scholarly journals Digital Quantification of Tumor PD-L1 Predicts Outcome of PD-1-Based Immune Checkpoint Therapy in Metastatic Melanoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Jan-Malte Placke ◽  
Camille Soun ◽  
Jenny Bottek ◽  
Rudolf Herbst ◽  
Patrick Terheyden ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Cox Regression ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Therapy Outcome ◽  
Tissue Samples ◽  
Pre Treatment ◽  
Digital Quantification

BackgroundPD-1-based immune checkpoint blockade (ICB) is a highly effective therapy in metastatic melanoma. However, 40-60% of patients are primarily resistant, with valid predictive biomarkers currently missing. This study investigated the digitally quantified tumor PD-L1 expression for ICB therapy outcome prediction.Patients and MethodsTumor tissues taken prior to PD-1-based ICB for unresectable metastatic disease were collected within the prospective multicenter Tissue Registry in Melanoma (TRIM). PD-L1 expression (clone 28-8; cut-off=5%) was determined by digital and physician quantification, and correlated with therapy outcome (best overall response, BOR; progression-free survival, PFS; overall survival, OS).ResultsTissue samples from 156 patients were analyzed (anti-PD-1, n=115; anti-CTLA-4+anti-PD-1, n=41). Patients with PD-L1-positive tumors showed an improved response compared to patients with PD-L1-negative tumors, by digital (BOR 50.5% versus 32.2%; p=0.026) and physician (BOR 54.2% versus 36.6%; p=0.032) quantification. Tumor PD-L1 positivity was associated with a prolonged PFS and OS by either digital (PFS, 9.9 versus 4.6 months, p=0.021; OS, not reached versus 13.0 months, p=0.001) or physician (PFS, 10.6 versus 5.6 months, p=0.051; OS, not reached versus 15.6 months, p=0.011) quantification. Multivariable Cox regression revealed digital (PFS, HR=0.57, p=0.007; OS, HR=0.44, p=0.001) and physician (OS, HR=0.54, p=0.016) PD-L1 quantification as independent predictors of survival upon PD-1-based ICB. The combination of both methods identified a patient subgroup with particularly favorable therapy outcome (PFS, HR=0.53, p=0.011; OS, HR=0.47, p=0.008).ConclusionPre-treatment tumor PD-L1 positivity predicted a favorable outcome of PD-1-based ICB in melanoma. Herein, digital quantification was not inferior to physician quantification, and should be further validated for clinical use.

LAG-3 expression on peripheral blood cells identifies patients with poorer outcomes after immune checkpoint blockade

2021 ◽  
Vol 13 (608) ◽  
pp. eabf5107
Author(s):  
Ronglai Shen ◽  
Michael A. Postow ◽  
Matthew Adamow ◽  
Arshi Arora ◽  
Margaret Hannum ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Peripheral Blood ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Clinical Activity ◽  
Multiparametric Flow Cytometry ◽  
Mutation Burden ◽  
Blocking Antibodies

Immune checkpoint blocking antibodies are a cornerstone in cancer treatment; however, they benefit only a subset of patients and biomarkers to guide immune checkpoint blockade (ICB) treatment choices are lacking. We designed this study to identify blood-based correlates of clinical outcome in ICB-treated patients. We performed immune profiling of 188 ICB-treated patients with melanoma using multiparametric flow cytometry to characterize immune cells in pretreatment peripheral blood. A supervised statistical learning approach was applied to a discovery cohort to classify phenotypes and determine their association with survival and treatment response. We identified three distinct immune phenotypes (immunotypes), defined in part by the presence of a LAG-3+CD8+ T cell population. Patients with melanoma with a LAG+ immunotype had poorer outcomes after ICB with a median survival of 22.2 months compared to 75.8 months for those with the LAG− immunotype (P = 0.031). An independent cohort of 94 ICB-treated patients with urothelial carcinoma was used for validation where LAG+ immunotype was significantly associated with response (P = 0.007), survival (P < 0.001), and progression-free survival (P = 0.004). Multivariate Cox regression and stratified analyses further showed that the LAG+ immunotype was an independent marker of outcome when compared to known clinical prognostic markers and previously described markers for the clinical activity of ICB, PD-L1, and tumor mutation burden. The pretreatment peripheral blood LAG+ immunotype detects patients who are less likely to benefit from ICB and suggests a strategy for identifying actionable immune targets for further investigation.

