Effects Of Immune Checkpoint Inhibitors Research Articles

The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype, promoting a favorable response to anti-PD-1 therapy via NLRP3 activation

The main challenges in the use of immune checkpoint inhibitors (ICIs) are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+ T cells. Transforming the tumor microenvironment (TME) from “cold” to “hot” and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment. We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+ mouse models. Using single-cell RNA sequencing, we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion, restoring T-cell function and promoting a favorable immunotherapy response. Mechanistically, we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling, thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production. As a result, APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment, thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity. Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86, p-NF-κB p65 and NLRP3 levels, accompanied by lower CD206 expression on macrophages. Collectively, these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.

Impact of antihistamine use on the survival outcomes of immune checkpoint inhibitors in advanced cancer patients.

Histamine and H1 receptors play a crucial role in the tumor microenvironment. Preclinical data showed that concomitant use of antihistamines and immune checkpoint inhibitors (ICIs) might increase the effect of ICIs. This study aimed to evaluate the impact of antihistamines on the oncological outcomes of ICIs. This retrospective study was conducted in a tertiary cancer center. Advanced cancer patients treated with ICIs were included in this study. A total of 133 patients receiving ICIs in the metastatic setting were included. Melanoma (33.1%) was the most common tumor type. The most common ICI was nivolumab (63.2%). Fifty-five (38.4%) patients received antihistamines concomitantly with ICIs. The most common antihistamine was pheniramine (85.5%). The median progression-free survival (PFS) (8.2 vs. 5.1 months, P = 0.016) and overall survival (OS) (16.2 vs. 7.7 months, P = 0.002) were longer in patients receiving antihistamines concomitantly with ICIs. In multivariate analysis, PFS [hazard ratio (HR) = 0.63, 95% CI: 0.40-0.98, P = 0.042] and OS (HR = 0.49, 95% CI: 0.29-0.81, P = 0.006) were also better in those patients after adjusting for confounding factors, such as performance status, bone or liver metastasis, and concurrent chemotherapy. This study suggested that antihistamines may enhance the efficacy of ICIs in patients with advanced cancer. If validated in prospective trials, antihistamines and ICIs combinations might be new options to improve oncological outcomes.

Emerging Role of Circular RNAs in Hepatocellular Carcinoma Immunotherapy.

Hepatocellular carcinoma (HCC) is a highly fatal malignancy with limited therapeutic options and high recurrence rates. Recently, immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) have emerged as a new paradigm shift in oncology. ICIs, such as programmed cell death protein 1 (PD-1) inhibitors, have provided a new source of hope for patients with advanced HCC. Yet, the eligibility criteria of HCC patients for ICIs are still a missing piece in the puzzle. Circular RNAs (circRNAs) have recently emerged as a new class of non-coding RNAs that play a fundamental role in cancer pathogenesis. Structurally, circRNAs are resistant to exonucleolytic degradation and have a longer half-life than their linear counterparts. Functionally, circRNAs possess the capability to influence various facets of the tumor microenvironment, especially at the HCC tumor-immune synapse. Notably, circRNAs have been observed to control the expression of immune checkpoint molecules within tumor cells, potentially impeding the therapeutic effectiveness of ICIs. Therefore, this renders them potential cancer-immune biomarkers for diagnosis, prognosis, and therapeutic regimen determinants. In this review, the authors shed light on the structure and functional roles of circRNAs and, most importantly, highlight the promising roles of circRNAs in HCC immunomodulation and their potential as promising biomarkers and immunotherapeutic regimen determinants.

