bluuebunny/crossref_metadata_2025_split huggingface dataset:
T cell receptor β-chain repertoire analysis to reveal potential predictive biomarker for the use of immune checkpoint blockade in patients with advanced solid tumors.
Authors: Li Ye , Jiao Shun Chang , Wu Liang Liang , Sun Sheng Jie , Wei Hua Feng , Liao Sheng You 
Published: May 2019

e14152 Background: Immune checkpoint blockade (ICB) targeted to CTLA-4, PD-1, and PD-L1 can promote antitumor T cell immunity and clinical responses. Tracking the dynamic changes of the T Cell Receptor (TCR) Immune Repertoire can reflect the evolution of the immune system in tumor immunotherapy patients, predict the immune response to ICB, and provide high-value information for clinical monitoring of immune function status of cancer patients to make effective clinical decisions. The purpose of this study was to explore the correlation between the peripheral blood TCR repertoire dynamic changes and the immune response of patients with anti-PD-1/PD-L1, and to accurately guide the individualized treatment of immunotherapy. Methods: We sequenced the TCRβ genes from T cells contained in peripheral blood mononuclear cells (PBMCs) from 24 advanced solid tumors patients (PD/7, PR/4, SD/13) treated with immune checkpoint blockade. Peripheral blood samples were collected from baseline, 8-week, and 16-week after treatment for each patient. bioinformatic analysis was used to detect the diversity and clonality changes of TCRβ-CDR3 sequence before and after treatment with ICB in patients, and provide auxiliary technology for further guiding clinical tumor immunotherapy. Results: The analysis result of Chao index showed that the TCR-CDR3 diversity in the PR group was significantly increased after treatment than SD or PD group. (pvalue = 0.001), and the number of CDR3 aa clonotypes also increased significantly (pvalue = 0.012). A total of 61 Vβ gene fragments and 15 Jβ gene fragments were uniquely identified during immunotherapy . There was a significant difference in the number of Vβ gene fragments between baseline samples and after treatment in PR group (pvalue = 0.042). Conclusions: In this project, PBMC samples was used to evaluate the changes of TCR repertoire between before and after treatment with immune checkpoint blockade in advanced solid tumor patients. The immune function status was significantly changed before and after treatment. Patients with PR had significantly increased diversity in TCR repertoire than patients with SD or PD. The results provide T cell receptor β-chain repertoire sequencing and analysis has potential to assess whether immune checkpoint blockade promotes global T cell expansion and/or loss of T cell clonotype diversity, and to identify predictive biomarker for the use of immune checkpoint blockade.
Prospective cardiac function monitoring in immunotherapy-treated patients.
Authors: Aras Mandar A , Cuevas Lauren , Bibby Dwight , Fang Qizhi , Daud Adil , Schiller Nelson B , Tsai Katy K. 
Published: May 2019

e14157 Background: Immune checkpoint inhibitors (ICI) demonstrate activity and long-term benefit in melanoma and other cancers. While certain immune-related toxicities have been well described, cardiac toxicities remain poorly characterized. We sought to characterize changes in cardiac function in advanced melanoma patients (pts) starting ICI treatment. Methods: A prospective, observational, single institution trial was performed to monitor cardiac function in pts receiving ICI. Eligible pts were adults with stage III/IV melanoma and ECOG 0-1, determined safe to exercise and without unstable cardiac symptoms. Pts received PD-1 monotherapy or combination ipilimumab/pembrolizumab. Rest and exercise stress cardiac testing (EKG, echocardiography) was conducted at baseline, at 3 months (mo), and at 6 mo. Patient-reported surveys were administered at baseline and at 6 mo. Results: Between Feb 2018 to Jan 2019, we prospectively identified 8 pts who completed baseline cardiac testing. As of Feb 2019, 6 pts completed 3-mo testing, and 4 completed 6-mo testing. Mean age was 57 years (range 34-68). 5 pts received pembrolizumab or nivolumab monotherapy, and 3 received ipilimumab/pembrolizumab. Resting LVOT-VTI decreased from 23.1±2.8 cm at baseline to 20.7±2.8cm at 6 mo (p = 0.047). Maximum HR at peak exercise decreased over time from 149.7±13 bpm at baseline to 114±20.5 bpm at 6 mo (p = 0.085) with concurrent decrease in maximum BP. Enrollment is ongoing. Conclusions: These data suggest measurable changes in left ventricular cardiac function at rest over time, in a prospective cohort of ICI-treated advanced melanoma pts. Further, we observe progressive loss of chronotropic and blood pressure response to exercise. These data have important implications for cancer survivorship in the era of immunotherapy. Updated data to be presented at the meeting include correlation with patient-reported symptoms. [Table: see text]
Host metabolic factors and prognosis in patients treated with immune checkpoint inhibitors for advanced malignancies.
Authors: Biello Federica , Audisio Marco , Genestroni Silvia , Borra Gloria , D'Avanzo Francesca , Lacidogna Gaetano , Sponghini Andrea Pietro , Rondonotti David , Forti Laura , Vignani Francesca , Barone Adesi Francesco , Di Maio Massimo , Sica Antonio , Gennari Alessandra 
Published: May 2019

