Correlation between immune‑related adverse events and treatment efficacy of anti‑PD1 immunotherapy in patients with esophageal squamous cell carcinoma

Cao, Ruijie; Wu, Chensi; Lv, Yalei; Xu, Shuo; Li, Cuizhen; Yin, Fei; Li, Jing

doi:10.3892/ol.2022.13641

Cited by 5 publications

(3 citation statements)

References 34 publications

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“…A growing body of evidence from our group and others has demonstrated that the longitudinal development of irAEs during ICI therapies is often associated with improved outcomes with ICIs. 3-27 Ongoing efforts have centered around an integrated approach to identifying genomic, transcriptomic, and microbiome-associated predictors of irAEs. 28,29 More recently, deconvoluting the role of somatic and germline associations with irAEs is an area of emerging interest to understand the role of baseline genotypic and phenotypic features in augmenting ICI-associated irAEs among at-risk individuals.…”

Section: Introductionmentioning

confidence: 99%

Association of Baseline Tumor-Specific Neoantigens and CD8⁺ T-Cell Infiltration With Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors

Kerepesi,

Abushukair,

Ricciuti

et al. 2024

JCO Precis Oncol

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PURPOSE Recent evidence has shown that higher tumor mutational burden strongly correlates with an increased risk of immune-related adverse events (irAEs). By using an integrated multiomics approach, we further studied the association between relevant tumor immune microenvironment (TIME) features and irAEs. METHODS Leveraging the US Food and Drug Administration Adverse Event Reporting System, we extracted cases of suspected irAEs to calculate the reporting odds ratios (RORs) of irAEs for cancers treated with immune checkpoint inhibitors (ICIs). TIME features for 32 cancer types were calculated on the basis of the cancer genomic atlas cohorts and indirectly correlated with each cancer's ROR for irAEs. A separate ICI-treated cohort of non–small-cell lung cancer (NSCLC) was used to evaluate the correlation between tissue-based immune markers (CD8+, PD-1/L1+, FOXP3+, tumor-infiltrating lymphocytes [TILs]) and irAE occurrence. RESULTS The analysis of 32 cancers and 33 TIME features demonstrated a significant association between irAE RORs and the median number of base insertions and deletions (INDEL), neoantigens (r = 0.72), single-nucleotide variant neoantigens (r = 0.67), and CD8+ T-cell fraction (r = 0.51). A bivariate model using the median number of INDEL neoantigens and CD8 T-cell fraction had the highest accuracy in predicting RORs (adjusted r2 = 0.52, P = .002). Immunoprofile assessment of 156 patients with NSCLC revealed a strong trend for higher baseline median CD8+ T cells within patients' tumors who experienced any grade irAEs. Using machine learning, an expanded ICI-treated NSCLC cohort (n = 378) further showed a treatment duration–independent association of an increased proportion of high TIL (>median) in patients with irAEs (59.7% v 44%, P = .005). This was confirmed by using the Fine-Gray competing risk approach, demonstrating higher baseline TIL density (>median) associated with a higher cumulative incidence of irAEs ( P = .028). CONCLUSION Our findings highlight a potential role for TIME features, specifically INDEL neoantigens and baseline-immune infiltration, in enabling optimal irAE risk stratification of patients.

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Section: Introductionmentioning

confidence: 99%

Association of Baseline Tumor-Specific Neoantigens and CD8⁺ T-Cell Infiltration With Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors

Kerepesi,

Abushukair,

Ricciuti

et al. 2024

JCO Precis Oncol

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“…Intriguingly, rash and pruritus always come out early, and most of these patients were proven pCR finally. Moreover, some literature did confirm that irAE is connected with better OS in melanoma ( 28 ), non-squamous NSCLC ( 29 ) and ESCC ( 30 ). The specific types of irAE might predict better prognosis as well, such as colitis and diarrhea ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

Association of early immune-related adverse events with treatment efficacy of neoadjuvant Toripalimab in resectable advanced non-small cell lung cancer

Tao,

Li,

Liu

et al. 2023

Front. Oncol.

