Receiving Immune Checkpoint Inhibitors Treatment Research Articles

Plasma metabolomics of immune-related adverse events for patients with lung cancer treated with PD-1/PD-L1 inhibitors

BackgroundMetabolomics has the characteristics of terminal effects and reflects the physiological state of biological diseases more directly. Several current biomarkers of multiple omics were revealed to be associated with immune-related...

Obesity and Survival After Immune Checkpoint Inhibition for Head and Neck Squamous Cell Carcinoma

For patients treated with immune checkpoint inhibitors (ICIs), recent data suggest that obesity has a beneficial effect on survival outcomes in various cancer types. Reports on this association in head and neck cancer are limited. To compare overall survival (OS) to 5 years and functional outcomes in patients with head and neck squamous cell carcinoma (HNSCC) treated with ICIs based on pretreatment body mass index (BMI). This retrospective population-based cohort study used data obtained from the TriNetX Global Collaborative Network database to identify patients with HNSCC who received ICI treatment between January 1, 2012, and December 31, 2023, resulting in a total of 166 patients (83 with BMI of 20.0-24.9 [normal BMI] and 83 with BMI of ≥30.0 [obesity BMI]) after propensity score matching (PSM) for pretreatment medical comorbidities and oncologic staging. Normal BMI vs obesity BMI. Overall survival and functional outcomes (dysphagia, tracheostomy dependence, and gastrostomy tube dependence) were measured to 5 years after ICI treatment and compared between patients with obesity BMI and normal BMI. Additional analyses compared OS and functional outcomes in the cohort with normal BMI and cohorts with overweight BMI (25.0-29.9) and underweight BMI (<20.0). Among the 166 patients included in the PSM analysis (112 men [67.1%]; mean [SD] age, 62.9 [15.4] years), obesity BMI was associated with significantly improved OS at 6 months (hazard ratio [HR], 0.54 [95% CI, 0.31-0.96]), 3 years (HR, 0.56 [95% CI, 0.38-0.83]), and 5 years (HR, 0.62 [95% CI, 0.44-0.86]) after ICI treatment, compared with patients with normal BMI. Obesity BMI was also associated with decreased risk of gastrostomy tube dependence at 6 months (odds ratio [OR], 0.41 [95% CI, 0.21-0.80]), 1 year (OR, 0.41 [95% CI, 0.21-0.78]), 3 years (OR, 0.35 [95% CI, 0.18-0.65]), and 5 years (OR, 0.34 [95% CI, 0.18-0.65]). Obesity was also associated with decreased risk for tracheostomy dependence at 1 year (OR, 0.52 [95% CI, 0.28-0.90]), 3 years (OR, 0.45 [95% CI, 0.45-0.90]), and 5 years (OR, 0.45 [95% CI, 0.45-0.90]). There were no differences in rates of dysphagia or immune-related adverse events between cohorts at any points. Using population-level data for patients with HNSCC treated with ICIs, these results suggest that having obesity was associated with improved 6-month, 3-year, and 5-year OS compared with having normal BMI. Additionally, obesity was associated with decreased gastrostomy and tracheostomy tube dependence compared with normal BMI. Further investigation is required to understand the mechanism of these findings.

Arrhythmias and electrocardiographic characteristics in cancer patients treated with immune checkpoint inhibitors

Objective: To evaluate the incidence of arrhythmias and electrocardiographic (ECG) characteristics in cancer patients treated with immune checkpoint inhibitors (ICIs). Methods: This was a cohort study conducted in the Fourth Hospital of Hebei Medical University. Cancer patients initiating ICIs treatments from November 2020 to September 2022 were included in this study. Baseline 12-leads ECG before ICIs initiation and post-treatment ECG were analyzed. An abnormal ECG was defined as the presence of any of the following changes: sinus arrhythmias, atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia, ventricular tachycardia, premature contractions, conduction disorder, and ST-T changes. Results: A total of 87 patients were enrolled, aged 63 (57, 68) years, with 66 (75.9%) males. And 44.8% (39/87) of patients presented with at least one confirmed cardiovascular disease or cardiovascular risk factor at baseline. The incidence of abnormal ECG increased from 31.0% (27/87) at baseline to 65.5% (57/87) after receiving (5.0±2.7) cycles of ICIs treatment (P<0.001). The incidence of sinus arrhythmias was significantly increased after ICIs treatment (23.0% (20/87) vs. 9.2% (8/87), P=0.023), of which only the incidence of sinus tachycardia was significantly increased (11.5% (10/87) vs. 2.3% (2/87), P=0.039). There was also a significantly increased incidence of ST-T changes after ICIs treatment (31.0% (27/87) vs. 17.2% (15/87), P=0.012), which mainly attributed to the T wave changes (29.9% (26/87) vs. 13.8% (12/87), P=0.001). The incidence of premature contractions was also significantly increased after ICIs treatment (9.2% (8/87) vs. 0, P=0.008). Additionally, compared with baseline, the P wave axis was significantly increased after ICIs treatment ((56.94±21.01)° vs. (52.00±22.69)°, P=0.043). After ICIs treatment, the heart rate was significantly increased ((79.07±15.37) beats/min vs. (75.64±13.37) beats/min, P=0.029). Sokolow-Lyon index ((2.21±0.81)mV vs. (2.33±0.75)mV, P=0.138), QTc interval ((431.44±36.04)ms vs. (428.00±30.05)ms, P=0.415) all showed signs of change after treatment, but did not reach the traditional significant level. Conclusions: The incidence of abnormal ECG is significantly increased after ICIs treatment, especially for sinus tachycardia, premature contractions and T wave changes; the P wave axis and heart rate is also significantly increased after treatment. It is important to perform regular ECG monitoring in patients receiving ICIs treatment.