scholarly journals Prediction of Immune-Checkpoint Blockade Monotherapy Response in Patients with Melanoma Based on Easily Accessible Clinical Indicators

2020 ◽  
Author(s):  
Hwa Kyung Byun ◽  
Jeesuk Chang ◽  
Minkyu Jung ◽  
Woong Sub Koom ◽  
Kee Yang Chung ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Risk Stratification ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Cox Regression ◽  
Immune Checkpoint Blockade ◽  
Clinical Activity ◽  
Clinical Indicators ◽  
Cox Regression Analysis ◽  
Cns Metastasis

Abstract Background: Immune checkpoint blocker (ICB) has shown significant clinical activity in melanoma. However, there are no clinically approved biomarkers to aid patient selection. We aimed to identify patients with advanced or metastatic melanoma who are likely to benefit from ICB monotherapy using easily accessible clinical indicators. Methods: We retrospectively reviewed the records of 134 patients with advanced or metastatic melanoma who received ICB monotherapy between 2014 and 2018. Prognostic factors of overall survival (OS) and progression-free survival (PFS) were determined using Cox regression analysis. Results: During the median follow-up of 13.7 months, the median OS and PFS were 18.4 and 3.4 months, respectively. Visceral/central nervous system (CNS) metastasis (OS: adjusted hazards ratio [HR], 1.82; p=.014; PFS: HR, 1.59; p=.024), lymphopenia (<1000 cells/µL) within 3 months (OS: HR, 1.89, p=.006; PFS: HR, 1.70; p=.010), and elevated baseline lactate dehydrogenase (LDH) level (OS: HR, 2.61; p<.001; PFS: HR, 2.66; p<.001) were independent prognostic factors for both poor OS and PFS. Development of immune-related adverse events (irAE; e.g., hypothyroidism or vitiligo) within 6 months showed a trend toward better OS in multivariate analysis (HR, 0.37; p=.058). Patients with normal LDH levels and no visceral/CNS metastasis had a substantially better OS than the others (median, 40.4 vs. 13.6 months; p<.001). Among others, patients who developed irAE within 6 months achieved long-term OS (median, 43.6 vs. 13.1 months; p=.008). A decision tree was suggested using four risk factors, and the risk stratification provided significant distinction between the survival curves. Conclusion: The four easily accessible clinical indicators associated with better treatment outcomes after ICB monotherapy in patients with advanced or metastatic melanoma were LDH level, the extent of disease, lymphopenia, and irAE. The combined use of these indicators can be clinically useful in improving risk stratification of patients treated with ICB monotherapy.

scholarly journals Immune Checkpoint Blockade induces peripheral cytotoxicity and persistence of large effector CD8+ T cell clones

2020 ◽  
Author(s):  
RA Watson ◽  
O Tong ◽  
R Cooper ◽  
CA Taylor ◽  
A Verge de Los Aires ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Sequencing Data ◽  
Clone Size ◽  
Cell Clones ◽  
Anti Cancer ◽  
Pre Treatment

ABSTRACTImmune checkpoint blockers (ICB) exert their anti-cancer effects via CD8+ T cells, although how responses vary over sub-populations and across clones is incompletely understood. We performed single-cell RNA-sequencing of CD8+ T cells and their receptors pre and post ICB across eight patients, integrating results with bulk-sequencing data (n=169). We identify seven phenotypic subsets with divergent sensitivity to ICB, finding the effector subset demonstrates the most pronounced changes. ICB response was related to clone size, with small and large clones markedly differing in the magnitude and immunological relevance of regulated genes. ICB upregulates mitotic pathways and promotes expansion and survival of larger, more cytotoxic clones. Notably, baseline cytotoxicity, but not correlates of mitosis, associated with progression-free survival; highlighting the importance of the pre-treatment CD8+ immune landscape in long-term response. This work further advances understanding of the molecular determinants of ICB response and assists in the search for peripheral prognostic biomarkers.

