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Keratinocyte differentiation antigen-specific T cells in immune checkpoint inhibitor-treated NSCLC patients are associated with improved survival.

ABSTRACT: Immune checkpoint inhibitors (ICIs) have improved the survival of patients with non-small cell lung cancer (NSCLC) by reinvigorating tumor-specific T cell responses. However, the specificity of such T cells and the human leukocyte antigen (HLA)-associated epitopes recognized, remain elusive. In this study, we identified NSCLC T cell epitopes of recently described NSCLC-associated antigens, termed keratinocyte differentiation antigens. Epitopes of these antigens were presented by HLA-A 03:01 and HLA-C 04:01 and were associated with responses to ICI therapy. Patients with CD8⁺ T cell responses to these epitopes had improved overall and progression-free survival. T cells specific for such epitopes could eliminate HLA class I-matched NSCLC cells ex vivo and were enriched in patient lung tumors. The identification of novel lung cancer HLA-associated epitopes that correlate with improved ICI-dependent treatment outcomes suggests that keratinocyte-specific proteins are important tumor-associated antigens in NSCLC. These findings improve our understanding of the mechanisms of ICI therapy and may help support the development of vaccination strategies to improve ICI-based treatment of these tumors.

SUBMITTER: Berner F

PROVIDER: S-EPMC8632109 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Keratinocyte differentiation antigen-specific T cells in immune checkpoint inhibitor-treated NSCLC patients are associated with improved survival.

Berner Fiamma F Niederer Rebekka R Luimstra Jolien J JJ Pop Oltin Tiberiu OT Jochum Ann-Kristin AK Purde Mette-Triin MT Hasan Ali Omar O Bomze David D Bauer Jens J Freudenmann Lena Katharina LK Marcu Ana A Wolfschmitt Eva-Maria EM Haen Sebastian S Gross Thorben T Dubbelaar Marissa Lisa ML Abdou Marie-Therese MT Baumgaertner Petra P Appenzeller Christina C Cicin-Sain Caroline C Lenz Tobias T Speiser Daniel E DE Ludewig Burkhard B Driessen Christoph C Jörger Markus M Früh Martin M Jochum Wolfram W Cozzio Antonio A Rammensee Hans-Georg HG Walz Juliane J Neefjes Jacques J Flatz Lukas L

Oncoimmunology 20211127 1

Immune checkpoint inhibitors (ICIs) have improved the survival of patients with non-small cell lung cancer (NSCLC) by reinvigorating tumor-specific T cell responses. However, the specificity of such T cells and the human leukocyte antigen (HLA)-associated epitopes recognized, remain elusive. In this study, we identified NSCLC T cell epitopes of recently described NSCLC-associated antigens, termed keratinocyte differentiation antigens. Epitopes of these antigens were presented by HLA-A 03:01 and ...[more]