Characterizations of multi-kingdom gut microbiota in immune checkpoint inhibitor-treated hepatocellular carcinoma

BackgroundThe association between gut bacteria and the response to immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) has been studied; however, multi-kingdom gut microbiome alterations and interactions in ICI-treated HCC...

Seasonal patterns in immunotherapy outcomes.

e14684 Background: Immune checkpoint inhibitors (ICIs) allow the immune system to target cancer cells. The immune system is affected by seasonal factors e.g. viruses, allergens, vaccines and ultraviolet exposure. There is evidence that some immune-related adverse events are more common in winter and that higher vitamin D (VD) levels and VD supplementation are associated with longer overall survival (OS). This study aimed to determine if season of ICI initiation was associated with OS. Methods: We evaluated patients who received ICI treatment at The Christie Hospital, UK, between 2017 and 2022. Season of ICI initiation was categorised as: (i) Nov-Apr vs May-Oct and (ii) Dec-Feb vs Jun-Aug (i.e. winter vs summer). For each category, median OS (mOS) was estimated using the Kaplan-Meier method. Adjusted Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals for associations of season of ICI initiation with OS and to test for interactions with ICI and diagnosis. Where data were available, associations of baseline VD levels and VD supplements with OS were estimated along with the association between season of ICI initiation and OS in patients with normal VD and/or receiving VD supplements. Results: 3010 patients were included and 1804 OS events occurred during 36.4 months [m] median follow-up. ICI indications included pembrolizumab or atezolizumab for advanced non-small cell lung cancer (NSCLC, 1st line n 304, median OS [mOS] 17.0 m; 2nd line n 197, mOS 10.7 m), pembrolizumab plus chemotherapy for advanced NSCLC (n 288, mOS 16.3 m), pembrolizumab or nivolumab for melanoma (advanced n 211, mOS 25.2 m; adjuvant n 226, mOS not reached), and ipilimumab + nivolumab for melanoma (n 203, mOS 45.4 m) or renal cancer (n 129, mOS 38.6 m). Confounders were balanced across seasons of ICI initiation, including sex (48% Nov-Apr vs 52% May-Oct), age (median 66.7 vs 67.2 years), PS 0/1 (83% vs 84%), body mass index (median 26.0 vs 25.7 kg/m2) and setting (adjuvant 13.0% vs advanced 12.4%). Season of ICI initiation was not associated with OS (Nov to Apr vs May to Oct mOS 20.8 vs 20.5 m, HR 1.01, 0.92-1.11; Dec-Feb vs Jun-Aug mOS 20.0 vs 21.3 m, HR 0.97, 0.85-1.10). Interactions with ICI and diagnosis were not significant. 214 patients had baseline VD levels and 96 received VD supplements before ICI initiation. VD deficiency was highest in February (23.6%) and lowest in August (1.1%). Among 209 patients with normal VD levels or receiving VD supplements, season of initiation was not associated with OS (Nov to Apr vs May to Oct mOS 45.4 vs 43.4 m; HR 0.98, 0.63-1.53). However, VD deficiency (n 37) was associated with shorter OS (HR 2.06, 1.21-3.52) and VD supplementation with longer OS (HR 0.69, 0.52-0.92). Conclusions: While VD deficiency and VD supplementation were associated with OS, season of ICI initiation was not. These results provide reassurance the OS benefits of ICIs remain similar irrespective of time of year of initiation despite seasonal factors that may influence the immune system.

Digital versus manual pathology scoring of PD-L1 in patients with esophageal squamous cell carcinoma (ESCC).