scholarly journals Treatment with therapeutic anticoagulation is not associated with immunotherapy response in advanced cancer patients

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Paul Johannet ◽  
Amelia Sawyers ◽  
Nicholas Gulati ◽  
Douglas Donnelly ◽  
Samuel Kozloff ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Advanced Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Coagulation Cascade ◽  
Advanced Cancer Patients ◽  
Clinical Endpoints

Abstract Background Recent preclinical data suggest that there may be therapeutic synergy between immune checkpoint blockade and inhibition of the coagulation cascade. Here, we investigate whether patients who received immune checkpoint inhibitors (ICI) and were on concomitant anticoagulation (AC) experienced better treatment outcomes than individuals not on AC.Affiliation: Kindly confirm if corresponding authors affiliation is identified correctly.The corresponding author's affiliation is correct. Methods We studied a cohort of 728 advanced cancer patients who received 948 lines of ICI at NYU (2010–2020). Patients were classified based on whether they did (n = 120) or did not (n = 828) receive therapeutic AC at any point during their treatment with ICI. We investigated the relationship between AC status and multiple clinical endpoints including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and the incidence of bleeding complications.Affiliations: Journal instruction requires a country for affiliations; however, this is missing in affiliations 1 to 5. Please verify if the provided country is correct and amend if necessary.The country is correct for all affiliations (1 - 5). Results Treatment with AC was not associated with significantly different BOR (P = 0.80), ORR (P =0.60), DCR (P =0.77), PFS (P = 0.59), or OS (P =0.64). Patients who received AC were significantly more likely to suffer a major or clinically relevant minor bleed (P = 0.05). Conclusion AC does not appear to impact the activity or efficacy of ICI in advanced cancer patients. On the basis of our findings, we caution that there is insufficient evidence to support prospectively evaluating the combination of AC and immunotherapy.

scholarly journals Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
James A. Hutchinson ◽  
Katharina Kronenberg ◽  
Paloma Riquelme ◽  
Jürgen J. Wenzel ◽  
Gunther Glehr ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Serum Antibody ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Effector Memory ◽  
Specific Memory ◽  
Immune Mediated ◽  
Antibody Titres ◽  
Pre Treatment ◽  
After Cancer

AbstractTreatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations.

scholarly journals Downregulation and Prognostic Performance of MicroRNA 224 Expression in Prostate Cancer

2013 ◽  
Vol 59 (1) ◽  
pp. 261-269 ◽  
Author(s):  
Konstantinos Mavridis ◽  
Konstantinos Stravodimos ◽  
Andreas Scorilas
Keyword(s):  
Prostate Cancer ◽  
Cox Regression ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Prognostic Indicator ◽  
Disease Stage ◽  
Clinical Value ◽  
Prostate Tumors ◽  
Tissue Samples ◽  
Total Rna

INTRODUCTION The extensive use of prostate-specific antigen as a general prostate cancer biomarker has introduced the hazards of overdiagnosis and overtreatment. Recent studies have revealed the immense biomarker capacity of microRNAs (miRNAs) in prostate cancer. The aim of this study was to analyze the expression pattern of miR-224, a cancer-related miRNA, in prostate tumors and investigate its clinical utility. METHODS Total RNA was isolated from 139 prostate tissue samples. After the polyadenylation of total RNA by poly(A) polymerase, cDNA was synthesized with a suitable poly(T) adapter. miR-224 expression was assessed by quantitative real-time PCR and analyzed with the comparative quantification cycle method, Cq(2−ΔΔCq). We performed comprehensive biostatistical analyses to explore the clinical value of miR-224 in prostate cancer. RESULTS miR-224 expression was significantly downregulated in malignant samples compared with benign samples (P &lt; 0.001). Higher miR-224 expression levels were found in prostate tumors that were less aggressive (P = 0.017) and in an earlier disease stage (P = 0.018). Patients with prostate cancer who were positive for miR-224 had significantly enhanced progression-free survival intervals compared with miR-224–negative patients (P = 0.021). Univariate bootstrap Cox regression confirmed that miR-224 was associated with favorable prognosis (hazard ratio 0.314, P = 0.013); nonetheless, multivariate analysis, adjusted for conventional markers, did not identify miR-224 as an independent prognostic indicator. CONCLUSIONS miR-224 is aberrantly expressed in prostate cancer. Its assessment by cost-effective quantitative molecular methodologies could provide a useful biomarker for prostate cancer.