Gut microbial structural variation associates with immune checkpoint inhibitor response

The gut microbiota may have an effect on the therapeutic resistance and toxicity of immune checkpoint inhibitors (ICIs). However, the associations between the highly variable genomes of gut bacteria and the effectiveness of ICIs remain unclear, despite the fact that merely a few gene mutations between similar bacterial strains may cause significant phenotypic variations. Here, using datasets from the gut microbiome of 996 patients from seven clinical trials, we systematically identify microbial genomic structural variants (SVs) using SGV-Finder. The associations between SVs and response, progression-free survival, overall survival, and immune-related adverse events are systematically explored by metagenome-wide association analysis and replicated in different cohorts. Associated SVs are located in multiple species, including Akkermansia muciniphila, Dorea formicigenerans, and Bacteroides caccae. We find genes that encode enzymes that participate in glucose metabolism be harbored in these associated regions. This work uncovers a nascent layer of gut microbiome heterogeneity that is correlated with hosts’ prognosis following ICI treatment and represents an advance in our knowledge of the intricate relationships between microbiota and tumor immunotherapy.

Sarcopenia affects the clinical efficacy of immune checkpoint inhibitors in patients with gastrointestinal cancers

The impact of sarcopenia on the efficacy of immune checkpoint inhibitors (ICI) in gastrointestinal cancer (GIC) patients remains uncertain in clinical practice. Hence, this study aims to investigate the potential correlation between sarcopenia and the clinical outcomes of GIC patients treated with ICIs. To gather pertinent studies, a systematic literature search was implemented across multiple databases, including PubMed, Embase, the Cochrane Library, and Google Scholar. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS), measured with the hazard ratio (HR). And the secondary outcomes, including disease control rate (DCR), overall response rate (ORR), and adverse events (AE), were evaluated with the odd ratio (OR). A total of 13 articles involving 1294 patients were collected for this analysis. The pooled results revealed that GIC patients with sarcopenia had significantly poorer OS (HR=1.697, 95% CI=1.367-2.106, p<0.001) and PFS (HR: 1.551, 95% CI: 1.312-1.833, p<0.001), and lower ORR (OR=0.594, 95% CI=0.388-0.909, p=0.016) and DCR (OR: 0.553, 95% CI: 0.360-0.850, p=0.007) compared to those without sarcopenia. However, sarcopenia did not increase the incidence of treatment-related adverse events compared with non-sarcopenia (OR=1.377, 95% CI=0.693-2.737, p=0.361). According to subgroup analysis, the association between sarcopenia and the therapeutic effect of ICI on patients with primary liver cancer or gastric cancer was consistent with the above findings. Sarcopenia is significantly correlated with poorer treatment response and worse long-term efficacy in GIC patients treated with ICIs. Moreover, sarcopenia does not increase the incidence of adverse events.

MODL-06. THE GUT MICROBIOTA OF BRAIN TUMOR PATIENTS CAN IMPACT IMMUNOTHERAPY EFFICACY IN A PRECLINICAL MODEL OF GLIOMA

Abstract Combination immune checkpoint inhibitors (ICI) can affect durable response in melanoma brain metastases (MBM) but have largely been ineffective for the treatment of glioblastoma (GBM), a primary brain tumor. Recent studies in animal models and humans have suggested that the microbe composition of the gut can influence the effectiveness of ICI in melanoma and other cancers. Our central hypothesis is that the gut microbiome can influence immunotherapy responsiveness for GBM patients. We obtained microbiome (stool) samples from GBM and MBM patients prior to beginning any treatment or surgical interventions. We then transplanted these microbiome samples into gnotobiotic mice to create humanized microbiome mice. We transplanted two GBM patients and two MBM patients microbiome samples to create 4 unique patient-derived humanized microbiome mouse lines (GBM1, GBM2, MBM1, and MBM2). Using 16s ribosomal RNA microbiome sequencing, we found that each patient-derived microbiome mouse line had a unique microbiome composition as measured by relative abundance and diversity of species. Mice from each line were then intracranially injected with GL261 murine glioma cells and treated with the ICI anti-PD-1 or isotype control. We found that MBM1 and GBM2 mice were resistant to anti-PD-1 and did not display prolonged survival with anti-PD-1 treatment. However, GBM1 and MBM2 mice were positive responders to anti-PD-1 and displayed significantly prolonged survival compared to isotype control. Additional microbiome sequencing analyses are ongoing that will reveal positive microbiome profiles among these patient-derived lines, and additional GBM and MBM patient-derived microbiome lines are being created and tested for immunotherapy efficacy. Ultimately, understanding how certain microbial communities can enhance the effectiveness of immunotherapy may lead to the development of new approaches that include modification or transplantation of microbe communities in GBM patients for increased therapeutic impact.