PMID: 34858733

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Project description:ImportanceImmune-related adverse events (irAEs) secondary to immune checkpoint inhibitor (ICI) therapy reportedly improve overall survival (OS) in patients with non-small cell lung cancer (NSCLC). However, studies have been small and the association between irAE severity and OS remains poorly defined.ObjectiveTo examine the association between irAEs and their severity with OS in patients with locally advanced or metastatic NSCLC receiving ICIs.Design, setting, and participantsThis retrospective observational cohort study included patients with NSCLC receiving ICIs between March 1, 2014, and November 30, 2021, with follow-up until March 31, 2023. Data analysis was completed April 26, 2023. The Alberta Immunotherapy Database, a provincial, multicenter cohort, was used to capture data from patients receiving ICIs in Alberta, Canada. Participants included 803 patients 18 years or older who received at least 1 cycle of ICI (alone or with chemotherapy), agnostic to treatment line.ExposureDeveloping an irAE mandating delay or discontinuation of ICI therapy and/or systematic corticosteroids for management of toxic effects (hereinafter referred to as clinically meaningful irAEs).Main outcomes and measuresThe primary outcome was association between irAEs and OS according to Kaplan-Meier analysis. Clinically meaningful irAEs were identified. Patients with poor prognosis (survival <3 months) who may have died prior to irAE development were excluded from OS analysis, mitigating immortal time bias. Adjusted Cox proportional hazards regression analyses ascertained variables associated with OS.ResultsAmong the 803 patients included in the analysis, the median age of patients with irAEs was 69.7 (IQR, 63.1-75.2) years and the median age of those without irAEs was 67.5 (IQR, 60.4-73.3) years, with comparable sex distribution (139 of 295 men [47.1%] and 156 of 295 women [52.9%] with irAEs vs 254 of 505 men [50.3%] and 251 of 505 women [49.7%] without irAEs). Mitigating immortal time bias (n = 611), irAEs were associated with OS (median OS with irAEs, 23.7 [95% CI, 19.3-29.1] months; median OS without irAEs, 9.8 [95% CI, 8.7-11.4] months; P < .001). No OS difference was associated with treatment in hospital vs as outpatients for an irAE (median OS, 20.8 [95% CI, 11.7-30.6] vs 25.6 [95% CI, 20.1-29.8] months; P = .33). Developing irAEs remained associated with OS in the total cohort after Cox proportional hazards regression with known prognostic characteristics (hazard ratio, 0.53 [95% CI, 0.40-0.70]; P < .001).Conclusions and relevanceIn this cohort study of 803 patients with locally advanced or metastatic NSCLC receiving ICIs, developing a clinically meaningful irAE was associated with improved OS. This association was not compromised by hospitalization for severe toxic effects. Whether and how ICI therapy resumption after an irAE is associated with OS warrants further study.

Project description:Introduction Immune checkpoint inhibitors (ICIs) produce a broad spectrum of immune-related adverse events (irAEs) affecting various organ systems. While ICIs are established as a therapeutic option in non-small cell lung cancer (NSCLC) treatment, most patients receiving ICI relapse. Additionally, the role of ICIs on survival in patients receiving prior targeted tyrosine kinase inhibitor (TKI) therapy has not been well-defined. Objective To investigate the impact of irAEs, the relative time of occurrence, and prior TKI therapy to predict clinical outcomes in NSCLC patients treated with ICIs. Methods A single center retrospective cohort study identified 354 adult patients with NSCLC receiving ICI therapy between 2014 and 2018. Survival analysis utilized overall survival (OS) and real-world progression free survival (rwPFS) outcomes. Model performance matrices for predicting 1-year OS and 6-month rwPFS using linear regression baseline, optimal, and machine learning modeling approaches. Results Patients experiencing an irAE were found to have a significantly longer OS and rwPFS compared to patients who did not (median OS 25.1 vs. 11.1 months; hazard ratio [HR] 0.51, confidence interval [CI] 0.39- 0.68, P-value <0.001, median rwPFS 5.7 months vs. 2.3; HR 0.52, CI 0.41- 0.66, P-value <0.001, respectively). Patients who received TKI therapy before initiation of ICI experienced significantly shorter OS than patients without prior TKI therapy (median OS 7.6 months vs. 18.5 months; P-value < 0.01). After adjusting for other variables, irAEs and prior TKI therapy significantly impacted OS and rwPFS. Lastly, the performances of models implementing logistic regression and machine learning approaches were comparable in predicting 1-year OS and 6-month rwPFS. Conclusion The occurrence of irAEs, the timing of the events, and prior TKI therapy were significant predictors of survival in NSCLC patients on ICI therapy. Therefore, our study supports future prospective studies to investigate the impact of irAEs, and sequence of therapy on the survival of NSCLC patients taking ICIs.