Exploratory biomarker findings from cohort 2 of MODUL: An adaptable, phase 2, signal-seeking trial of fluoropyrimidine + bevacizumab ± atezolizumab maintenance therapy for BRAFwt metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3570-3570
Author(s):  
Josep Tabernero ◽  
Axel Grothey ◽  
Dirk Arnold ◽  
Michel Ducreux ◽  
Peter J. O'Dwyer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Maintenance Treatment ◽  
Predictive Biomarkers ◽  
Experimental Treatment ◽  
Progression Free Survival ◽  
Phase 2 ◽  
First Line ◽  
Tissue Samples ◽  
First Line Therapy

3570 Background: MODUL is an adaptable, phase 2, signal-seeking trial testing novel agents as first-line therapy for predefined subgroups of patients with metastatic colorectal cancer (mCRC). Previously reported findings demonstrated that adding atezolizumab to fluoropyrimidine (FP)/bevacizumab as first-line maintenance treatment after induction with FOLFOX + bevacizumab did not improve efficacy outcomes in BRAFwt mCRC. Given these efficacy results, exploratory assessments on tumour samples were conducted to provide insights into factors that might affect efficacy of maintenance treatment and provide guidance on appropriate therapeutic strategies for BRAFwt mCRC. Methods: In patients with BRAFwt tumours (Cohort 2), experimental treatment was FP/bevacizumab + atezolizumab. Primary efficacy endpoint: progression-free survival (PFS). Overall survival (OS) was a secondary endpoint. Archival tissue samples from 104 patients were analysed by immunohistochemistry (IHC) at HistoGeneX (PD-L1; CD8/GrB/FoxP3). SP142 antibody was used for PD-L1 IHC analysis, which evaluated PD-L1low (IC 0–1) vs PD-L1high (IC > 1) in correlation with PFS and OS in the control and experimental arms. CD8/GrB/FoxP3 triplex staining was also performed to evaluate potential correlations with efficacy. Results: 445 patients with BRAFwt mCRC were randomised (2:1 ratio) to maintenance treatment in Cohort 2. Archival samples from 104 patients were analysed: FP/bevacizumab + atezolizumab (n = 82); FP/bevacizumab (n = 22). The biomarker evaluable population (BEP) for PD-L1 was n = 81 for FP/bevacizumab + atezolizumab [PD-L1low n = 35 (43%); PD-L1high n = 46 (57%)] and n = 22 for FP/bevacizumab [PD-L1low n = 16 (72%); PD-L1high n = 6 (28%)]. The BEP for CD8/GrB was n = 50 for FP/bevacizumab + atezolizumab and n = 16 for FP/bevacizumab. No difference in PFS or OS was observed in the FP/bevacizumab + atezolizumab vs FP/bevacizumab arms for PD-L1high [PFS: HR = 1.5 (95% CI 0.45−4.8), p = 0.51; OS: HR = 1.3 (95% CI 0.38−4.1), p = 0.71] or PD-L1low [PFS: HR = 0.92 (95% CI 0.47−1.8), p = 0.81; OS: HR = 0.78 (95% CI 0.4−1.5), p = 0.48]. Similar results were observed with CD8/GrBhigh [PFS: HR = 0.73 (95% CI 0.27−2.0), p = 0.55; OS: HR = 0.66 (95% CI 0.24−1.8), p = 0.44], CD8/GrBlow [PFS: HR = 1.0 (95% CI 0.42–2.5), p = 0.96; OS: HR = 0.73 (95% CI 0.3–1.8), p = 0.5], FoxP3high [PFS: HR = 0.97 (95% CI 0.37−2.5), p = 0.95; OS: HR = 0.95 (95% CI 0.36−2.5), p = 0.91] and FoxP3low [PFS: HR = 0.73 (95% CI 0.29−1.9), p = 0.53; OS: HR = 0.5 (95% CI 0.19−1.3), p = 0.18]. Conclusions: These findings suggest that PD-L1, CD8/GrB and FoxP3 might not be predictive biomarkers in BRAFwt mCRC. Further analyses are needed to further evaluate potential predictive and prognostic factors of response in this setting. Clinical trial information: NCT02291289.