Abstract 18700: Immune Checkpoint Inhibitor-Related Myocarditis and Overlapping Syndromes

Background: Immune checkpoint inhibitor (ICI)-related myocarditis is a rare adverse effect of ICI's. When accompanied by overlapping myasthenia gravis, prognosis is worsened. While established guidelines aid in the treatment of ICI-associated adverse events, management of overlapping syndromes is complex and challenging. Case description: A 66-year-old man with metastatic renal cell carcinoma recently started on ipilimumab and nivolumab presented with dizziness and diplopia. He had high-grade atrioventricular (AV) block with junctional escape. He had elevated troponin, transaminases, and creatinine kinase. Coronary angiogram showed no evidence of obstructive coronary artery disease. A permanent pacemaker was placed. Cardiac MRI showed no specific features of myocarditis, though quality was limited by pacemaker artifact; left ventricular ejection fraction was 29%. MRI of the orbits showed no signs of extraocular myositis. Acetylcholine receptor (AChR) antibody and muscle-specific kinase (MuSK) antibody was negative. Given ongoing suspicion for ICI-associated adverse events, the patient underwent endomyocardial biopsy. This revealed lymphocytic myocarditis, confirming the diagnosis of ICI-related myocarditis. Despite improvement of troponin, transminases, and creatinine kinase, he developed progressive weakness, dysphagia, and respiratory failure, and died one month after initial presentation. Discussion: We highlight a case of ICI-related myocarditis presenting as high-grade AV block with concurrent hepatitis, myositis, and probable serologic-negative myasthenia gravis (MG). Overlapping syndromes are common in patients with exposure to ICI's, and are associated with significantly higher mortality. Although steroids are first-line for treating ICI-associated adverse events including myocarditis, they can initially lead to acute worsening of MG symptoms. While our patient had laboratory and biomarker improvement of his myocarditis, hepatitis, and myositis, he developed progressive weakness and respiratory failure. Our case highlights the complexity and challenges of managing ICI-related myocarditis and overlapping syndromes, including MG, and its poor prognosis despite prompt treatment.

Effect of immunotherapy on health-related quality of life outcomes in patients with advanced gastro-esophageal cancers: A meta-analysis.

245 Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care, with increasing data demonstrating improved survival outcomes using ICIs among patients with advanced gastroesophageal cancer (aGEC). ICIs are also associated with a lower incidence of grade ≥3 adverse effects (AEs) compared to chemotherapy (CT), suggesting that ICIs may have favorable effects on health-related quality of life (HRQoL). This meta-analysis sought to evaluate the effects of ICIs on the HRQoL of patients with aGEC. Methods: An online bibliographic search was conducted on Medline via PubMed using MeSH-based terms to retrieve randomized controlled trials (RCTs) that evaluated the effects of ICIs on HRQoL in patients with aGEC. We included RCTs that incorporated ICIs as part of the intervention arm either as monotherapy (second-line) or as a combination therapy (first-line) with another ICI or CT. We combined the HRQoL measures into a meta-analysis using standard random effects models, from which estimates of the average mean difference (MD) were obtained with 95% confidence intervals. We assessed heterogeneity of the study outcomes using the Q and I2 statistics. Results: 11 phase-3 RCTs were included, with a mean enrollment of 820 patients. Most (n=X) of the RCTs had ICI plus CT combination in the intervention arm, three had ICIs as monotherapy, and one had doublet ICI therapy in the intervention arm. All RCTs had CT for the control arm. Collectively, trials reported 37 HRQoL measures using 5 different HRQoL tools. The pooled analysis favored the intervention over the control arm in terms of Functional Assessment of Cancer Therapy-Esophageal (FACT-E) scores [MD 2.7 (95% CI 0.1 to 5.3), p&lt;0.05]. In a subgroup analysis of 8 RCTs comparing combination therapy with ICIs plus CT versus CT alone, the effect estimates favored the ICI arm regarding the FACT-E [MD 2.7 (95% CI 0.1 to 5.3), p&lt;0.05] and the EORTC QLQ-OES18 pain scale [MD -2.2 (95% CI -4.3 to -0.2), p&lt;0.05]. We found no statistically significant differences in HRQoL scales in subgroup analysis of ICI monotherapy versus CT. Conclusions: In this meta-analysis, we found that the inclusion of ICIs as first-line treatment for aGECs yielded better HRQoL outcomes than CT. Further research on the impact of ICIs on HRQoL is needed, yet with increasing evidence that ICIs improve survival outcomes in patients with aGEC, these corresponding benefits with HRQoL are encouraging.[Table: see text]