Project description:BackgroundFor patients with advanced non-small cell lung carcinoma (NSCLC), immune checkpoint inhibitor (ICPI) and chemotherapy (chemo) ICPI represent two distinct first-line standard-of-care regimens without clear and established biomarkers to inform the optimal choice for individual patients. Here, we examined the complementary roles of tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) immunohistochemistry (IHC) to inform first-line therapy using a large real-world (rw) data set.Materials and methodsThe study included patients with NSCLC from an rw de-identified clinico-genomic database. All patients underwent genomic testing using Foundation Medicine's tissue comprehensive genomic profiling assay and PD-L1 IHC assay scored for tumor cell staining (TS).ResultsOf 2165 patients included in the analysis, 150 exhibited durable benefit from first-line ICPI regimens (these patients were enriched for PD-L1 TS ≥50, non-squamous histology, and TMB ≥20 mutations/megabase (muts/Mb)). Comparing low TMB (<10 muts/Mb), high TMB (10-19 muts/Mb), and very high TMB (≥20 muts/Mb) receiving ICPI alone, we observed a stepwise increase in median rwPFS (real world-progression free survival) (6.5, 7.5, 17.2 months) and rwOS (real world-overall survival) (10.1, 11.8, 26.9 months) as TMB increased. In the low PD-L1 (TS <50%) cohort, TMB <20 muts/Mb showed a more favorable rwPFS (HR: 0.56 (95% CI: 0.40 to 0.79)) and rwOS (HR 0.74 (95% CI: 0.58 to 0.96)) on chemoICPI when compared with ICPI alone while the point estimate in rwPFS favored monoICPI in the TMB ≥20 muts/Mb cohort, the CI is wide and does not reach statistical significance (HR: 1.68 (95% CI: 0.52 to 5.48)).ConclusionThis study provides evidence that higher TMB cut-offs, such as 20 muts/Mb, can identify patients with prolonged benefit from ICPI. TMB ≥20 muts/Mb is a potential biomarker that may identify patients in whom an ICPI without chemo could be considered, even in the setting of lower PD-L1 levels. Prospective validation of these findings could increase access to chemo-sparing regimens for the first-line treatment of advanced NSCLC.

Project description:BackgroundOptimal prognostic biomarkers for patients with gastric cancer who received immune checkpoint inhibitor (ICI) are lacking. Inflammatory markers including lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation index (SII) are easily available. However, its correlation with ICI is unknown in gastric cancer. Here, we evaluated the potential association between LMR, PLR, and SII with clinical outcomes in gastric cancer patients undergoing ICI therapy.MethodsWe examined LMR, PLR, SII at baseline, and 6 (± 2) weeks later in 139 patients received ICI therapy between August 2015 and April 2019 at Peking University Cancer Hospital (Beijing, China). Landmark analysis at 6 weeks was conducted to explore the prognostic value of LMR, PLR, and SII on progress-free survival (PFS), and overall survival (OS). A Cox proportional hazards model was used to compute mortality hazard ratios (HRs) for LMR, adjusting for potential confounders including age, sex, ECOG, tumor location, tumor differentiation, tumor stage, line of therapy, and type of anti-PD-1/PD-L1 therapy.ResultsAmong 139 patients, 103 (74.1%) were male, median age was 60 years. Median duration of therapy was 6 cycles. We observed that both LMR at baseline and week 6 were independent prognostic factors. Patients with a higher LMR (≥ 3.5) at baseline or week 6 had superior PFS [baseline: HR 0.58, 95% confidence interval (CI): 0.38-0.91; week 6: HR 0.48, 95% CI: 0.29-0.78] and OS (baseline: HR 0.38, 95% CI: 0.24-0.62; week 6: HR 0.52, 95% CI: 0.31-0.88) compared with patients with a lower LMR (< 3.5). Furthermore, for patients with both LMR ≥ 3.5 at baseline and LMR ≥ 3.5 at week 6 were estimated to have much better PFS (HR 0.41, 95% CI: 0.23-0.72) and OS (HR 0.34, 95% CI: 0.18-0.64) than patients with both LMR < 3.5 at baseline and LMR < 3.5 at week 6.ConclusionsBaseline and early changes in LMR were strongly associated with survival in gastric cancer patients who received ICI therapy, and may serve to identify patients most likely to benefit from ICI.

Dataset Information

Keratinocyte differentiation antigen-specific T cells in immune checkpoint inhibitor-treated NSCLC patients are associated with improved survival.

Publications

Keratinocyte differentiation antigen-specific T cells in immune checkpoint inhibitor-treated NSCLC patients are associated with improved survival.

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