e16023 Background: Immune checkpoint inhibitors (ICIs) are standard-of-care for patients with ESCC, but the association between PD-L1 and clinical outcomes of patients with ESCC receiving ICIs treatment is unclear. Currently, different PD-L1 antibody clones, scoring, and cutoffs were used for different ICIs development in ESCC. Thus, we develop a digital pathology (DP) algorithm to generate multiple scores at the same time with high reproducibility. We evaluate DP algorithm by: (1) comparing the digital and manual scores of SP263 and 22C3 assays; (2) evaluating the association with OS. Methods: Tumor tissue samples were collected from ESCC patients treated at National Taiwan University Hospital between 2017 and 2020. Slides were tested for PD-L1 using SP263 and 22C3 assays at a College of American Pathologists accredited central laboratory. H&amp;E and PD-L1 slides were scanned for whole slide images (WSIs) using DP200 scanner at 20x. HALO (v3.5) by indica labs was used for DP development by deep learning neural network algorithms. WSIs of SP263 were annotated for region of interest (ROI), tumor/stroma area, and tumor, immune and fibroblast cells by board certified pathologists. After the algorithm is developed and run on SP263 WSIs, a board-certified pathologist reviewed the images and provided an agreement score of DP markups. The images were excluded if an agreement was less than 80%. This algorithm was then applied to 22C3 WSIs. Data of areas and cells were exported for subsequent statistical analysis using R. We calculated the DP scores based on the definition of manual readouts of TAP, CPS and s/iTILs in ROI and tumor and stroma regions in both clones’ WSIs. These DP scores were compared with manual scores using Spearman’s rank-order correlation. Association with OS were evaluated using cox proportional hazard regression. Results: Of 235 evaluable images, twelve (5.1%) were excluded due to the low agreement with the pathologist's judgment. DP generated scores showed a strong correlation with pathologists scoring (rho = 0.80 for SP263 and rho = 0.74 for 22C3). DP generated CPS-like and TAP-like scores in ROI, and tumor and stroma regions from SP263 and 22C3 also demonstrated a strong correlation between each other (rho: 0.77 - 0.86). However, s/iTILs correlation between DP and pathologist score is negligible (rho: 0.002 - 0.34). While examining the association of PD-L1 scores and s/iTILs with OS, no clear associations were found with either DP or pathologists’ scores, after adjusting for stage, ECOG, age and gender. Conclusions: DP algorithms developed in this study demonstrated the efficiency of generating multiple DP scores of CPS, TAP, and s/iTILs from one image at the same time, which performed comparable to manual scores. DP algorithm developed based on SP263 is generalizable to 22C3 and showed a good performance. Further algorithm adjustment will be made to overcome the misclassification in the 12 failed cases.

WhARIO: whole-slide-image-based survival analysis for patients treated with immunotherapy.

Immune checkpoint inhibitors (ICIs) are now one of the standards of care for patients with lung cancer and have greatly improved both progression-free and overall survival, although of the patients respond to the treatment, and some face acute adverse events. Although a few predictive biomarkers have integrated the clinical workflow, they require additional modalities on top of whole-slide images and lack efficiency or robustness. In this work, we propose a biomarker of immunotherapy outcome derived solely from the analysis of histology slides. We develop a three-step framework, combining contrastive learning and nonparametric clustering to distinguish tissue patterns within the slides, before exploiting the adjacencies of previously defined regions to derive features and train a proportional hazards model for survival analysis. We test our approach on an in-house dataset of 193 patients from 5 medical centers and compare it with the gold standard tumor proportion score (TPS) biomarker. On a fivefold cross-validation (CV) of the entire dataset, the whole-slide image-based survival analysis for patients treated with immunotherapy (WhARIO) features are able to separate a low- and a high-risk group of patients with a hazard ratio (HR) of 2.29 ( to 3.56), whereas the TPS 1% reference threshold only reaches a HR of 1.81 ( to 2.69). Combining the two yields a higher HR of 2.60 ( to 3.94). Additional experiments on the same dataset, where one out of five centers is excluded from the CV and used as a test set, confirm these trends. Our uniquely designed WhARIO features are an efficient predictor of survival for lung cancer patients who received ICI treatment. We achieve similar performance to the current gold standard biomarker, without the need to access other imaging modalities, and show that both can be used together to reach even better results.

Impact of Nutritional Status on Neutrophil-to-Lymphocyte Ratio as a Predictor of Efficacy and Adverse Events of Immune Check-Point Inhibitors.

The neutrophil -to-lymphocyte ratio (NLR) is useful for predicting the effectiveness of treatment with immune checkpoint inhibitors (ICIs) and immune-related adverse events (irAEs). Because a growing body of evidence has recently shown that the number of lymphocytes that comprise NLR fluctuates according to nutritional status, this study examined whether the usefulness of NLR varies in ICI treatment due to changes in nutritional status. A retrospective analysis was performed on 1234 patients who received ICI treatment for malignant tumors at our hospital. Progression-free survival (PFS) was significantly prolonged in patients with NLR < 4. Multivariate analysis revealed that the factors associated with the occurrence of irAE were NLR < 4 and the use of ipilimumab. However, when limited to cases with serum albumin levels <3.8 g/dL, lymphocyte counts significantly decreased, and the associations between NLR and PFS and between NLR and irAE occurrence disappeared. In contrast, when limited to the cases with serum albumin levels ≥3.8 g/dL, the associations remained, with significantly prolonged PFS and significantly increased irAE occurrence at NLR < 4. NLR may be a good predictive tool for PFS and irAE occurrence during ICI treatment when a good nutritional status is maintained.

Cerebral 18F-FDG PET/CT Metabolism as Diagnostic Signature for Central Nervous System Toxicity After Immune Checkpoint Blockade Cancer Treatment.

