA-4, TIM-3, LAG-3, and TIGIT-are upregulated within the TME, leading to Tcell exhaustion and diminished immune responses. The blockade of these checkpoints is shown to restore T-cell functionality and is proposed as a strategy to convert cold tumors into hot ones with robust effector cell infiltration. The therapeutic potential of chimeric antigen receptor (CAR)T cell therapy is also explored, and targeting specific tumor-associated antigens, such as glycoproteins and receptor tyrosine kinases, is highlighted. It is suggested that CART cell efficacy can be enhanced by combining these cells with immune checkpoint inhibitors and other immunomodulatory agents, thereby overcoming the barriers imposed by the immunosuppressive TME. Moreover, the role of the microbiome in regulating estrogen metabolism and systemic inflammation is reviewed. Alterations in the gut microbiota are shown to affect the TME, and microbiome-based interventions are proposed as an additional means to facilitate the cold-to-hot transition. It is concluded that by targeting the metabolic and immunological pathways that underpin immune suppression-through combination strategies involving checkpoint blockade, CART cell therapies, and microbiome modulation-the conversion of the breast TME from cold to hot can be achieved. This reprogramming is anticipated to enhance immune cell infiltration and function, thereby improving the overall efficacy of immunotherapies and leading to better clinical outcomes for breast cancer patients.

Associations between immune-related adverse events from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity and survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally funded basket trial (NCT02834013) for patients with rare cancers (n = 684) to evaluate associations between immune-related adverse events and overall survival and progression-free survival (PFS).

Patients were treated with nivolumab and ipilimumab; the trial was opened at more than 1000 sites. Landmark Cox regression models were used to assess first cycle immune-related adverse event associations with PFS and overall survival.

We found that grade 1-2 treatment-related immune-related adverse events in the first cycle of therapy were associated with longer overall survival (multivariable hazard ratio [HR] = 0.61, 95% confidence interval [CI] = 0.49 to 0.75; P < .001) compared with no treatment-related immune-related adverse event, while grade 3-4 immune-related adverse events were associated with shorter overall survival (HR = 1.41, 95% CI = 1.04 to 1.90; P = .025). Similar but weaker associations were observed with PFS and grade 1-2 treatment-related immune-related adverse events (HR = 0.83, 95% CI = 0.67 to 1.01; P = .067) and grade 3-4 (HR = 1.35, 95% CI = 1.02 to 1.78; P = .037) compared with no treatment-related immune-related adverse events. Grade 1-2 dermatologic toxicity was associated with improved overall survival compared with other grade 1-2 toxicities (HR = 0.67, 95% CI = 0.52 to 0.85; P = .002). There was no statistically significant overall survival difference between patients with grade 1-2 fatigue, gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities vs other grade 1-2 toxicities.

In this large cohort of patients with rare tumors receiving checkpoint inhibitor therapy, grade of immune-related adverse event in the first cycle was predictive for survival.

Immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced malignancy but can induce immune-related adverse events (irAE). The mechanisms behind these sporadic and sometimes life-threatening irAEs remain largely unexplored. Here, we present a case report and in-depth molecular analysis of an erythema nodosum (EN) like irAE occurring in a melanoma patient with isolated brain metastasis, aiming to explore the potential mechanism of this irAE.

We performed RNA and T cell receptor (TCR) sequencing on the patient's resected brain metastasis and biopsy of EN-like irAE. Single cell RNA/TCR sequencing was conducted on the patient's peripheral blood mononuclear cells (PBMC) at baseline, 3 weeks after ipilimumab and nivolumab combination therapy, during EN toxicity and after resolution.

The site of EN-like irAE showed a distinct accumulation of pro-inflammatory immune cells, accompanied by the upregulation of inflammatory and interferon response signatures. In addition, clonal expansion and activation of irAE-associated CD8 T cells and upregulation of monocyte-specific interferon signatures occurred concurrently with irAE onset.

The unique immune landscape at the EN-like irAE could indicate that this irAE is distinct from anti-tumor immune and analogous non-ICI autoimmune milieus. Our data also suggests that systemic immune activation induced by ICI treatment, as reflected in PBMC, may help monitor the patient's treatment response and access irAE risk.