e14162 Background: It is well established that an altered host metabolism has an impact on cancer outcome, possibly mediated by several mechanisms, including hyperglicaemia, hyperinsulinemia and presence of chronic inflammation. The aim of our analysis was to evaluate the correlation between host metabolism and clinical outcome in patients with advanced melanoma, kidney and non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (anti-CTLA4, anti PD1 and anti PDL1). Methods: The relationship between presence of type 2 diabetes mellitus (DMII) at baseline and outcome was assessed in 187 patients treated with immune checkpoint inhibitors in two cancer centers. Progression Free Survival (PFS) and Overall Survival (OS) were calculated by Kaplan-Meier estimation; multivariate Cox analysis was performed according to age, gender, BMI (normal < 25 kg/m2, overweight 25-30 kg/m2, obese > 30 kg/m2), type of cancer and line of treatment. Results: One-hundred-sixty-eight patients were available for our analysis. Twenty-eight patients (17%) were diabetic at baseline. Median age was 65 (range 25-80); 83 patients were males (49%); 82 (48%) had advanced melanoma, 83 (49%) NSCLC and 3 (3%) kidney cancer. One-hundred-two (60%) patients had BMI < 25, 51 (30%) were overweight and 16 (10%) were obese. The first line of treatment was immunotherapy in 83 (49%) patients. By univariable analysis median PFS was 4.2 months in non diabetics vs 6.4 in diabetics patients (HR 0.95; 95%CI 0.58-1.58); median OS was 6.17 and 9.1 months, respectively (HR 1.00; 95%CI 0.58-1.75). At multivariable analysis, taking into account DMII, BMI, sex, age, line of treatment and type of cancer, we found that BMI ≤25 was associated with a two fold increase in risk of progression (PD) or death (p = 0.005), whereas patients who received immunotherapy as second or subsequent line had a two fold increase in risk of PD or death (p = 0.003). Conclusions: The results of our analysis show that in patients with advanced cancer treated with immune checkpoint inhibitors, the presence of DMII does not adversely affect the clinical outcome. Conversely, lower BMI was associated with a significantly worse PFS and OS, independently from type of cancer, age and gender. As expected, patients who received immunotherapy in later lines of treatment had a significantly shorter survival.
Incidence and characteristics of emergency department presentations during immune checkpoint inhibitor therapy.
Authors: Smith Daniel Arnold , Laukamp Kai , Campbell Melanie , Devita Robert , Nelson Ariel Ann , Hoimes Christopher J. , Ramaiya Nikhil H. 
Published: May 2019