Our aim was to investigate probable biomarkers specific to immune-related central nervous system toxicity (CNST) in cancer patients treated with immune checkpoint inhibitors (ICI) by analysis of 18F-FDG PET/CT images. Methods: Cancer patients receiving ICI treatment were enrolled in a multicenter observational study that analyzed regional metabolic changes before and during CNST onset from January 2020 to February 2022. In 1:1 propensity score-matched pairs, the regional SUVmean of each bilateral brain lobe of CNST patients (CNST+) was compared with that of patients who had central nervous system infections (CNSIs) and patients without CNST or CNSI (CNST-). In a validation cohort, patients were recruited from February 2022 to July 2023 and followed up for 24 wk after the start of ICI. Early changes in regional SUVmean at 5-6 wk after therapy initiation were evaluated for ability to predict later CNST onset. Results: Of 6,395 ICI-treated patients, 2,387 underwent prognostic 18F-FDG PET/CT and 125 of the scanned patients had CNST (median time from ICI treatment to onset, 9 wk; quartile range, 2-23 wk). Regional 18F-FDG PET/CT SUVmean changes were higher in CNST+ than in CNST- patients (117 patient pairs) but were lower than in CNSI patients (50 pairs). Differentiating analysis reached an area under the curve (AUC) of 0.83 (95% CI, 0.78-0.88) for CNST+ versus CNST- and of 0.80 (95% CI, 0.72-0.89) for CNST+ versus CNSI. Changes in SUVmean were also higher before CNST onset than for CNST- (60 pairs; AUC, 0.74; 95% CI, 0.66-0.83). In a validation cohort of 2,878 patients, preonset changes in SUVmean reached an AUC of 0.86 (95% CI, 0.79-0.94) in predicting later CNST incidence. Conclusion: Brain regional hypermetabolism could be detected during and before CNST clinical onset. CNST may be a distinct pathologic entity versus brain infections defined by 18F-FDG PET/CT brain scans. Regional SUV differences may be translated into early diagnostic tools based on moderate differentiating accuracy in our study.

Octamer-binding transcription factor 4-positive circulating tumor cell predicts worse treatment response and survival in advanced cholangiocarcinoma patients who receive immune checkpoint inhibitors treatment

BackgroundOctamer-binding transcription factor 4-positive circulating tumor cell (OCT4+CTC) exhibits high stemness and invasive potential, which may influence the efficacy of immune checkpoint inhibitors (ICI). This study aimed to assess the prognostic role of OCT4+CTC in advanced cholangiocarcinoma (CCA) patients who received ICI treatment.MethodsIn total, 40 advanced CCA patients who received ICI treatment were included, and CTC and OCT4 counts were detected via a Canpatrol system and an RNA in situ hybridization method before ICI treatment. Patients were subsequently divided into none CTC, OCT4−CTC, and OCT4+CTC groups. Patients were followed up for a median of 10.4 months.ResultsThe percentages of patients in none CTC, OCT4−CTC, and OCT4+CTC groups were 25.0%, 30.0%, and 45.0%, respectively. The proportion of patients with lymph node metastasis was highest in OCT4+CTC group, followed by none CTC group, and lowest in OCT4−CTC group (P = 0.025). The objective response rate (ORR) was lowest in OCT4+CTC group, moderate in OCT4−CTC group, and highest in none CTC group (P = 0.009), while disease control rate was not different among three groups (P = 0.293). In addition, progression-free survival (PFS) (P < 0.001) and overall survival (OS) (P = 0.001) were shorter in the OCT4+CTC group than in none CTC & OCT4−CTC group. Moreover, OCT4+CTC (versus none CTC) was independently linked with poorer PFS [hazard ratio (HR) = 6.752, P = 0.001] and OS (HR = 6.674, P = 0.003) in advanced CCA patients.ConclusionOCT4+CTC relates to lymph node metastasis and shows a good predictive value for poor treatment response and survival in advanced CCA patients who receive ICI treatment.

Unveiling the role of FTO polymorphisms in predicting response to immune checkpoint inhibitors: A retrospective study

BackgroundIdentifying patients who can benefit from immune checkpoint inhibitors (ICIs) is a critical challenge in immunotherapy. This study aimed to investigate the association between fat mass and obesity-associated protein (FTO) polymorphisms and ICIs treatment outcomes. MethodThis retrospective study was conducted on 371 patients with malignant tumors who received ICIs treatment and were followed-up for a minimum duration of 12 months. Seven variants in FTO gene were genotyped using the Sequenome MassARRAY platform, and their associations with ICIs treatment outcomes were analyzed. ResultsPharmacogenomic research revealed that individuals carrying the rs11075995AT/TT genotype were more likely to benefit from ICIs treatment compare to TT genotype. Cox regression analysis showed that rs1125338TT carriers exhibited a shorter progression-free survival (PFS, hazard ratio (HR) = 1.72, 95 % confidence interval (CI) = 1.12–2.46), while rs12596638GG carriers experienced extended PFS (HR = 0.71, 95 % CI = 0.50–0.99). Multiple Cox regression analysis indicated that rs12596638GG (HR = 6.81, 95 %CI = 1.20–38.56) and rs1125338CC (HR = 1.78, 95 %CI = 0.07–0.45), rs12600192CC (HR = 0.13, 95 %CI = 0.037–0.44) genotypes were independently associated with overall survival (OS) after adjusting clinical characteristics. Furthermore, patients with rs12600192CC genotype had a lower risk of severe irAEs compared to those with GG/GC genotypes (P < 0.01). ConclusionWe identified FTO gene polymorphisms associated with treatment outcomes of ICI treatment in patients with multiple solid cancers, which might serve as potential predictive biomarkers.

Impact of immune checkpoint inhibitors (ICIs) therapy on interferon-γ release assay (IGRA) and diagnostic value in non-small cell lung cancer (NSCLC) patients

BackgroundTuberculosis (TB), a highly contagious respiratory disease, presents a significant global health threat, with a notable increase in incidence reported by the WHO in 2022. Particularly, the interplay between TB and non-small cell lung cancer (NSCLC) gains attention, especially considering the rising use of immune checkpoint inhibitors (ICIs) in cancer treatment. This interplay may influence TB diagnostics and reactivation, warranting a closer examination.MethodsA retrospective analysis was conducted on clinical data of NSCLC patients with positive T-SPOT results before undergoing anti-tumor treatment at Zhongshan Hospital (Xiamen), Fudan University, from January 1, 2021 to December 31, 2022. We assessed the incidence of tuberculosis reactivation and treatment outcomes among these patients. Moreover, we compared the differences in tuberculosis activity between the ICIs and non-ICIs treatment groups. Additionally, we observed the changes in T-SPOT spot count before and after immunotherapy, analyzing their association with tuberculosis activity and prognosis.ResultsA total of 40 NSCLC patients with positive T-SPOT results before treatment were included in the study, with 26 patients in the ICIs treatment group and 14 patients in the non-ICIs treatment group. The study found no significant differences between the two groups in terms of gender, age, stage, histological type, performance status, driver gene expression, and distant metastasis. With a median follow-up time of 10.0 (6.0-14.5) months, three cases (11.5%) in the ICIs treatment group developed tuberculosis activity, diagnosed at 2, 3, and 12 months after ICIs treatment initiation. Conversely, no tuberculosis activity was observed in the non-ICIs treatment group, and the difference between the two groups was not significant (P = 0.186). Among the 32 patients who received ICIs treatment, spot count dynamics were diverse: four cases (12.5%) showed an increase, 12 cases (37.5%) had no change, and 16 cases (50.0%) had a decrease. During the follow-up, the progression rate (PD) was 50.0%, 75.0%, and 62.5% in the three groups, respectively (P = 0.527). Similarly, the mortality rate was 0%, 25.0%, and 25.0%, respectively (P = 0.106). Interestingly, among the patients with decreased spot counts, three cases (18.75%) were diagnosed with active pulmonary tuberculosis.ConclusionsFor NSCLC patients with a positive T-SPOT response undergoing ICIs treatment, our study observed indications of active tuberculosis. The varied T-SPOT spot count changes post-ICIs treatment suggest a complex interaction, potentially linking T-SPOT spot count reduction to tuberculosis reactivation risk. These preliminary findings underscore the importance of further research to more accurately assess T-SPOT’s diagnostic utility in this context.

The association between baseline TPOAb and/or TgAb positivity and thyroid immune-related adverse events in patients with malignancies following treatment with immune checkpoint inhibitors

Objective: To investigate the association between positive anti-thyroid peroxidase antibody (TPOAb) and/or anti-thyroglobulin antibody (TgAb) and the occurrence of thyroid immune-related adverse events (irAEs) in patients with malignant tumors who treated with immune checkpoint inhibitors (ICIs). Methods: A case-control study. A total of 116 patients with malignant tumor who received ICIs treatment and underwent thyroid function evaluation at Peking Union Medical College Hospital from January 2017 to April 2023 were enrolled retrospectively, including 77 males and 39 females, with a median age of (M(Q1, Q3)) 63.0 (55.0, 70.0) years. The patients were divided into the euthyroid group (n=58) and the thyroid irAEs group (n=58) according to whether thyroid irAEs occurred after ICIs treatment. The clinical characteristics and baseline anti-thyroid antibodies associated with the occurrence of thyroid irAEs after ICIs treatment in patients with malignant tumors were evaluated. Variables with statistical significance in univariate analysis were included in multivariate logistic regression model to analyze the risk factors for thyroid irAEs in patients with malignant tumors who received ICIs treatment. Results: In irAEs group, therewore 4 (3.4%) cases of clinical thyrotoxicosis, 23(19.8%) cases of subclinical thyrotoxicosis, 23 (19.8%) cases of clinical hypothyroidism, and 8(6.9%) cases of subclinical hypothyroidism. The positive rate of anti-thyroid antibodies at baseline in the thyrioid irAEs group was higher than that in the euthyroid group［16/58（27.6%）vs 3/58（5.2%），P=0.001］. After at least one course of ICIs treatment, the incidence of thyroid irAEs in patients with positive anti-thyroid antibodies at baseline was 84.2% (16/19), whereas it was 43.3% (42/97) in patients with negative anti-thyroid antibodies(P=0.001). Univariate logistic regression analysis showed that gender (OR=2.812, 95%CI:1.257-6.293), baseline thyroid autoantibodies were positive (OR=6.984, 95%CI: 1.909-25.547), baseline TgAb positivity (OR=8.909, 95%CI: 1.923-41.280), and baseline TPOAb positivity (OR=7.304, 95%CI: 1.555-34.308) were associated with thyroid irAEs (all P<0.05). Multivariate logistic regression analysis indicated that baseline TgAb positivity (OR=7.637, 95%CI: 1.617-36.072) was a risk factor for thyroid irAEs (P=0.01). Conclusions: The incidence of thyroid irAEs is higher in patients who are positive for baseline TPOAb and/or TgAb compared to those who are negative for TPOAb and TgAb. Patients with positive TgAb at baseline are at high risk of developing thyroid irAEs.