We describe two patients who experienced serious multiple immune-related adverse events (irAEs), treatment interruption, and steroid administration. Despite these challenges, they achieved a remarkable antitumor effect beyond the expected. Various carcinomas demonstrated a possible correlation between the antitumor effect of immune checkpoint inhibitors and the intensity of irAEs, but few studies report on malignant pleural mesothelioma (MPM). Our two cases exhibited much stronger irAEs than usual. These two cases still demonstrated a complete response (CR) or near CR partial response, indicating a correlation between irAEs and the antitumor effect in MPM.

Survival outcomes of patients with metastatic urothelial carcinoma (mUC) are still suboptimal and strategies to enhance response to immune-oncology (IO) compounds are under scrutiny. In preclinical studies, it has been demonstrated that antihistamines may reverse macrophage immunosuppression, reactivate T cell cytotoxicity, and enhance the immunotherapy response. We aimed to evaluate the role of concomitant antihistamines administration on oncological outcomes among patients with mUC.

We relied on individual patient data from IMvigor210 (phase II single-arm trial on second line atezolizumab for mUC) and IMvigor211 trials (phase III randomized trial on second line atezolizumab vs chemotherapy for mUC). Among individuals treated with IO we identified patients who did and did not receive antihistamines. Multivariable Cox or competing-risks regression models were used to predict progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS). The impact of antihistamines on the outcomes was assessed after adjusting for potential confounders.

Among 896 patients with locally advanced or metastatic urothelial cancer who had progressed after first-line chemotherapy, 155 (17 %) received antihistamines during the delivery of IO. Patients receiving antihistamines had longer OS (Hazard Ratio [HR]:0.59; 95 % Confidence interval [CI]: 0.47-0.74; P < 0.001), PFS (HR:0.70; 95 %CI: 0.57-0.87; P = 0.001) and CSS [sHR:0.58; 95 %CI:0.45-0.75; P < 0.001)] relative to those who had not used antihistamine drugs. A sensitivity analysis, after the exclusion of patients who experienced adverse events and received antihistamines, yielded similar findings of prolonged CSS (sHR 0.78; 95 %CI: 0.59-0.98, P = 0.031) and OS (HR 0.71; 95 %CI: 0.52-0.94, P = 0.021).

Concomitant antihistamines administration was associated with improved OS, CSS, and PFS in patients receiving atezolizumab as second line treatment for mUC. Further mechanistic and clinical investigation is warranted to elucidate the role of antihistamines in IO.

Introduction Pembrolizumab, an immune checkpoint inhibitor targeting programmed death-1 (PD-1)/PD-1 ligand (PD-L1), has demonstrated antitumor effects but can cause immune-related adverse events (irAEs) such as hypothyroidism. The neutrophil-to-lymphocyte ratio (NLR) may be linked to pembrolizumab efficacy and irAE risk. This study investigated the relationship between NLR trends and hypothyroidism onset, assessing its predictive potential. Methods This retrospective study analyzed 136 patients with advanced or recurrent cancer treated with pembrolizumab at The Jikei University Hospital, Tokyo, Japan, from February 2017 to September 2023. Patients were categorized based on hypothyroidism development, and their baseline NLR and time to treatment failure (TTF) were compared. NLR trends before hypothyroidism onset were also evaluated. Patients were further stratified based on onset timing (<90 days vs. ≥90 days), and NLR parameters prior to onset were also compared. Results Hypothyroidism occurred in 33 of 136 patients (24%). The hypothyroidism group had a significantly lower baseline NLR (P = 0.006) and longer TTF (P = 0.006). No significant NLR changes were observed before hypothyroidism onset (P = 0.626). However, the maximum NLR until onset was significantly lower in patients with early-onset hypothyroidism (<90 days) (P = 0.016). In contrast, no significant differences were observed in the mean and minimum NLR. A receiver-operating characteristic (ROC) analysis identified a maximum NLR cutoff of 4.3 for predicting early-onset hypothyroidism (P = 0.002, area under the curve (AUC) = 0.770). Conclusions A low baseline NLR was associated with hypothyroidism onset, and a persistently low NLR may contribute to early onset. These findings suggest that continuous NLR monitoring during pembrolizumab treatment may aid in predicting the risk of hypothyroidism and facilitate its appropriate management.

Corticosteroid is effective in alleviating immune-related adverse events (irAEs) of immune checkpoint blockade (ICB). However, prophylactic use of corticosteroid to prevent irAEs is not recommended due to a looming concern that it may attenuate anti-tumor effect of ICB. This study aims to investigate whether corticosteroid premedication may compromise anti-tumor efficacy of dual ICB, a regimen that may cause significant irAEs.

Orthotopic BNL 1MEA.7R.1 and subcutaneous Hepa1-6 syngeneic hepatocellular carcinoma (HCC) models were used. Low-dose (LD; 10 µg) or high-dose (HD; 200 µg) dexamethasone (Dexa) was intraperitoneally administered before each dose of anti-CTLA-4 and anti-PD-1. Tumor shrinkage, T cell priming, cytokine quantitation, as well as cytotoxicity and single-cell RNA-sequencing (scRNA-seq) of tumor-infiltrating T cells were assessed.

In the orthotopic model, dual immune checkpoint blockade (dICB) plus phosphate buffered saline (PBS) significantly reduced the mean tumor weight (adjusted for SE) (0.73±0.18 g vs 2.45±0.54 g; p=0.03), while neither LD nor HD Dexa premedication affected dICB-induced tumor shrinkage. In the subcutaneous model, dICB plus PBS or LD Dexa yielded a complete tumor response (CR) rate of 100%, while dICB plus HD Dexa yielded a CR rate of 85.7% (p>0.05, comparing to dICB plus PBS). ScRNA-seq analysis demonstrates that Dexa did not affect dICB-induced reduction of major clusters of exhausted CD4+ and CD8+ T cells but halved dICB-induced expansion of effector memory CD8+ T cells. Nevertheless, Dexa premedication, regardless of dosage, did not diminish dICB-induced T cell priming, cytokine production, or cytotoxicity of tumor-infiltrating CD8+ T cells.

Corticosteroid premedication does not significantly compromise anti-tumor efficacy of dICB treatment in murine HCC models. These results suggest that clinical investigations of prophylactic corticosteroids to alleviate severe irAEs may be feasible.

Autoimmune neurology is a rapidly expanding field driven by the discovery of neuroglial autoantibodies and encompassing a myriad of conditions affecting every level of the nervous system. Traditionally, autoantibodies targeting intracellular antigens are considered markers of T cell-mediated cytotoxicity, while those targeting extracellular antigens are viewed as pathogenic drivers of disease. However, recent advances highlight complex interactions between these immune mechanisms, suggesting a continuum of immunopathogenesis. The breakdown of immune tolerance, central to these conditions, is affected by modifiable and non-modifiable risk factors such as genetic predisposition, infections, and malignancy. While significant therapeutic advancements have revolutionized treatment of certain diseases, such as neuromyelitis optica, our understanding of many others, particularly T cell-mediated conditions, remains limited, with fewer treatment options available. Future research should focus on improving effector function modeling and deepening our understanding of the factors influencing immune tolerance, with the goal of providing novel treatment options and improving patient care.

Immune checkpoint inhibitors (ICI) have improved the therapeutic arsenal in outpatient oncology care; however, data on necessity of hospitalizations associated with immune-related adverse events (irAEs) are scarce. Here, we characterized hospitalizations of patients undergoing ICI, from the prospective cohort study of the immune cooperative oncology group (ICOG) Hannover.

Between 12/2019 and 06/2022, 237 patients were included. Clinical data and characteristics of ICI were collected during a 6-month observation period after the initiation of therapy. Descriptive statistics and Kaplan-Meier statistics were administered.

During the observation period, 30/237 patients were hospitalized (HA(+)). Most common underlying tumor entities were malignant melanoma (59.5%), renal cell carcinoma (13.1%), and nonsmall-cell lung carcinoma (12.7%). HA(+) patients exhibited an increased rate of pulmonary and cerebral metastases. We observed a significantly higher hospitalization rate during dual ICI with Nivolumab and Ipilimumab (p = 0.001). The predominant irAEs for hospitalization were colitis (26.7%), followed by hypophysitis (13.3%), leading to a median hospitalization of 7 (1-34) days. Interdisciplinary consultations were frequent, especially to gastroenterology (46.7%) and neurology (26.7%). Although a trend toward a prolonged overall survival in the HA(+) subgroup was identified, no statistically significant differences were found.

The hospitalization rate of 12.6% is comparable to rates reported in previous studies. There was a disproportionate admission of patients with immune-related colitis and hypophysitis compared to the prevalence described under ICI. We observed a high need for interdisciplinary consultations in line with the heterogeneity of immune-mediated side effects. Compared to non-hospitalized patients, there was no survival disadvantage in the HA(+) cohort.

With a relatively low hospitalization rate, short length of stay, and good clinical outcome, our data support the outpatient nature of ICI. The findings underscore the importance of interdisciplinary collaboration and vigilant monitoring of irAEs to ensure timely recognition and management.

Currently, the use of immune checkpoint inhibitors (ICIs) has shown notable clinical efficacy in treating various malignant tumors, significantly improving patient prognosis. However, while ICIs enhance the body's anti-tumor effects, they can also trigger immune-related adverse events (irAEs), with ICI-associated colitis being one of the more prevalent forms. This condition can disrupt treatment, necessitate drug discontinuation, and adversely affect therapeutic outcomes. In severe cases, irAEs may even become life-threatening. A recent case report by Hong et al highlights the importance of vigilance for ICI-associated colitis in patients experiencing symptoms such as diarrhea and abdominal pain, which can arise both during and even after completion of ICI treatment. Early identification, multidisciplinary management, and continuous monitoring of patients are essential steps to further improve outcomes.

[Figure: see text].

Tertiary lymphoid structures (TLS) are accumulations of lymphoid cells that arise in ectopic sites through the process of lymphoid neogenesis in chronic inflammation in autoimmunity, microbial infections, organ rejection, aging, and cancer. Their cellular composition and function and regulation via members of the lymphotoxin (LT)/tumor necrosis factor (TNF) family resemble that of secondary lymphoid organs (SLOs). Tumor-associated (TA)-TLS can be associated with favorable clinical outcomes. Immunotherapy in the form of immune checkpoint inhibitors (ICI) has contributed to tremendous advances in cancer therapy. However, ICI are effective in only some tumors, can give rise to resistance, and can precipitate immune-related adverse events (irAEs), many of which appear to have hallmarks of autoimmunity and can resemble TLS. TA-TLS correlate with a positive response to immunotherapy, but they can also be associated with susceptibility to irAEs, suggesting that TA-TLS in combination with ICI could lead to uncontrolled autoimmunity. The tumor environment can be manipulated to ensure that, not only the number of TLS, but also their cellular composition and appropriate function allow for judicious combinations of TLS and immunotherapy that can synergize and contribute to better outcomes with a minimum of destructive irAEs. Strategies include directed delivery of lymphoneogenic cytokines and chemokines or vascular growth factors directly, via transgenes or via adenovirus vectors.

Treating non-small-cell lung cancer (NSCLC) has gained increased importance in recent years due to the high mortality rate and dismal five-year survival rate. Immune checkpoint inhibitors (ICI) are a promising approach with exceptional outcomes in NSCLC thanks to the antigenic nature of cells. Conversely, immune system over-stimulation with ICI is a double-edged sword that can lead to various negative effects ranging from mild to life-threatening. This review explores current breakthroughs in nanoparticle-based ICI and their limitations. The PubMed, Scopus and Web of Science were examined for relevant publications. Thirty-eight trials (N = 16,781) were included in the analyses. The mixed effects analyses on quantifying the treatment effect contributed significantly to the subgroups within studies for ICI treatment effect. Models confirmed ICI's higher impact on treatment effectivity and the decrease in respondents' mortality compared to conventional treatment regiments. ICI might be used as first-line therapy due to their proven effectiveness and safety profile.

As the understanding of immune-related mechanisms in the development and progression of cancer advances, immunotherapies, notably Immune Checkpoint Inhibitors (ICIs), have become integral in comprehensive cancer treatment strategies. ICIs reactivate T-cell cytotoxicity against tumors by blocking immune suppressive signals on T cells, such as Programmed Death-1 (PD-1) and Cytotoxic T-lymphocyte Antigen-4 (CTLA-4). Despite their beneficial effects, ICIs are associated with immune-related adverse events (irAEs), manifesting as autoimmune side effects across various organ systems. A particularly alarming irAE is life-threatening myocarditis. This rare but severe side effect of ICIs leads to significant long-term cardiac complications, including arrhythmias and heart failure, and has been observed to have a mortality rate of up to 50% in affected patients. This greatly limits the clinical application of ICI-based immunotherapy. In this review, we provide a comprehensive summary of the current knowledge regarding the diagnosis and management of ICI-related myocarditis. We also discuss the utility of preclinical mouse models in understanding and addressing this critical challenge.

Immune checkpoint inhibitors (ICIs) are an important therapeutic pillar in metastatic urothelial carcinoma (mUC). The occurrence of immune-related adverse events (irAEs) appears to be associated with improved outcomes in observational studies. However, these associations are likely affected by immortal time bias and do not represent causal effects. The aim of this study was to assess the effect of irAEs on outcomes while correcting for immortal time bias, using target trial emulation (TTE).

TTE was contrasted to adjusted naïve and time-updated Cox models. We performed a multi-institutional retrospective study involving mUC patients under ICI. The primary objective was to assess the impact of irAEs on progression-free survival (PFS) and overall survival (OS). Secondary endpoints included the influence of irAEs on objective response rates (ORRs) to ICI and the influence of systemic corticosteroids on outcomes.

Among 335 patients (median age: 69 yrs), 69.6% received ICI in the second line or further lines. During a median follow-up of 21.1 months, 122 (36.4%) patients developed irAEs of any grade (grade ≥ 3: 14.9%). Hazard ratios (HRs) for PFS ranged from 0.37 for naïve adjusted Cox model to 0.88 (95% confidence interval (CI), 0.59-1.30) with time-updated covariates, and from 0.41 to 1.10 (95% CI, 0.69-1.75) for OS. TTE accounting for immortal time bias yielded a HR of 1.02 (95% CI, 0.72-1.44) for PFS, and 0.90 (95% CI, 0.62-1.30) for OS. In contrast to the naïve Cox model (HR = 2.26, 95% CI 1.26-4.05), the presence of irAEs was no longer a predictive factor for improved ORR in time-updated Cox models (HR = 1.27, 95% CI 0.68-2.36) and TTE (HR = 1.43, 95% CI 0.89-2.29). In patients with irAEs, systemic corticosteroids did not negatively impact survival.

Using TTE, we were able to show that the occurrence of irAEs is no longer associated with better survival or improved response rates to ICI in mUC patients, in contrast to the naïve analysis. These findings demonstrate that TTE is a suitable formal framework to avoid immortal time bias in studies with time-dependent non-interventional exposures.

Immune checkpoint inhibitors (ICIs) have advanced the treatment of metastatic melanoma by blocking immune system down-regulators enhancing T-cell-mediated anti-tumor responses. However, many ICIs induce immune-related adverse effects (irAEs) that can impact many organ systems.

Strategies used to manage irAEs include corticosteroids, anti-tumor necrosis factor alpha (TNF-α) agents, other biological therapies, fecal microbiota transplantation (FMT), and emerging regimens. In this review, we describe current evidence for the efficacy of ICIs, acute and chronic immune toxicities, and strategies to manage toxicities for patients treated with ICIs.

IrAE management will likely evolve by developing more tailored approaches to prevent toxicities, improving non-steroidal management strategies and tailoring the dose of steroids, and identifying biomarkers of severe toxicities.