scholarly journals Publisher Correction: Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma

2018 ◽  
Vol 24 (12) ◽  
pp. 1942-1942 ◽  
Author(s):  
Noam Auslander ◽  
Gao Zhang ◽  
Joo Sang Lee ◽  
Dennie T. Frederick ◽  
Benchun Miao ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Prediction Of Response ◽  
Robust Prediction

scholarly journals 240 Discovery of biomarkers of resistance to immune checkpoint blockade in non-small-cell lung cancer (NSCLC) using high-plex digital spatial profiling

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A258-A258
Author(s):  
Myrto Moutafi ◽  
Sandra Martinez-Morilla ◽  
Prajan Divakar ◽  
Ioannis Vathiotis ◽  
Niki Gavrielatou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Biomarker Discovery ◽  
Univariate Analysis ◽  
Predictive Biomarkers ◽  
Protein Detection ◽  
Statistical Testing ◽  
Multiple Testing Correction ◽  
Stromal Compartment ◽  
Pre Treatment

BackgroundDespite the clinical effectiveness of Immune Checkpoint Inhibitors (ICI) in lung cancer, only around 20% remain disease free at 5 years. Predictive biomarkers for ICIs are neither sensitive nor specific. Here, we used the GeoMx Digital Spatial Profiler (DSP) (NanoString, Inc.) to analyze high-plex protein in a quantitative and spatially resolved manner from single formalin-fixed paraffin embedded tissue sections toward the goal of identification of new biomarkers with better predictive value.MethodsPre-treatment samples from 56 patients with NSCLC treated with ICI were collected, represented in Yale tissue microarray 471 (YTMA471), and analyzed. A panel of 71 photocleavable oligonucleotide-labeled primary antibodies (NanoString Human IO panel) was used for protein detection. Protein expression was measured in 4 molecularly defined tissue compartments, defined by fluorescence co-localization (tumor [panCK+], leukocytes [CD45+/CD68-], macrophages [CD68+] and an aggregate stromal immune cell compartment, defined as the sum of leukocyte and macrophage expression [panCK-/CD45+/CD68+]) generating 284 variables representing potential predictive biomarkers. Promising candidates were orthogonally validated with Quantitative Immunofluorescence (QIF). Pre-treatment samples from 40 patients with NSCLC (YTMA404) that received ICI, and 174 non-ICI treated operable NSCLC patients (YTMA423) were analyzed to provide independent cohort validation. All statistical testing was performed using a two-sided significance level of α=0.05 and multiple testing correction (Benjamini-Hochberg method, FDR < 0.1).ResultsInitial biomarker discovery on 284 protein variables were generated by univariate analysis using continuous log-scaled data. High PD-L1 expression in tumor cells predicted longer survival (PFS; HR 0.67, p=0.017) and validated the training cohort. We found 4 markers associated with PFS, and 3 with OS in the stromal compartment. Of these, expression of CD66b in stromal immune cells predicted significantly shorter OS (HR 1.31, p=0.016) and shorter PFS (HR 1.24, p = 0.04). Tertile analysis using QIF on all three tissue cohorts for CD66b expression, assessed by QIF, showed that CD66b was indicative but not prognostic for survival [discovery cohort, YTMA471 (OS; HR 3.02, p=0.013, PFS; HR 2.38, p=0.023), validation cohort; YTMA404 (OS; HR 2.97, p=0.018, PFS; HR 1.85, p=0.1), non-ICI treated cohort YTMA423 (OS; HR 1.02, p>0.9, PFS; HR 0.72, p=0.4)].ConclusionsUsing the DSP technique, we have discovered that CD66b expressed in the stromal immune [panCK-/CD45+/CD68+] molecular compartment is associated with resistance to ICI therapy in NSCLC. This observation was validated by an orthogonal approach in an independent ICI treated NSCLC cohort. Since CD66b identifies neutrophils, further studies are warranted to characterize the role of neutrophils in ICI resistance.AcknowledgementsDr Moutafi is supported by a scholarship from the Hellenic Society of Medical Oncologists (HESMO)Ethics ApprovalAll tissue samples were collected and used under the approval from the Yale Human Investigation Committee protocol #9505008219 with an assurance filed with and approved by the U.S. Department of Health and Human Services