Abstract 7527: Investigating biomarkers for immune-related adverse events following immune checkpoint inhibitor therapy in recurrent lung cancer patients

Abstract Background: The application of immune checkpoint inhibitors (ICIs) as adjuvant therapy post-lung cancer surgery is expected to confer significant benefits. However, the risk factors for severe immune-related adverse events (irAEs) remain incompletely understood, and managing irAEs may require long-term steroid use. The identification of biomarkers for irAEs in patients with surgically resected lung cancer is an urgent need. Methods: We analyzed 43 lung cancer patients who received ICI treatment for recurrence postoperatively. Macrodissection of lung cancer lesions was performed on FFPE specimens from resected lungs, from which total RNA was extracted. We conducted gene expression analysis of 770 immune-related genes using the PanCancer Immune Profiling Panel (NanoString Technologies, Inc., Seattle, WA, USA). The relationship between gene expression changes and irAEs or the efficacy of ICI treatment was examined. For validation, immunostaining of proteins strongly associated with irAEs was performed to determine their expression status in tissue specimens. Results: Among the 43 patients (30 males, 13 females, median age 68), 28 had adenocarcinoma, and 15 had squamous cell carcinoma. PD-L1 positivity was observed in 36 patients. The treatment regimens included pembrolizumab monotherapy for 18 patients and combination immunotherapy for 25 patients, with 25 patients responding to treatment and 7 developing irAEs. There was a marked difference in gene expression between adenocarcinoma and squamous cell carcinoma, with a notably higher number of tumor-infiltrating lymphocytes (TILs) in adenocarcinoma. An increase in TILs was observed in cases with irAEs across both cancer types. Additionally, an increased CD8/Treg ratio and CD8/exhausted T cell ratio were noted in adenocarcinomas with irAEs. A strong correlation between IRF5 gene expression and the occurrence of irAEs in adenocarcinoma was also confirmed by immunohistochemistry. Conclusion: We have identified tumor immune microenvironments correlated with the onset of irAEs following ICI treatment in patients with postoperative recurrence of lung cancer. This discovery could contribute to perioperative treatment strategies and improve our understanding of tumor immune mechanisms. Citation Format: Yujin Kudo, Jun Matsubayashi, Satoshi Takahashi, Masaru Hagiwara, Masatoshi Kakihana, Toshitaka Nagao, Tatsuo Ohira, Norihiko Ikeda. Investigating biomarkers for immune-related adverse events following immune checkpoint inhibitor therapy in recurrent lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7527.

Identification of immune-related gene signature for non-small cell lung cancer patients with immune checkpoint inhibitors

BackgroundThe utilization of immune checkpoint inhibitors (ICIs) has become the established protocol for treating advanced non-small cell lung cancer (NSCLC). This work aimed to identify the immune-related gene signature that can predict the prognosis of NSCLC patients receiving ICI treatment. MethodsThe ImmPort database was queried to obtain a list of immune-related genes (IRGs). Differentially expressed IRGs in NSCLC patients were identified using the TCGA database. RNA-seq data and clinical information from NSCLC patients receiving immunotherapy were obtained from the GEO database (GSE93157 and ////). A gene signature was generated through multivariate Cox and LASSO regression analyses. The prognostic value and function of this gene signature were thoroughly investigated using comprehensive bioinformatics analyses. ResultsA total of 6 prognostic-related genes were identified from 617 differentially expressed genes, and two prognostic-related differentially expressed genes (CAMP and IL17A) were determined to construct gene signature. Our gene signature demonstrated superior performance compared to other clinicopathological parameters in predicting the prognosis of NSCLC patients receiving immunotherapy, with an area under the ROC curve (AUC) of 0.812. Furthermore, immune infiltration analysis indicated that the high-risk group was enriched with resting CD4 T cell memory, while the low-risk group showed a "hot" tumor microenvironment that promotes anti-tumor immunity in NSCLC patients. ConclusionGene signatures based on immune-related genes exhibited excellent indicator performance of prognosis and immune infiltration, which has the potential to be an effective biomarker for NSCLC with ICI treatment.