e14164 Background: Immune checkpoint inhibitors (ICIs) have emerged as a novel class of anticancer agents with unique response and toxicity profiles. Oncology patients undergoing ICI therapy can present acutely with cancer- or treatment-related complications, but knowledge of these acute clinical presentations is limited. The objective of this study was to investigate the features of emergency department (ED) presentations of patients undergoing ICI therapy. Methods: A retrospective chart review was performed of 1044 adult oncology patients at a single institution from 2010-2018 who underwent treatment with one or more ICI. The number of patient visits to the ED during and up to one month following ICI treatment was recorded, in addition to various clinical and demographic data. These data were compared based on stratification by number of ED visits (0 visits, 1 visit, or ≥2 visits) using Likelihood Ratio Chi-Square and Mann–Whitney U tests. Results: Mean age for the 1044 patients receiving ICI therapy was 64±13 years, with 57% males and 43% females. Primary cancer distribution included 42.0% lung, 24.2% melanoma, 6.9% head & neck, 5.1% kidney, 4.0% bladder, and 17.8% other malignancy. 83.4% of patients were treated with a single ICI, 14.9% with 2 ICIs, and 1.2% with 3-4 ICIs. 56.0% of patients had no ED visits during their treatment duration, 27.0% had 1 ED visit, and 17.0% had ≥2 ED visits. Patients with lung, kidney, and bladder cancer were more likely to present to the ED (p = < 0.001). Black ethnicity was the only demographic feature associated with more ED visits (p = 0.017). Patients receiving ≥2 ICIs or monotherapy with nivolumab, pembrolizumab, or atezolizumab more frequently presented to the ED compared to other ICIs (p = < 0.001). Patients with 1 or ≥2 ED visits had longer durations of ICI therapy (136±12 days and 216±15 days, respectively) compared to patients with no ED visits (127±8 days) (p = < 0.001). Patients with no ED visits also demonstrated better overall survival (p = < 0.001). Conclusions: More frequent ED visits during ICI therapy is statistically associated with several key clinical factors, including primary cancer type, ethnicity, specific ICI agent, ICI therapy duration, and overall survival.
An immune response-associated genomic model to predict early resistance to PD1/PD-L1 blockade among real-world TMB-high Chinese cancer patients.
Authors: Xu Qiang , Lu Shichun , Wang Guan , Wei Jinwang , Wu Angela , Dai Chun , Cai Xin , Luo Ying , Sun Wending 
Published: May 2019

e14167 Background: TMB-high was used as a favorable biomarker to predict the response to anti-PD-1/PD-L1 therapy, but a substantial portion of the TMB-high patients suffered from early resistance with limited clinical benefits but potential severe adverse effects. Methods: Whole-exome sequencing were performed in more than 200 advanced cancer patients, who received anti-PD-1 therapy alone or in combination with chemotherapy and targeted therapy across 20 provinces of China, with quarterly follow-ups. The genomic profiles of the patients with progressive disease (PD) and complete remission (CR) outcomes were individually analyzed and the potential resistance and hypersensitive biomarkers were identified. These biomarkers were formulated into an immune response-associated genomic (IRAG) model based on XGBoost algorithm to predict the sensitivity to PD-1 blockage and early resistance among TMB-high patients. Results: Non-synonymous somatic mutations (CTNNB1, B2M, PD-L1 and HLA class I genes), somatic gene amplifications (MDM2/4, CDK4, CCND1/FGF3/FGF4/FGF19, FLT3 and MYC), chromosome 9p21 deletion, and loss of heterozygosity in chromosome 6 HLA-I region were identified as potential resistance biomarkers in the PD group. TMB-high, microsatellite instability (MSI), TMB-low with indel-proportion high, POLE loss-of-function mutations, Epstein-Barr virus infection and DNA mismatch repair-deficient germline and somatic mutations were identified as potential hypersensitivity biomarkers in the CR group. By combining all genomic resistance and hypersensitivity biomarkers, we developed a quantitative IRAG model and separated the patients into three groups: TMB-low, TMB-high/IRAG-low and TMB-high/IRAG-high. The PFS in TMB-high/IRAG-low group was characterized with early clinical resistance, similar to the TMB-low group (median: 3.8 vs. 4.2 months, p = 0.22). The reanalysis of the patient set with known clinical outcomes showed that the TMB-high/IRAG-high group had a significantly longer PFS than the other two groups. (median: 10 vs. 3.8, 4.2 months, p < 0.001). The TMB-high/IRAG-high group clearly showed higher chromosomal stability with fewer somatic copy number alterations. Conclusions: We developed a model based on one single genomic assay (whole-exome) to successfully identify those TMB-high patients who suffered from early resistance to PD-1 inhibitors. Larger cohort and independent analyses are necessary to verify the validity of these results.
Development of imjSCORE for early prediction of response to nivolumab among patients with advanced cancer.
Authors: Janicek Milos Josef , Cirstea Diana , Denis Gerald V , Lerner Adam 
Published: May 2019