Pembrolizumab combined with neoadjuvant chemotherapy (NAC) is the current standard of care in early stage triple-negative breast cancer (TNBC) based on higher event-free survival and pathological complete response (pCR) in Keynote-522 (KN-522) clinical trial. However, this aggressive five-drug regimen is associated with increased risks for immune-related adverse events (irAEs). We investigated real-world clinical outcomes and toxicity of this regimen as well as factors predictive of pCR and irAEs.

We identified and abstracted data from 153 early-stage TNBC patients treated with the KN-522 regimen between July 1, 2021, and December 31, 2023, at 4 academic institutions in the U.S. Descriptive analysis was conducted, univariate and multivariate analyses were performed to identify factors associated with pCR and irAEs.

The median age was 52 years (interquartile range, 42-60years), with 66% White and 24% Black patients with stage I/II (67%), node-negative disease (58%), grade 3 (86%) tumors, and ≥1 comorbidities (68%). Approximately 21% discontinued pembrolizumab, because of toxicity; ∼50% received a lower relative dose intensity (RDI) of chemotherapy (dose reduction or discontinuation). Of the 153 patients, 99 (64.7%) achieved pCR and 83 (54%) experienced an irAE, with 18 (12%) having ≥ grade 3 irAE. The majority (90%) of the irAEs were observed during neoadjuvant phase. Stage I/II versus stage III disease (OR 1.55, CI 1.04-2.33, P = .03), age (OR 0.96, CI 0.93-0.99, P = .01) and full versus reduced RDI of NAC (OR 1.53, CI 1.04-2.26, P = .03) were associated with higher pCR rates on multivariate analyses. Fewer cycles of pembrolizumab were associated with a higher likelihood of irAEs (OR 1.52, CI 1.07-2.16, P = .02), likely explained by the early discontinuation and receipt of less than 8 cycles of pembrolizumab in patients who experienced irAEs.

Our study validates the clinical efficacy of KN-522 regimen; however, we observed a higher incidence of irAEs (54%) in this real-world population. Lower stage and younger age were associated with higher likelihood of achieving pCR. Toxicity-related chemotherapy dose reduction or discontinuation was observed to adversely impact the likelihood of achieving pCR.

Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with a poor prognosis. Therapeutic options for patients with advanced ACC who have failed standard treatments are limited. Single-agent immunotherapy as a second-line treatment has shown unsatisfactory clinical outcomes. This phase II trial (NCT04318730) evaluated the efficacy and safety of the PD-1 inhibitor camrelizumab combined with the VEGFR inhibitor apatinib in previously treated advanced ACC. The primary endpoint was objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. A total of 21 patients with advanced ACC received at least one dose of camrelizumab and apatinib. The ORR was 52% (95% CI, 30-74%), meeting the primary endpoint, and the disease control rate (DCR) was 95% (95% CI, 76-100%). The median PFS was 13.3 months (95% CI, 8.4-NE), and the median OS was 20.9 months (95% CI, 11.0-NE). The most common grade 3-4 treatment-related adverse events were alanine aminotransferase elevation, aspartate aminotransferase elevation, and lymphopenia. Predefined exploratory analyses indicated that patients with higher peripheral blood CXCR3 + CD8 + T cell abundance, lower immunosuppressive CD4 + T cell abundance, and higher overlap of clonotypes between tumor-infiltrating T cells and circulating T cells, were more likely to respond favorably to the combined therapy.

Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II-III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8+ T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8+ T cells, follicular helper T cells and shorter distances between tumor and CD8+ T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon's two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890 .

Real-world, large-scale studies on the association between immune-related adverse events (irAE) and immune checkpoint inhibitor therapy effectiveness are limited. We evaluated overall survival (OS) and progression-free survival based on the occurrence and grade of irAEs.

We used data from Japanese patients with unresectable advanced or recurrent non-small cell lung cancer (NSCLC) who received atezolizumab and were enrolled in J-TAIL, a multicenter, prospective, single-arm observational study.