Antitumor activity of pegylated human interferon β as monotherapy or in combination with immune checkpoint inhibitors via tumor growth inhibition and dendritic cell activation

Type I interferons (IFN), especially human IFN alpha (IFNα), have been utilized for antitumor therapy for decades. Human interferon beta (IFNβ) is rarely used for cancer treatment, despite advantages over IFNα in biological activities such as tumor growth inhibition and dendritic cell (DC) activation. The utilization of pegylated human IFNβ (PEG-IFNβ), as monotherapy or in combination with immune checkpoint inhibitors (ICIs) was evaluated in this study through in vivo efficacy studies in syngeneic mouse melanoma, non-small cell lung cancer (NSCLC), and colon adenocarcinoma (COAD) models resistant to immune checkpoint inhibitors (ICIs). In vitro comparative study of PEG-IFNβ and pegylated IFNα-2b was performed in terms of tumor growth inhibition against human melanoma, NSCLC and COAD cell lines and activation of human monocyte-derived DCs (MoDCs). Our data demonstrate that the in vivo antitumor effects of PEG-IFNβ are partially attributable to tumor growth-inhibitory effects and DC-activating activities, superior to pegylated IFNα-2b. Our findings suggest that utilizing PEG-IFNβ as an antitumor therapy can enhance the therapeutic effect of ICIs in ICI-resistant tumors by directly inhibiting tumor growth and induction of DC maturation.

Durvalumab-induced Pure White Cell Aplasia.

Immune checkpoint inhibitors (ICI) have gained approval as a treatment for a wide array of cancers. Their mechanism of action prevents the inactivation of cytotoxic T-cells, allowing for its cytotoxic response. However, the upregulation of the immune system by ICI also leads to many undesired adverse events known as immune-related adverse events (irAEs), ranging from dermatologic manifestations, such as rashes, to inflammation of mucous membranes, to hematologic toxicities. Here, we report a case of ICI-induced pure white cell aplasia, secondary to the agent durvalumab, which responded to treatment with filgrastim, prednisone, and cyclosporine. ICI-neutropenia accounts for 0.6% of all irAEs or 17% of hematologic irAEs. Given the rarity of hematologic irAEs, the available treatment guidelines are based on expert consensus. As ICI becomes more widely used, we can expect an increase in the prevalence of rare irAEs as well. This case report aims to present a rare side effect of ICI and demonstrate its response to immunosuppressive therapy while providing guidance for future clinicians and further elucidating the mechanism behind these irAEs.

Evaluating the effect of immune checkpoint inhibitors on venous thromboembolism in non-small cell lung cancer patients