scholarly journals Checkpoint-blocker induced autoimmunity is associated with pretreatment T cell expression profiles and favourable outcome in melanoma

2020 ◽  
Author(s):  
W. Ye ◽  
A Olsson-Brown ◽  
R. A. Watson ◽  
V. T. F. Cheung ◽  
R. D. Morgan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Outcome ◽  
Adverse Events ◽  
Metastatic Melanoma ◽  
T Cell Receptor ◽  
Immune Checkpoint ◽  
Single Agent ◽  
Cell Receptor ◽  
Pre Treatment

1Abstract1.1BackgroundImmune checkpoint blockers (ICBs) activate CD8+ T cells to elicit anti-cancer activity but frequently lead to immune-related adverse events (irAEs). The relationship of irAE with baseline parameters and clinical outcome is unclear. We investigated associations between irAE development, CD8+ T cell receptor diversity and expression and clinical outcome in a non-trial setting.1.2MethodsPatients ≥18 years old with metastatic melanoma (MM) receiving combination ICB (ipilimumab plus nivolumab – cICB, n=60) or single-agent ICB (nivolumab/pembrolizumab – sICB, n=78) were prospectively recruited. We retrospectively evaluated the impact of irAEs on survival. This analysis was repeated in an independent cohort of MM patients treated at a separate institution (n=210, cICB:74, sICB:136). We performed RNA sequencing of CD8+ T cells isolated from patients prior to treatment, analysing T cell receptor clonality differential transcript expression according to irAE development.1.3Results48.6% of patients experienced treatment-related irAEs within the first 5 cycles of treatment. Development of irAE prior to the 5th cycle of ICB was associated with longer progression-free and overall survival (PFS, OS) in the primary cohort (log-rank test, PFS: P=0.00034; OS: P<0.0001), replicated in the secondary cohort (OS: P=0.00064). Across cohorts median survival for those patients not experiencing irAE was 14.4 (95% CI:9.6-19.5) months vs not-reached (95% CI:28.9 - Inf), P=3.0×10−7. Pre-treatment performance status and neutrophil count, but not BMI, were additional predictors of clinical outcome. Analysis of CD8+ T cells from 128 patients demonstrated irAE development was associated with increased T cell receptor diversity post-treatment (P=4.3×10−5). Development of irAE in sICB recipients was additionally associated with baseline differential expression of 224 transcripts (FDR<0.1), enriched in pro-inflammatory pathway genes including CYP4F3 and PTGS2.1.4ConclusionsEarly irAE development post-ICB is strongly associated with favourable survival in MM and increased diversity of peripheral CD8+ T cell receptors after treatment. irAE post-sICB is associated with pre-treatment upregulation of inflammatory pathways, indicating irAE development may reflect baseline immune activation states.Key messageImmune-related adverse events (irAEs) commonly occur in patients with metastatic melanoma treated with immune checkpoint blockade (ICB) therapy. In real world setting we find development of early irAEs post-ICB treatment is associated with survival benefit, indicative of a shared mechanism with anti-tumour efficacy. CD8+ T cells from patients who develop irAE show increased receptor diversity, and pre-treatment samples from patients who develop irAE post single-agent anti-PD1 show over-expression of inflammatory pathways, indicating baseline immune state can determine irAE development.

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