Among the 1,002 patients, 190 (19.0%) developed irAEs. The most common irAEs were skin disorders (3.8%) of any grade and interstitial lung disease (1.5%) of grade ≥3. Patients who developed irAEs within 4 or 6 weeks of treatment initiation had higher baseline C-reactive protein levels than those without irAEs. OS was longer in patients with irAEs [HR, 0.66; 95% confidence interval (CI), 0.54-0.82], particularly in those with low-grade irAEs (HR, 0.45; 95% CI, 0.33-0.62), than in patients without irAEs. The HR (95% CI) for OS in patients with low-grade and high-grade skin or endocrine disorder-related irAEs was 0.42 (0.28-0.64) and 0.37 (0.15-0.88), respectively. The HR (95% CI) for OS in patients with low-grade and high-grade irAEs other than skin or endocrine disorders was 0.44 (0.30-0.65) and 1.27 (0.96-1.69), respectively.

In patients with unresectable advanced or recurrent NSCLC treated with atezolizumab in real-world settings, irAEs are associated with a clinical benefit except in those with high-grade irAEs other than skin and endocrine disorders.

Immune checkpoint inhibitors are useful for treating NSCLC but can cause life-threatening irAEs. This study had a large sample size and stratified the analysis by irAE type and grade. The results suggest that improved management of irAEs may improve the therapeutic effect of atezolizumab.

The addition of pembrolizumab to chemotherapy in high-risk early triple-negative breast cancer (TNBC) improves cancer outcomes. However, pembrolizumab induces varied immune-related adverse events (irAEs) where some can be severe or lifelong. This retrospective study describes real-world patterns of irAEs in patients with TNBC who received pembrolizumab.

We evaluated irAEs in patients with TNBC from a comprehensive cancer center and a community hospital who received pembrolizumab with chemotherapy between 2021 and 2023, excluding those enrolled in clinical trials. We used national guidelines to grade toxicities. Logistic regression assessed the effect of clinicopathologic variables on irAEs adjusting for covariates.

We identified 233 patients with a median age of 51 years, 62% had stage II TNBC, 35% had stage III TNBC, 25% were Hispanic, 21% were Black, and 42% were White. Eighty patients (34%) developed 100 separate irAEs. The most common irAEs were endocrinopathies (52%) and GI (23%); there were 26 grade ≥3 irAEs, which all resulted in hospitalization, the most common being GI (13 instances); 45 required systemic steroids, 16 required additional immunosuppressive therapy, and 32 patients discontinued pembrolizumab because of irAEs. Two patients who developed colitis eventually died due to complications. Most (67 instances) irAEs were unresolved at the time of last follow-up, but 55% (37/67) had improved to grade 1. No clinicopathologic factors were associated with the development or severity of irAEs.

In this real-world diverse population, we observed rates of irAEs comparable with KEYNOTE-522, where endocrinopathies were the most prevalent, but GI irAEs were also prevalent and severe. This emphasizes a critical issue as pembrolizumab is increasingly being used in early TNBC and could have long-term survivorship implications.

Immune-related pneumonitis (irP) is one of the most important immune-related adverse events caused by immune checkpoint inhibitors (ICIs). After corticosteroid therapy irP frequently relapses, which can interfere with cancer therapy. However, risk factors for irP relapse are unknown.

This study was a follow-up analysis of a phase II study that evaluated 56 patients with grade ≥ 2 irP treated with oral prednisolone, 1 mg/kg/day, tapered over 6 weeks. Clinical factors including patient characteristics, blood test findings, and response to prednisolone therapy were assessed to identify risk factors for irP relapse using the Fine-Gray test.

Among 56 patients with irP, 22 (39.3%) experienced irP relapse after 6 weeks of prednisolone therapy during the follow-up observation period. Radiographic organising pneumonia (OP) pattern and duration to irP onset ≥ 100 days from ICI initiation were determined to be significant risk factors for irP relapse in a multivariate Fine-Gray test (hazard ratio [HR] = 3.17, 95% CI 1.37-7.32, p = 0.007, and HR = 2.61, 95% CI 1.01-6.74, p = 0.048, respectively). Other patient characteristics, blood test findings, irP severity, and response to prednisolone therapy were not associated with irP relapse.