Nomograms confirm serum IL-6 and CRP as predictors of immune checkpoint inhibitor efficacy in unresectable hepatocellular carcinoma.

Immunotherapy based on immune checkpoint inhibitors (ICIs) has become the first-line treatment for unresectable hepatocellular carcinoma (uHCC). However, only a small portion of patients are responsive to ICIs. It is important to identify the patients who are likely to benefit from ICIs in clinical practice. We aimed to examine the significance of serum IL-6 and CRP levels in predicting the effectiveness of ICIs for uHCC. We retrospectively recruited 222 uHCC patients who received ICIs treatment (training cohort: 124 patients, validation cohort: 98 patients). In the training cohort, patients are categorized into the response group (R) and no-response group (NR). The levels of serum IL-6 and CRP were compared between the two groups. Internal validation was performed in the validation cohort. Survival analysis was carried out using the Kaplan-Meier method and Cox proportional hazard regression model. The nomograms were developed and assessed using the consistency index (C-index) and calibration curve. Serum levels of IL-6 and CRP were significantly lower in the R group than in the NR group (9.94 vs. 36.85 pg/ml, p< 0.001; 9.90 vs. 24.50 mg/L, p< 0.001, respectively). An ROC curve was employed to identify the optimal cut-off values for IL-6 and CRP in both groups, resulting in values of 19.82 pg/ml and 15.50 mg/L, respectively. Multivariate Cox regression analysis revealed that MVI (HR 1.751, 95%CI 1.059-2.894, p=0.029; HR 1.530, 95%CI 0.955-2.451, p=0.077), elevated IL-6 (HR 1.624, 95%CI 1.016-2.596, p=0.043; HR 2.146, 95%CI 1.361-3.383, p =0.001) and high CRP (HR 1.709, 95%CI 1.041-2.807, p=0.034; HR 1.846, 95%CI 1.128-3.022, p = 0.015) were independent risk factors for PFS and OS, even after various confounders adjustments. Nomograms are well-structured and validated prognostic maps constructed from three variables, as MVI, IL6 and CRP. Low levels of IL-6 and CRP have a positive correlation with efficacy for uHCC patients receiving ICIs.

Association between immune checkpoint inhibitor medication and uveitis: a population-based cohort study utilizing TriNetX database.

To explore the associations between the use of immune checkpoint inhibitors (ICIs) and the risk of developing uveitis among cancer patients. Cancer patients who received ICI therapy and a comparison group of cancer patients who did not receive ICI therapy were retrospectively recruited from the TriNetX electronic heath-record registry. The outcome of interest was the development of new-onset uveitis. Propensity score matching based on a 1:1 ratio was conducted in order to reduce bias. Multi-variate cox proportional hazard models and Kaplan Meier method were also utilized to assess for the risk of uveitis among cancer patients who received ICI therapy. 71931 cancer patients (54.7% male; 76.5% white; mean age at index 63.6 ± 12.2 years) who received ICI treatment (ICI group) and 71931 cancer patients (54.7% male; 77% white; mean age at index 63.5 ± 12.4 years) who never received ICI (comparison group) were recruited. Associated Kaplan-Meier curves showed significantly increased uveitis risk among the ICI group for all follow-up years (p<0.001). The risk of uveitis was also higher among the ICI group during the 144-month follow-up period with a hazard ratio (HR) of 2.39 (95% CI: 2.07-2.75). Increased risk for specific uveitis diseases, such as iridocyclitis, chorioretinal inflammation, retinal vasculitis, unspecified purulent endophthalmitis, pan-uveitis and sympathetic uveitis were found. Subgroup analysis demonstrated an elevated hazard ratio for the development of uveitis among ICI recipients, spanning individuals below the age of 65 as well as those aged 65 and older. The elevated hazard ratio for uveitis development among ICI recipients was also observed across all genders, among those of white and Asian ethnicities, those with smoking history, and those with comorbid conditions such as hypertension and dyslipidemia, in comparison to their non-ICI counterparts. An additional subgroup analysis on monotherapy versus combinatory ICI regimens was also conducted. Individuals who received monotherapy from the class of anti-PD-1 (HR:1.98 [CI: 1.65-2.37]) and anti-CTLA-4 (HR:5.86 [CI:1.99-17.24]) exhibited elevated hazard ratios for uveitis development compared to their non-ICI comparators. Those exposed to combinatory ICI regimens, specifically a combination of anti-PD-1 and anti-CTLA4 (HR: 5.04 [CI:3.55-7.16]), showed increased hazard ratios for uveitis development compared to their non-ICI comparators. In contrast, individuals exposed to a combination of anti-PD-1 and anti-PD-L1 (HR: 2.47 [CI:0.81-7.50]) did not demonstrate an increased risk for uveitis compared to their non-ICI comparators. A significantly increased risk for uveitis diseases was found among the ICI group from the first year of follow-up. Increased awareness should be promoted on the occurrence of uveitis among cancer patients receiving ICI therapy.