ABSTRACT Objective Currently, immune checkpoint inhibitors (ICIs) therapy is one of the main methods of treatment in non-small cell lung cancer (NSCLC). This study aimed to explore the risk factors of VTE and evaluate the effect of ICIs on VTE in patients with NSCLC. Research design and methods We retrospectively studied patients with NSCLC who were divided into VTE group and without VTE (Non-VTE) group. We identified the risk factors of VTE in NSCLC patients and evaluated the effect of ICIs on VTE in NSCLC patients. Results We found that clinical stage III-IV (P = 0.015) and Khorana score (KS) ≥ 2 (P = 0.047) were independent risk factors for the occurrence of VTE in NSCLC, and treatment with ICIs reduced the risk of VTE occurrence (P = 0.028). There were no differences of survival rates in the 12-month (P = 0.449), 24-month (P = 0.412), or 36-month (P = 0.315) between the VTE and non-VTE groups. History of anti-angiogenic therapy (P = 0.033) and chronic obstructive pulmonary disease (COPD) (P = 0.046) were independent risk factors for VTE in NSCLC patients who were treated with ICIs. Conclusion This study suggests that we should strengthen anticoagulant therapy when using ICIs for NSCLC patients with a history of anti-angiogenic therapy and COPD.

THU092 Characterizing Immune Checkpoint Inhibitor Induced Hypophysitis In A Large Urban Health Care System

Abstract Disclosure: M. Gogerly-Moragoda: None. U. Sharif Khawaja: None. K.C. Cheesman: None. A. Leiter: None. E.J. Gallagher: Consulting Fee; Self; Novartis Pharmaceuticals, Flare Therapeutics, Seagen, SynDevRx. INTRODUCTION Over the past decade, immune checkpoint inhibitors (ICIs) have transformed cancer therapy in multiple tumor types and improved outcomes. Endocrine immune related adverse events are well recognized side effects of ICIs. ICI induced hypophysitis is potentially life-threatening if not identified and treated. The present study examines the incidence and presentation characteristics of hypophysitis in a real-world cohort including a multitude of ICIs and tumor types. METHODS We conducted a retrospective analysis of all patients treated with ICIs at a large health system from 2011-2020. Patient demographics, type of cancer, type of ICI, endocrine symptoms and laboratory values were collected to characterize hypophysitis within the cohort. RESULTS A total of 1703 patients were treated with ICIs from 2011-2020 of whom 32 (1.9%) developed clinically apparent hypophysitis. Of the 32 patients, 26 patients were confirmed to have secondary adrenal insufficiency (AI), with 6 possible secondary AI. A majority were diagnosed in the outpatient setting (n=21, 66%). For those with hypophysitis, the most common tumor type was melanoma (n=12, 38%), followed by lung cancer (n=9, 28%) and genitourinary cancers (n=8, 25%). Combination cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, ipilimumab and programmed cell death protein 1 (PD-1) inhibitor, nivolumab (n=9, 28%) was the most common regimen, followed by monotherapies ipilimumab (n=6, 19%), nivolumab (n=6, 19%), pembrolizumab (n=6, 19%), the programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab (n=3, 9%), with the remainder on durvalumab or combination durvalumab and tremelimumab. The most common presenting symptom was fatigue (n=21, 66%) with headache (n=8, 25%) and vision changes (n=2, 6%) being less common. The median time to presentation was 5 months with most presenting within 12 months of starting ICI (n=24, 75%). However, a subset of patients presented after 18 months on treatment (n=6, 19%), none of whom received ipilimumab. Seven patients underwent cosyntropin stimulation tests and six had muted responses, despite having low or inappropriately normal ACTH levels. DISCUSSION In this real-world dataset, we found a low percentage of hypophysitis across multiple tumor and ICI types. Secondary AI was most commonly seen with ipilimumab treatment. Notably, the subset of patients who presented after 18 months were all on PD-1 / PD-L1 inhibitors, which potentially indicates a distinct mechanism of hypophysitis with these agents compared with CTLA-4 inhibitors, and the new need to monitor these patients with labs and symptom review beyond the initial few months from ICI start. The muted cortisol response to cosyntropin was surprising in the setting of acute hypophysitis and warrants further investigation in these patients. Presentation: Thursday, June 15, 2023

Single-cell RNA-seq reveals characteristics in tumor microenvironment of PDAC with MSI-H following neoadjuvant chemotherapy with anti-PD-1 therapy