In irP patients treated with 6-week prednisolone tapering therapy, OP pattern and duration to irP onset ≥ 100 days were associated with relapse risk. Assessment of the risk factors for irP relapse will be helpful for irP management.

Describe the demographic data and clinical phenotype of cranial palsy induced by immune checkpoint inhibitors (CNP-ICI).

A systematic literature review of the literature was performed in Pubmed, Web of Science, and Embase, including 68 articles and 136 patients (PROSPERO no. CRD42024517262).

Out of the 1205 articles screened, 68 articles were included after fulfilling the inclusion criteria, for a total of 136 patients. All articles were case reports and case series. In the cohort studied, 52% of patients were treated with anti PD-1/PDL-1 therapies, 14% with anti CTLA-4 therapies, and 34% with a combination of anti CTLA-4 and anti PD-1/PDL-1 therapies. The facial nerve was the most affected cranial nerve, involved in 38% of cases, followed by the optic nerve (35%), the cochleovestibular nerve (12%), and the abducens nerve (10%). The median time from the initial immune checkpoint inhibitor (ICI) injection to the onset CNP-ICI was 10 weeks (IQR 4-20). Magnetic resonance imaging demonstrated contrast enhancement or abnormal signal of the affected nerve in 43% of cases. Cerebrospinal fluid analysis indicated lymphocytic pleocytosis in 59% of cases. At the onset of immune-related adverse events, 89% of patients discontinued immunotherapy, and 92% received treatment for CNP-ICI. Treatment regimens included corticosteroids in 86% of cases, intravenous immunoglobulin in 21%, and plasma exchange in 5.1%. Among the whole population, 33% achieved recovery, 52% showed clinical improvement, 16% remained stable, and 3% experienced worsening of their condition. Rechallenge with immunotherapy was significantly associated with the emergence of new immune-related Adverse Events (irAEs).

ICI therapy may lead to cranial nerve involvement, particularly affecting the facial nerve, typically presenting around 10 weeks after treatment initiation. While corticosteroid therapy often resulted in patient improvement, rechallenging with ICIs were associated with new irAEs.

Immune-mediated sinusitis is poorly described and may easily go undiagnosed. We conducted a retrospective, multicenter, national study focusing on symptomatic immune-mediated sinusitis in patients receiving immune checkpoint inhibitors (ICIs) for melanoma treatment. Twelve patients were included (50% women, median age 58 years). Overall, the paraclinical assessment, the inefficacy of antibiotic/antihistaminic treatment, the improvement of symptoms on immunosuppressants and/or after ICI discontinuation, and the presence of multiple concomitant immune-related adverse-events, suggested a noninfectious etiology. Recognizing this toxicity is imperative for limitation of diagnostic wandering and appropriate treatment. However, additional epidemiological studies are needed to assess its prevalence as a potential immune-related adverse-event, and its prognostic value in patients treated with ICIs.

Immune checkpoint inhibitors have revolutionized cancer treatment by targeting the cytotoxic T lymphocyte antigen-4 and programmed death-1/ligand-1. Although immune checkpoint inhibitors show promising therapeutic efficacy, they often cause immune-related adverse events. Immune-related adverse events differ from the side effects of conventional chemotherapy and require vigilant monitoring. These events predominantly affect organs, such as the colon, liver, lungs, pituitary gland, thyroid and skin, with rare cases affecting the heart, nervous system and other tissues. As immune-related adverse events result from immune activation, indicating the reinvigoration of exhausted immune cells that attack both tumors and normal tissues, it is theoretically possible that immune-related adverse events may signal a better response to immune checkpoint inhibitor therapy. Recent retrospective studies have explored the link between immune-related adverse event development and clinical efficacy; however, the predictive value of immune-related adverse events in the immune checkpoint inhibitor response remains unclear. Additionally, studies have focused on immune-related adverse events, timing of onset and immunosuppressive treatments. This review focuses on pivotal studies of the association between immune-related adverse events and outcomes in patients treated with immune checkpoint inhibitors.