e14169 Background: Cross-sectional Imaging (CI) plays an essential role in early assessment of patients on immune checkpoint inhibitors (ICIs), yet often remains inconclusive in the setting of advanced disease, prior cancer treatment, toxicity, and cancer unrelated findings. Best timing of scans is also uncertain and may affect interpretation. We propose here a robust, reproducible imjScore based on measurable tumor response on the first two re-staging scans and their ratios that may predict treatment impact. Our approach incorporates the prognostic aspect of early imaging, time lag of ICIs effect, and alternative measures of treatment impact. Methods: Retrospective review of CI studies was performed in 92 patients with advanced stage solid tumors treated with Nivolumab during 6/2015-8/2018 at Boston Medical Center utilizing standard clinical protocols. Time on therapy (TOTx) was used as a surrogate marker of therapy impact. Modified imRECIST score utilizing Σ of 4 discrete cancer lesions at baseline (< 1 month before Nivolumab), 1st, and 2nd CI since initiation of Nivolumab were adjusted for TOTx. Our imjSCORE averages "predicted days on therapy" calculated from best fit function of tumor change/day [%] at each time point vs. TOTx and ratios between 1st and 2nd scan. Results: Median TOTx was 70 days (range from 1 to 1029). Differences in imRECIST scores derived from two early restaging CI studies adjusted for TOTx were able to identify with high statistical significance two groups of "SHORT" vs "LONG" sojourn on Nivolumab based on Median of 70 days. Early progression curve was associated with shorter benefit of Nivolumab; subset with pseudo-progression curve showed still significantly shorter sojourn on Nivolumab compared to initial regression or stable score curves (P < .002). Conclusions: The development of imjScore may differentiate with high likelihood patients with short versus long sojourn on Nivolumab. Our CI-based evaluation using the imjSCORE suggests a clear benefit from early imaging with a response curve and standardized point analysis of the 1st and 2nd post-treatment scans. If validated with other ICIs, this scoring tool may allow early prediction of ICIs treatment response and clinical outcome. Further correlation of imjSCORE with clinical biomarkers may be useful to build predictive nomograms of "short" versus "long" treatment impact.
Recurrent and de-novo autoimmune hemolytic anemia in patients treated with immunotherapy for advanced cancer.
Authors: Jain Natasha A. , Rogers Kerry Anne , Wang Tzu-Fei , Zhao Songzhu , Wei Lai , Otterson Gregory Alan , Owen Dwight Hall 
Published: May 2019

e14170 Background: Immunotherapy (IO) has brought dramatic clinical benefit to cancer patients. Serious immune-related adverse events (irAE) have been reported, however, hematological toxicities such as autoimmune hemolytic anemia (AIHA) remains poorly characterized. Here we performed a single institution retrospective study to determine the incidence and risk factors for AIHA and if prior positive direct anti-globulin test (DAT) or anti-RBC alloantibodies (alloAb) on type and screen predicts subsequent AIHA in patients treated with IO. Methods: This is a retrospective review of patients treated with IO between November 2012 and February 2017 at the Ohio State University. Patients who received IO either on clinical trial or as standard of care were included. The electronic medical records were reviewed for patients who developed AIHA. Overall survival (OS) was calculated from the date of initiation of IO to death from any cause or date or last follow-up. Medians and 95% CIs were estimated using Kaplan-Meier method and differences compared using the Log-Rank test. The association between irAE and DAT or alloAb testing was studied using Fisher’s exact test. Results: In 1,097 patients treated with IO, we identified 179 (16.6%) patients who had a DAT or alloAb testing at any time, 126 (11.5%) had this done prior to receiving IO. Of the 179 tested 10 (5.6%) had positive alloAb and 7 (3.9%) had a positive DAT. During treatment, two patients with prior history of AIHA experienced recurrence of AIHA during treatment. Three patients had positive DAT after IO, one was diagnosed as a delayed hemolytic transfusion reaction, and the patient required transfusion every 2 weeks since DAT positivity. The other two with positive DAT were not diagnosed with AIHA and did not require intervention. Patients with positive baseline alloAb (n = 6) had higher rate of irAE than patients without (n = 120) (13.3% vs 2.1%, p = 0.03), including 2 thyroid dysfunction, 2 skin rash, 2 myalgia, 2 hemolytic anemia. Patients with a positive DAT at baseline did not have a higher rate of irAEs (p = 0.09). Median OS for the entire cohort was 7.6 (5.8-9.9) months. No association was found between baseline positive DAT or alloAb and OS (p = 0.1748 and p = 0.3164 respectively). Conclusions: The incidence of hemolytic anemia in patients treated with IO was low. Presence of alloAb at baseline may predict irAE during IO treatment as patients with positive alloAb at baseline had a higher rate of irAE than those without.
A novel noninvasive biomarker based on peripheral PD-1posi CD8 T-cell receptor repertoire correlated with clinical outcomes to immunotherapy in non-small cell lung cancer.
Authors: Han Jie-Fei , Wang Zhijie , Bai Hua , Chen Si , Wang Yuqi , Duan Jianchun , Wang Jie 
Published: May 2019