Guanylate binding protein 5 triggers NF-κB activation to foster radioresistance, metastatic progression and PD-L1 expression in oral squamous cell carcinoma

Radioresistance and metastasis are critical issues in managing oral squamous cell carcinoma (OSCC). Although immune checkpoint inhibitors (ICIs) has been recommended to treat OSCC, lacking useful biomarkers limited their anti-cancer effectiveness. We found that guanylate binding protein 5 (GBP5) is upregulated in primary tumors and associates with radioresistance in OSCC. GBP5 expression causally associated with cellular radioresistance and migration ability in the OSCC cell variants. GBP5 upregulation was examined to be correlated with NF-κB activation and programmed cell death-ligand 1 (PD-L1) elevation in OSCC samples. GBP5 knockdown was mitigated, but overexpression enhanced, NF-κB activity and PD-L1 expression in the OSCC cells. NF-κB inhibition by SN50 dramatically suppressed the GBP5-forested irradiation resistance, cellular migration ability and PD-L1 expression in OSCC cells. Importantly, GBP5 upregulation predicted a favorable outcome in cancer patients received ICI treatment. Our findings provide GBP5 as a useful biomarker to predict the anti-OSCC effectiveness of irradiation and ICIs.

Atherosclerotic Cardiovascular Events in Cancer Patients Treated With Immune Checkpoint Inhibitors: A Retrospective Cohort Study

Immune checkpoint inhibitors (ICIs) are effective therapies for numerous cancers, but have been associated with atherosclerotic cardiovascular disease (ASCVD). This study aimed to identify predictors for ASCVD events among cancer patients treated with ICIs and the cardiovascular risk factor (CVRF) control of those who developed ASCVD. A single-centre retrospective study of 366 cancer patients who received ICIs from 2018 to 2020 was performed. Demographic, baseline CVRF, cancer history, and ICI regimen data were obtained from medical records. The primary end point of ASCVD events was defined as myocardial infarction, coronary revascularisation, ischaemic stroke, or acute limb ischaemia. Cox proportional multivariable modelling and competing risks analysis were performed to assess ASCVD predictors. Descriptive analysis was performed to describe CVRF management among those who developed ASCVD events. Over a median follow-up of 3.4 years (2.8-4.3), 26 patients (7.1%) experienced 27 ASCVD events (seven myocardial infarction, one coronary revascularisation, 13 ischaemic stroke, and six acute limb ischaemia events). There were 226 (61.8%) cancer-related deaths and no cardiac deaths. History of ASCVD before ICI initiation was independently associated with ASCVD events on traditional Cox modelling (hazard ratio [HR] 4.00; 95% confidence interval [CI] 1.79-8.91; p<0.01) and competing risks analysis (HR 4.23; 95% CI 1.87-9.60; p<0.01). A total of 17 patients developed ASCVD events after ICI cessation (median 1.4 years). Among those with ASCVD events, 12 had prior ASCVD, 16 had hypertension, nine had hypercholesterolaemia, and four had diabetes, and nine were actively smoking. Variable prescription of cardiovascular preventative therapies was noted. History of ASCVD was associated with subsequent ASCVD events among patients treated with ICIs, which could occur even after active treatment was stopped. Identification and aggressive management of modifiable CVRFs should be considered throughout cancer survivorship in patients who received ICI treatment.

Efficacy of immune checkpoint inhibitors in non-small cell lung cancer with NTRK family mutations

BackgroundThe efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) patients harboring neurotrophin receptor kinase (NTRK) family mutations remains obscure.MethodsThe Zehir cohort from cBioPortal was used to analyze the mutations (MT) frequency of NTRK family in patients with NSCLC, and their correlation with clinical characteristics and patient survival. The influence of NTRK MT on ICIs efficacy was evaluated in ICIs-treated patients from Samstein cohort and further validated by use of data from OAK/POPLAR cohort.ResultsIn the Zehir cohort, a significant difference was observed in median overall survival (mOS) between patients with NTRK MT and wild-type (WT) (mOS: 18.97 vs. 21.27 months, HR = 1.34, 95%CI 1.00-1.78; log-rank P = 0.047). In Samstein cohort, the mOS of NTRK mutant patients receiving ICIs has improved compared to WT patients (mOS: 21.00 vs. 11.00 months, log-rank P = 0.103). Notably, in subgroup analysis, ICIs significantly prolonged mOS in patients with NTRK3 MT than in WT patients (mOS: not available vs. 11.00 months, HR = 0.36, 95%CI 0.16–0.81; log-rank P = 0.009). Identical mOS between NTRK MT and WT patients receiving ICIs treatment (mOS: 13.24 vs. 13.50 months, log-rank P = 0.775) was observed in OAK/POPLAR cohort. Moreover, a similar programmed death ligand 1 (PD-L1) expression, but higher tumor mutational burden (TMB), blood TMB (bTMB) and enriched anti-tumor immunity were observed in NTRK MT compared to WT (P < 0.05).ConclusionTaking high TMB or bTMB into consideration, patients with NTRK mutant NSCLC could benefit from ICIs treatment.