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BackgroundNeoadjuvant immunotherapy with anti-PD-1 was proved promising in resectable non-small cell lung cancer (NSCLC). Immune-related adverse events (irAEs) have been preliminarily implicated their association with treatment efficacy. Here we elucidated the early onset of irAEs associated with better clinical outcomes in a prospective study (Renaissance study).MethodsWe conducted the prospective study of NSCLC patients treated by neoadjuvant Toripalimab (240mg, every 3 weeks) plus double platinum-based chemotherapy from December 2020 to March 2022 at Peking University Cancer Hospital. Patients were enrolled if they have resectable IIB-IIIB NSCLC without EGFR/ALK mutation. Data were analyzed to explore the relationship between clinical outcome and irAEs after neoadjuvant treatment. A multidisciplinary team including physicians, surgeons, and radiologists, confirmed the irAEs according to the clinical manifestation. The relationship between irAEs and pathological outcomes was analyzed. The Renaissance study was approved by the Peking University Ethic board (2020YJZ58) and registered at https://clinicaltrials.gov/ as NCT04606303.ResultsFifty-five consecutive patients were enrolled with a male-to-female ratio of 10:1, the median age was 62 years old (IQR: 45-76), of which 44 patients (80%) were diagnosed with squamous cell carcinoma. Forty-eight of 55 patients finally received thoracic surgery with a median preoperative waiting time of 67 days (IQR 39-113 days). Pathological results demonstrated that 31 (64.6%) patients achieved major pathological response (MPR) and 24 (50.0%) achieved complete pathological response (pCR). Among 48 patients who received R0 resection, immunotherapy-related thyroid dysfunction, rash/pruritus and enteritis occurred in 11 patients (22.9%), 7 patients (14.6%), and 1 patient (2.1%), respectively. Six patients (54.5%) with thyroid dysfunction achieved MPR with 5 (45.5%) achieved pCR, and a median time to onset was 45 days (IQR 21-91 days). Six patients (85.7%) with rash or pruritus achieved MPR and 5 patients (71.4%) achieved pCR, with median time to onset being 8 days (IQR 6-29 days). Furthermore, irAEs had no significant influence on operation time (170.6 min vs 165.7 min, P=0.775), intraoperative blood loss (67.4 mL vs 64.3 mL, P=0.831) and preoperative waiting time (93 days vs 97 days, P=0.630) when comparing with patients without irAEs (Figure 1).ConclusionThe immunotherapy-related rash is potentially associated with pathological outcomes in NSCLC patients after neoadjuvant chemo-immunotherapy, suggesting easy-to-find irAEs, such as rash, can be used as indicators to predict response to neoadjuvant chemo-immunotherapy.Clinical trial registrationclinicaltrials.gov/, identifier NCT04606303.

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“…ICIs are immunotherapies that target immune cell surface checkpoints and enhance immunity through the use of antibodies to ‘tumor escape’, ultimately leading to an antitumor response by turning off the immune system’s braking mechanisms. 43–47 An increasing number of studies have demonstrated the efficacy and safety of ICIs in patients with ESCC. In a phase III clinical trial of advanced ESCC second-line therapy (RATIONALE-302, NCT03430843), the use of tislelizumab was associated with improved OS and better safety compared to chemotherapy alone.…”

Section: Discussionmentioning

confidence: 99%

Retrospective study of the combination of TP and PF regimens with or without immune checkpoint inhibitors for the first-line treatment of locally advanced or advanced esophageal squamous cell carcinoma