e14174 Background: Although advances on exploration of biomarkers personalized the immune checkpoint blockades (ICBs) delivery, non-invasive blood-based approach remainsan intriguing area for further investigation.This study investigated the feasibility of peripheral isolated PD-1posiCD8T cell receptor (TCR) repertoire profiling in predicting the clinical outcomes of ICBs treatment for non-small cell lung cancer (NSCLC) patients. Methods: The study comprised two independent cohorts (A and B), ultimately recruiting total 40 from 51 patients with stage IIIB-IV NSCLCs who received anti-PD-1/PD-L1 therapy between March 14, 2017 and May 2, 2018. Peripheral blood samples of pre- and post-ICBs (the timepoint of first imaging evaluation) were prospectively collected, and PD-1posiCD8 T cells were isolated by flow cytometry for TCR sequencing. The diversity and clonality of the TCR repertoire were calculated for biomarker profiling. Cohort A (n = 25) was used as a training set for discovery of TCR diversity in the prediction of response to ICBs, and cohort B (n = 15) as a validation set. Progression-free survival (PFS) and response to ICBs treatment were correlated with TCR diversity and clonality. Results: In cohort A, patients with high pre-ICBs PD-1posiCD8 TCR diversity had longer PFS than those with low diversity (6.5 vs. 2.6 months, p = .045), which were substantially validated in cohort B. By using the incorporated set, pre-ICBs PD-1posiCD8 TCR diversity exhibited an optimal Youden's index of 0.81 with a sensitivity of 0.87 and a specificity of 0.94 in clarifying clinical response of ICBs (PR+SD vs. PD). Patients with increased PD-1posiCD8 TCR clonality demonstrated significantly improved PFS (7.3 vs. 2.7 months, p = .005) compared to those with decreased TCR clonality. Interestingly, two patients with initial pseudo-PD exhibited similar change of TCR clonality and expansion of dominant TCR clones with those with PR, but not PD. Conclusions: Peripheral PD-1posiCD8 TCR repertoire sequencing might be a promising non-invasive approach for selecting patients who could benefit from ICBs treatment, which guaranteed the further investigation and validation by larger cohorts.
Correlation of CD28 expression on CD8+ T cells with prognosis in advanced lung adenocarcinomas and squamous cell carcinomas.
Authors: Liu Chao , Jing Wang , Zhu Hui , Yu Jinming 
Published: May 2019

e14185 Background: Programmed death-1 (PD-1)-targeted therapies that treat non-small cell lung cancer (NSCLC) to salvage exhausted CD8 T cells depends on CD28 costimulatory pathway. However, the prognostic values of CD8+CD28+ T and CD8+CD28- T in advanced NSCLC and the impact of histological type on them remains unclear. Methods: Of 232 advanced NSCLC patients, 101 treatment-naïve individuals were eligible and included in our study. Flow cytometry was used to evaluate CD8+CD28+ T, CD8+CD28- T, CD4+CD25hi T, B, natural killer, γδT, and natural killer T cells in patients’ peripheral blood. Results: Multivariate analysis showed that increased levels of CD8+CD28+ T cells independently predicted favorable overall survival (OS) [hazard ratio (HR): 0.59, 95% confidence interval (CI): 0.28-0.93, P = 0.034] and progression-free survival (PFS) (HR: 0.60, 95%CI: 0.27-0.98, P = 0.033) in ADs but not in SCCs. In addition, high levels of CD8+CD28- T cells independently predicted unfavorable OS (HR: 1.57, 95%CI: 1.13-3.34, P = 0.039) and PFS (HR: 2.08, 95%CI: 1.02-4.23, P = 0.043) in SCCs but not in ADs. ADs had higher levels of CD4+CD25hi T and CD8+CD28- T, and lower NK (all P < 0.05) cell counts than SCCs. Conclusions: The prognostic values of peripheral CD8+CD28+ and CD8+CD28- T cells in advanced NSCLC patients differ depending on histological type. These results could help refine the CD28-dependent PD-1-targeted therapies for advanced NSCLC with ADs and SCCs.