Accumulating evidence suggests the minority of patients with advanced pancreatic ductal adenocarcinoma (PDAC) that have microsatellite instability high (MSI-H) can benefit from immune checkpoint inhibitors (ICIs). However, the effects of ICIs on the tumor microenvironment (TME) of PDAC remain elusive. We conducted single-cell RNA-seq (scRNA-seq) analysis on a residual lesion from a MSI-H PDAC patient who received a radical operation after eight cycles of neoadjuvant treatment (nab-paclitaxel/gemcitabine plus pembrolizumab). Multiple tumor subclusters were identified in residual lesion after neoadjuvant treatment, one of which was mainly composed of cells in the S and G2M phases. This subcluster also had enriched expression of MKI67 and PCNA and cell cycle-related signatures and was thus defined as a proliferating tumor subcluster. This subcluster had higher S_score, Fatty acid_score, UPR_score, and Glycolysis_score than others. We also identified characteristics of the TME after neoadjuvant treatment by comparing the excised primary tumors form nontreated PDAC and the residual lesion. The residual lesion was characterized with activated pancreatic stellate cells (PSCs) and exhausted T cells (Tex). We compared the receptor-ligand interactions between the two groups, and found that no checkpoint receptor-ligand pairs between T cells and tumor cells were identified in the residual lesion, while there were many checkpoint receptor-ligand pairs in the nontreated primary PDAC. In conclusion, our findings revealed the characteristics of residual lesion of advanced PDAC with MSI-H upon combination treatment of chemotherapy and immunotherapy, which might provide some valuable clues for solving the puzzle of ICI in PDAC.

Isolated Neutropenia Due to Immune Checkpoint Inhibitors.

In this article, we explore the correlation between immune checkpoint inhibitors (ICIs) and neutropenia. Immune checkpoint inhibitors have revolutionized cancer treatment and management by maximizing the innate abilities of the immune system. However, this therapeutic potential is accompanied by a range of immune-related adverse effects (irAEs), including neutropenia, which is a rare but potentially life-threatening side effect of this mode of cancer treatment. Through an in-depth analysis of various case reports, we have compiled a detailed table summarizing the occurrences of neutropenia associated with different ICIs, the grades of neutropenia, treatments used, and patient outcomes. Management of neutropenia must include an approach based on early diagnosis of the condition and a treatment based on its severity. This review discusses different therapeutic interventions, ranging from the administration of corticosteroids and intravenous immunoglobulin (IVIG) to the use of granulocyte colony-stimulating factor (filgrastim) and, in very severe cases, a stem cell transplant. We have also enlisted salient side effects caused by these interventions.Our findings emphasize that while neutropenia is a relatively rare adverse effect of ICIs, its severity necessitates increased awareness among healthcare professionals. As ICIs continue to be seen as an integral component of cancer therapy, a comprehensive understanding of neutropenia as a side effectand its management is critical for optimizing patient outcomes. A crucial purpose of this review is to highlight the need to achieve a balance between acquiring the therapeutic benefits of various treatment strategies for irAEs and considering their potential side effects, especially with the use of steroids. Achieving this equilibrium is very important in optimizing patient care during immunotherapy, as these irAE management options can bothmitigate the neutropenia triggered by ICIs and potentially give rise to secondary complications. Therefore, a careful assessment of the risks and benefits associated with each treatment approach is essential in tailoring irAE management.

The prognostic significance of histologic variant on survival outcomes in patients with metastatic urothelial carcinoma receiving immune checkpoint inhibitor therapy

BackgroundWhile the treatment guidelines have been established for pure urothelial carcinoma (pUC), patients with variant type urothelial carcinoma (vUC) face limited effective treatment options. The effectiveness of immune checkpoint inhibitors (ICI) in patients with vUC remains uncertain and necessitates additional research.MethodWe conducted a retrospective, multicenter study to explore the effectiveness of ICI in patients with pUC or vUC in Taiwan. We evaluated the overall response rate (ORR) through univariate logistic regression analysis and examined the overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier analysis. Additionally, we employed univariate and multivariate Cox proportional hazards models to analyze the data.ResultA total of 142 patients (116 pUC, 26 vUC) were included in our final analysis. The ORR was marginally higher in patients with pUC compared to those with vUC (34.5% vs. 23.1%, p = 0.26). Among all patients, 12.9% with pUC achieved a complete response (CR) after ICI treatment, while no vUC cases achieved CR (p = 0.05). There were no significant differences in PFS (median 3.6 months vs. 4.1 months, p = 0.34) or OS (median 16.3 months vs. 11.0 months, p = 0.24) when comparing patients with pUC or vUC. In the subgroup analysis, patients with pUC who underwent first-line ICI treatment exhibited significantly improved OS compared to those with vUC (24.6 months vs. 9.1 months, p = 0.004).ConclusionThe use of ICI as monotherapy is a feasible and effective treatment approach for patients with metastatic vUC.

Gene signature from cutaneous autoimmune diseases provides potential immunotherapy-relevant biomarkers in melanoma

Immune checkpoint inhibitors (ICIs) are promising agents for treating melanoma. Given that autoimmune skin diseases exhibit hyper immune reaction, investigation of immune cells from autoimmune skin disease is crucial to validate the effectiveness of ICIs in melanoma treatment. We employed multipanel markers to predict the response to immune checkpoint inhibitors by characterizing the gene expression signatures of skin immune cells in systemic lupus erythematosus (SLE), atopic dermatitis (AD), and psoriasis (PS). By analyzing single-cell RNA sequencing data from each dataset, T cell gene signatures from autoimmune skin diseases exhibit a complex immune response in tumors that responded to immunotherapy. Based on that CD86 and CD80 provide essential costimulatory signals for T cell activation, we observed that interaction of CD86 signaling has been enhanced in the T cells of patients with SLE, AD, and PS. Our analysis revealed a common increase in CD86 signals from dendritic cells (DCs) to T cells in patients with SLE, AD, and PS, confirming that dendritic cells produce pro-inflammatory cytokines to activate T cells. Thus, we hypothesize that T cell gene signatures from autoimmune skin diseases exhibit a pro-inflammatory response and have the potential to predict cancer immunotherapy. Our study demonstrated that T cell gene signatures derived from inflammatory skin diseases, particularly SLE and PS, hold promise as potential biomarkers for predicting the response to immune checkpoint blockade therapy in patients with melanoma. Our data provide an understanding of the immune-related characteristics and differential gene expression patterns in autoimmune skin diseases, which may represent promising targets for melanoma immunotherapy.

Immunologic Significance of CD80/CD86 or Major Histocompatibility Complex-II Expression in Thymic Epithelial Tumors

IntroductionUnresectable or recurrent thymic epithelial tumors (TETs) have a poor prognosis, and treatment options are limited. This study aimed to investigate the immunologic significance of CD80/CD86 or major histocompatibility complex class II (MHC-II) expression in TETs, as potential predictive biomarkers for immune checkpoint inhibitors (ICIs). MethodsWe analyzed CD80, CD86, MHC class I (MHC-I), and MHC-II expression in TETs using immunohistochemistry and investigated their association with T-cell infiltration or ICI efficacy. In addition, we generated CD80- or MHC-II–expressing mouse tumors, evaluated the effects of ICIs, and analyzed tumor-infiltrating lymphocytes. We also performed tumor-rechallenge experiments in vivo. ResultsWe found that approximately 50% and 30% of TETs had high expression of CD80/CD86 and MHC-II in tumor cells, respectively, and that this expression was related to T-cell infiltration in clinical samples. In mouse models, both CD80 and MHC-II increase the effects of ICIs. In addition, senescent T cells and long-lived memory precursor effector T cells were significantly decreased and increased, respectively, in tumor-infiltrating lymphocytes from CD80-expressing tumors, and rechallenged tumors were completely rejected after the initial eradication of CD80-expressing tumors by programmed cell death protein 1 blockade. Indeed, patients with CD80-high thymic carcinoma had longer progression-free survival with anti–programmed cell death protein 1 monoclonal antibody. ConclusionsHalf of the TETs had high expression of CD80/CD86 or MHC-II with high T-cell infiltration. These molecules could potentially increase the effects of ICIs, particularly inducing a durable response. CD80/CD86 and MHC-II can be predictive biomarkers of ICIs in TETs, promoting the development of drugs for such TETs.

Immune Checkpoint Inhibitors in Advanced Cutaneous Squamous Cell Carcinoma: Real-World Experience from a Canadian Comprehensive Cancer Centre.

Immune checkpoint inhibitors (ICI) cemiplimab and pembrolizumab have revolutionized the treatment of advanced cutaneous squamous cell carcinoma (cSCC). We aimed to evaluate the effectiveness and safety of ICI in a real-world cSCC population, including patients with conditions that would exclude clinical trial participation. In this single-center, retrospective cohort study, we included all non-trial patients with advanced cSCC treated with ICI between 2017 and 2022. We evaluated investigator-assessed best overall response (BOR) and immune-related adverse events (irAEs). We correlated survival outcomes with age, performance status, immune status and irAEs. Of the 36 patients identified, the best overall response (BOR) to ICI was a partial response (PR) in 41.7%, a complete response (CR) in 27.8%, and stable disease in (SD) 13.9%. The progression-free survival (PFS) rate for 1 year was 58.1%; the median PFS was 21.3 months (95% CI 6.4-NE). The 1-year overall survival (OS) was 76.7%, and the median OS was 38.6 months (95% CI 25.4-NE). Immune-compromised patients, ECOG performance 2-3, and age ≥ 75 years were not significantly associated with PFS or OS. IrAE grades 3-4 were seen in 13.9% of patients. In our Canadian experience with real-world patients, ICI was an effective and safe treatment for advanced cSCC patients. Patients achieved great benefits with ICI regardless of age, immune status or ECOG performance status. We acknowledge the small sample size and retrospective methodology as the main limitations of our study.

Long response to camrelizumab in metastatic lung squamous cell carcinoma with high PD-L1 expression despite EGFR G719S mutation: A case report

Immune checkpoint inhibitors (ICIs) have been widely used in non-small cell lung cancer with wildtype EGFR/ALK genes. However, the effect of ICIs on advanced NSCLC with EGFR genes sensitive mutations has been controversial. There are no reports on whether ICIs monotherapy can be used in the treatment of NSCLC with EGFR sensitive mutations. A patient with metastatic lung squamous cell carcinoma with EGFR G719s mutations, high PD-L1 score and a tuberculosis history was given first-line treatment of afatinib, camrelizumab monotherapy (200 mg, intravenous, once every three weeks) from February 24,2020 to January 2023. The patient achieved partial response (PR) after treatment with camrelizumab. The progress-free survival (PFS) due to camrelizumab monotherapy was more than 34 months.It is concluded that camrelizumab has promising potential effectiveness as a treatment option for lung squamous cell cancer with EGFR G719 mutations and high PD-L1 score.

Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses.

Immune checkpoint inhibitors (ICIs) are potentially life-saving cancer therapies that can trigger immune-related adverse events (irAEs). irAEs can impact any organ and range in their presentation from mild side effects to life-threatening complications. The relationship between irAEs and antitumor immune responses is nuanced and may depend on the irAE organ, the tumor histology, and the patient. While some irAEs likely represent an immune response against antigens shared between tumor cells and healthy tissues, other irAEs may be entirely unrelated to antitumor immune responses. Clinical observations suggest that low-grade irAEs have a positive association with responses to ICIs, but the correlation between severe irAEs and clinical benefit is less clear. Currently, severe irAEs are typically treated by interrupting or permanently discontinuing ICI treatment and administering empirically selected systemic immunosuppressive agents. However, these interventions could potentially diminish the antitumor effects of ICIs. Efforts to understand the mechanistic relationship between irAEs and the tumor microenvironment have yielded meaningful insights and nominated therapeutic targets for irAE management that may preserve or even boost ICI efficacy. We explore the clinical and molecular relationship between irAEs and antitumor immunity as well as the role that irAE treatments may play in shaping antitumor immune responses.