et al. 2023

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Objective: To investigate the efficacy and safety differences between the cisplatin + paclitaxel (TP) and cisplatin + fluorouracil (PF) regimens in combination with or without immune checkpoint inhibitors (ICIs) in advanced esophageal squamous cell carcinoma (ESCC) first-line treatment and prognostic factors. Methods: We selected the medical records of patients with late stage ESCC admitted to the hospital between 2019 and 2021. Based on the first-line treatment regimen, control groups were divided into chemotherapy plus ICIs ( n = 243) and non-ICIs ( n = 171), 119 (49%) in the TP + ICIs group, 124 (51%) in the PF + ICIs group, 83 (48.5%) in the TP group, and 88 (51.5%) in the PF group in the control group. We analyzed and compared factors related to efficacy, safety, or response to toxicity and prognosis across four subgroups. Results: The overall objective response rate (ORR) and disease control rate (DCR) of the TP plus ICIs group were 42.1% (50/119) and 97.5% (116/119), respectively, which were 6.6% and 7.2% higher than those of the PF plus ICIs group. Patients in the TP combined with ICIs group had higher overall survival (OS) and progression-free survival (PFS) than those in the PF combined with ICIs group [hazard ratio (HR) = 1.702, 95% confidence interval (CI): 0.767–1.499, p = 0.0167 and HR = 1.158, 95% CI: 0.828–1.619, p = 0.0055] ORR and DCR were 15.7% (13/83) and 85.5% (71/83) in the TP chemotherapy alone group, significantly higher than the PF group [13.6% (12/88) and 72.2% (64/88)] ( p < 0.05), OS and PFS were also better in patients treated with TP regimen chemotherapy than PF (HR = 1.173, 95% CI: 0.748–1.839, p = 0.0014 and HR = 0.1.245, 95% CI: 0.711–2.183, p = 0.0061). Furthermore, following the combination of TP and PF diets with ICIs, the OS of the patients was higher than that of the group treated with chemotherapy alone (HR = 0.526, 95% CI: 0.348–0.796, p = 0.0023 and HR = 0.781, 95% CI: 0.0.491–1.244, p < 0.001). Regression analysis showed that the neutrophil-to-lymphocyte ratio (NLR), the control nuclear status score (CONUT), and the systematic immune inflammation index (SII) were independent prognostic factors for the efficacy of immunotherapy ( p < 0.05). The overall incidence of treatment-associated adverse events (TRAEs) was 79.4% (193/243) and 60.8% (104/171) in the experimental and control groups, respectively, and there was no statistically significant difference in TRAEs between TP + ICIs (80.6%) and PF + ICIs (78.2%) (61.4%) and PF groups (60.2%) ( p > 0.05). Overall, 21.0% (51/243) of patients in the experimental group experienced immune-related adverse events (irAEs), and all of these adverse effects were tolerated or remitted following drug treatment without affecting follow-up. Conclusion: The TP regimen was associated with better PFS and OS with or without ICIs. Furthermore, high CONUT scores, high NLR ratios, and high SII were found to be associated with poor prognosis in combination immunotherapy.

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Correlation between immune‑related adverse events and treatment efficacy of anti‑PD1 immunotherapy in patients with esophageal squamous cell carcinoma

Cited by 5 publications

References 34 publications

Association of Baseline Tumor-Specific Neoantigens and CD8⁺ T-Cell Infiltration With Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors

Association of Baseline Tumor-Specific Neoantigens and CD8⁺ T-Cell Infiltration With Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors

Association of early immune-related adverse events with treatment efficacy of neoadjuvant Toripalimab in resectable advanced non-small cell lung cancer

Retrospective study of the combination of TP and PF regimens with or without immune checkpoint inhibitors for the first-line treatment of locally advanced or advanced esophageal squamous cell carcinoma

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Correlation between immune‑related adverse events and treatment efficacy of anti‑PD1 immunotherapy in patients with esophageal squamous cell carcinoma

Cited by 5 publications

References 34 publications

Association of Baseline Tumor-Specific Neoantigens and CD8+ T-Cell Infiltration With Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors

Association of Baseline Tumor-Specific Neoantigens and CD8+ T-Cell Infiltration With Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors

Association of early immune-related adverse events with treatment efficacy of neoadjuvant Toripalimab in resectable advanced non-small cell lung cancer

Retrospective study of the combination of TP and PF regimens with or without immune checkpoint inhibitors for the first-line treatment of locally advanced or advanced esophageal squamous cell carcinoma

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Product

Resources

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Association of Baseline Tumor-Specific Neoantigens and CD8⁺ T-Cell Infiltration With Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors

Association of Baseline Tumor-Specific Neoantigens and CD8⁺ T-Cell Infiltration With Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors