bluuebunny/crossref_metadata_2025_split huggingface dataset:
Addition of immunotherapy in adjuvant setting could be a promising avenue of colorectal cancer (CRC) treatment, especially in patients with higher levels of programmed cell death ligand-1 (PD-L1) positive circulating epithelial tumor cells (CETC) after neoadjuvant chemotherapy.
Authors: Pizon Monika , Schott Dorothea , Pachmann Ulrich A. , Pachmann Katharina , Agrawal Siddarth , Sawicki Tomasz , Agrawal Anil Kumar , Rudnicki Jerzy , Ziolkowski Piotr , Wozniak Marta 
Published: May 2019

e14036 Background: CRC is the third most frequent cancer in men and second in women worldwide. Recently, immune checkpoint molecules such as PD-1/PD-L1 have been identified as a possible target for immunotherapy in CRC and are increasingly being tested in clinical trials in combination with chemotherapy. However, the role of PD-L1 expression in CRC tumor cells and its interaction with other clinicopathologic factors remains elusive. In this study, we evaluated the impact of neoadjuvant chemotherapy on the fraction of PD-L1 positive CETCs and to compare its expression to the primary tumor. Methods: CETCs were determined from the blood of 20 patients suffering from CRC in different stages of the disease. The number of CETCs and their expression of PD-L1 were investigated using the maintrac method. In parallel, PD-L1 expression and tumor infiltrating lymphocytes (TILs) were assessed by immunohistochemistry on tissue biopsies. Results: PD-L1 expression could be assessed in all patients with detectable CETCs with a median of 50%. CETCs were more frequently found to be PD-L1 positive than tissue, and no correlation was observed between tissue and CETCs PD-L1 expression. Interestingly, patients with neoadjuvant chemotherapy had more positive PD-L1 CETCs compared to patients without chemotherapy (mean 66,7 vs. 35,2 p < 0.05), but the total number of CETCs was significantly lower in the neoadjuvant group. Also, patients with mucinous adenocarcinoma had more PD-L1 positive CETCs compared to other histological subtypes. The number of TILs was higher in patients with lymph node metastasis and larger tumors. TILs count did not differ in patients with and without neoadjuvant chemotherapy. Conclusions: Assessment of PD-L1 expression in CETCs is feasible, and CETCs are more often positive than in tissue. PD-L1 expression on CETCs was higher in patients who received neoadjuvant chemotherapy. Further studies are necessary to validate these findings.
Clinical implication of monitoring PD-L1+ circulating tumor cells (CTCs) in patients with non-small cell lung cancer (NSCLC) receiving immunotherapy.
Authors: Hoffmann Andrew Daniel , Davis Andrew A. , Iams Wade Thomas , Oh Michael S , Lentz Robert William , Chae Young Kwang , Liu Huiping 
Published: May 2019

e14044 Background: CTCs not only constitute a cellular component of liquid biopsy for dynamic, longitudinal information of malignancies, but also pose a continuous threat to seed new metastasis. Detection of these cells can help identify patients with residual disease and poor prognosis. However, it is unknown if heterogeneous CTCs can be profiled to monitor cancer stemness and immunotherapy response for patients. Limited clinical data exist for monitoring CTCs for markers of cancer stem cells, such as CD44 or CD166, and immunotherapy therapeutic targets including PD-L1. We hypothesized that dynamic monitoring of CTC positivity for these markers would correlate with responses to immune checkpoint inhibitor treatment for patients with NSCLC. Methods: As part of a prospective analysis of peripheral blood cells, 30 patients with NSCLC undergoing immunotherapy (pembrolizumab or atezolizumab) or combination therapy with chemotherapy had blood samples collected at 3-4 week intervals for up to 24 weeks. Peripheral blood mononuclear cells were isolated and analyzed for CD45, to identify non-leukocyte putative CTCs, CD166 and CD44, to identify cancer stem cell markers among potential CTCs, and PD-L1. Patients were evaluated for response based on RECIST criteria. Statistical analysis was performed using one-way ANOVA on samples from each time point. Results: A decrease in PD-L1+ CD45- cells (CTCs) at the second interval was most strongly associated with initial response. In contrast, increasing number of PD-L1+ CD45- cells were found among patients with progressive disease as compared to those with stable disease or a partial response (p = 0.01). (1) CD45- cells, (2) CD44+; CD45- cells and (3) CD166+; CD45- cells demonstrated no significant association with clinical outcomes. Baseline PD-L1 level on CTCs did not correlate with the PD-L1 level on tissue. Conclusions: We report the feasibility and potential clinical significance of monitoring surface markers on CTCs in the blood before and after initiation of immunotherapy. Our findings that PD-L1+ CTCs increased among non-responders to immunotherapy warrant further validation. Testing is ongoing to evaluate how these changes predict long-term outcome to treatment for patients.
Role of the expression of PD-L1 and CD47 on circulating tumor cells (CTCs) in the prediction of outcome in metastatic breast cancer (mBC) patients.
Authors: Agelaki Sofia , Papadaki Maria A. , Tsoulfas Panormitis G , Aggouraki Despoina , Monastirioti Alexia A , Merodoulaki Katerina A , Thomopoulou Konstantina , Papadaki Chara , Mavroudis Dimitrios 
Published: May 2019

e14045 Background: CTCs expressing innate (CD47) and adaptive (PD-L1) immune checkpoints may have enhanced potential to escape immunosurveillance. In the current study, we evaluated the incidence and clinical relevance of CTCs expressing CD47 and/or PD-L1 in patients with mBC. Methods: Blood was obtained from 98 mBC patients before the initiation of first-line therapy. Triple immunofluorescence staining for cytokeratins (CK), CD47 and PD-L1 was performed on peripheral blood mononuclear cells (PBMC) cytospins and 1*106 PBMCs per patient were analyzed using the Ariol microscopy system. CD47 and PD-L1 expression levels on CK+ CTCs were normalized using MDA.MB.231 breast cancer cells as controls. Results: CK+ CTCs were detected in 22 out of 98 patients (22.4%) (total CTC No: 43; range: 1-12). High CD47 and PD-L1 expression was identified in 41.9% and 11.6% of CTCs, respectively, whereas in 9.1% of CTCs, high expression was observed for both markers. CTCs with high expression of at least one marker ( CD47high and/or PD-L1high) were identified in 11.2% of patients, albeit with a differential distribution among patients with triple-negative, hormone receptor-positive and HER2-positive primary tumors (27.3%, 12.5% and 0%, respectively, p = 0.040; Chi-square test). CD47high and/or PD-L1high CTCs were associated with disease progression (27.8% vs 5.6%, p = 0.005; Chi-square test) and shorter PFS [median: 5.8 (4.1-7.5) vs 13.3 (11.4-15.2) months, p = 0.010; Kaplan-Meier], whereas the detection of PD-L1high CTCs only was correlated with reduced OS [median: 23.8 (5.8-41.8) vs 35.7 (29.9-41.4) months, p = 0.043]. Multivariate Cox-regression analysis revealed that CD47high and /or PD-L1high CTCs predicted for increased risk of relapse [HR: 2.7 (95% CI: 1.3-5.7); p = 0.009], whereas PD-L1high CTCs were associated with high risk of death [HR: 4.8 (95% CI: 1.4-16.6); p = 0.011]. Conclusions: The immune checkpoints CD47 and PD-L1 are co-expressed in a subset of CTCs in mBC patients. The detection of high CD47 and/or PD-L1 expression on CTCs is associated with triple-negative tumors, disease progression and poor patient outcome and could serve for the refinement of prognosis in mBC. Patients bearing this CTC population may benefit from anti-CD47 and anti-PD-L1 immunotherapy strategies.
Correlation of HERVK with efficacy on anti-PD-1/PD-L1 therapy in a pilot metagenomics study on Chinese advanced lung cancer patients.
Authors: Tao Haitao , Hu Yi 
Published: May 2019

e14046 Background: Patient selection for PD-1 inhibitors in NSCLC is still based on imperfect screening biomarkers, including PD-L1 expression and tumor mutational burden(TMB).There are several reports show certain bacteria or virus infections are correlated with efficacy and prognosis on PD-1 inhibitors treatment. In order to explore more potential biomarkers for anti-PD-1 therapy, we investigate whether we can discover microorganisms in Chinese lung cancer patients and whether certain microorganism are correlated with efficacy or prognosis on anti-PD-1 therapy using metagenomics technology. Methods: In this study, 30 advanced lung cancer patient were enrolled, including 15 cases of adenocarcinoma, 12 cases of squamous carcinoma, 2 cases of Small cell lung cancer. 10 patients received PD-1/PD-L1 inhibitors as first-line therapy and other patients as second-line therapy. Among these 30 patients, 15 PR,1 CR, 10 PD, 4 SD according to RECIST 1.1. Plasma cell-free DNA (cfDNA) were collected from these patients prior to anti-PD-1 treatment and whole-genome sequencing of cfDNA at average coverage 5X was performed on Illumina NovaSeq in 2 ×150bp length model. A bioinformatics pipeline composed of 4 tools: BWA/Sambama/Kraken2/Bracken, was constructed to analyze the sequencing data. Non-human derived reads were extracted by sambama from the bam file that generated by BWA. Bacteria/Virus abundance in each sample was estimated through Bracken, followed by bac/vir database alignment in Kraken2. Results: In our pilot study, 4 patients were selected for metagenomics sequencing(1CR, 1PR, 2PD). Interestingly, over 100 different microbial sequence were detected in every patient. Compare microorganism in CR+PR patients to PD patients, Human endogenous retrovirus K (HERVK) were quite abundant in CR/PR patients but not in PD patients: 5.6 times more abundant in CR/PR patients comparing to PD patients. (HERVK abundance: CR:PR:PD = 1.20% : 0.32% : (0.17%, 0.10%)). HERVK is a family of human endogenous retroviruses associated with certain malignant tumors, studies have indicated that HERVK may trigger an antigen specific immune response for certain cancer patients. Conclusions: Metagenomics sequencing on plasma cfDNA could be a potential biomarker discovery approach to identify prognostic biomarkers for anti-PD-1 therapy. HERVK are correlated with efficacy on anti-PD-1 treatment in our pilot study, however more thorough investigation need to be conducted to confirm whether HERVK can be served as efficacy biomarkers for anti-PD-1.
Association of relative neutrophilia with a distinct immunoinhibitory milieu in non-small cell lung cancer.
Authors: Mitchell Kyle Gregory , Diao Lixia , Tran Hai T. , Negrao Marcelo Vailati , Karpinets Tatiana , Wang Jing , Parra Cuentas Edwin Roger , Corsini Erin M , Reuben Alexandre , Federico Lorenzo , Bernatchez Chantale , Vaporciyan Ara A. , Swisher Stephen , Cascone Tina , Wistuba Ignacio Ivan , Heymach John , Zhang Jianjun , Gibbons Don Lynn , Haymaker Cara L. , Sepesi Boris 
Published: May 2019

e14047 Background: Elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with poor prognosis in non-small cell lung cancer (NSCLC); the biological underpinnings of this observation have not been fully elucidated. We examined the relationships between peripheral neutrophil counts (PMN), NLR, circulating cytokines and angiogenic factors (CAF), and tumor microenvironment (TME) features in NSCLC. Methods: 150 patients with resectable NSCLC were enrolled in an immunoprofiling project. A panel of 43 CAFs was used to analyze preoperative plasma samples. Chemotherapy-naïve patients with CAF and a complete blood count ≤30 days preoperatively were included (n = 66; Table). For a subset, transcriptional signatures (MCP-counter, n = 50) and flow cytometry (n = 19) were used to identify TME phenotypes. Results: Increased PMNs were associated with increased pro-inflammatory CAF such as IL-1b (r = 0.392) and IL-6 (r = 0.339), as well as Th17/Tc17 associated CAF IL-17A (r = 0.320) and TNF-a (r = 0.368). Elevated NLR was inversely correlated with the lymphocyte activation marker soluble CD27 (r = -0.320, p = 0.009). This negative association was mirrored in the TME, as tumor neutrophil signatures were inversely correlated with a local IFN-g gene signature (r = -0.626, p < 0.001). Interestingly, a Th17/Tc17 peripheral signature (elevated IL-17A) was associated with an enrichment of CD8+TIM3+ cells (r = 0.623, p = 0.042) in the tumor. While this requires confirmation in a larger cohort, this correlation provides a potential rationale for targeting TIM3 in this population. Upon analysis of clinical characteristics, peripheral PMNs and NLR were higher among patients with squamous histology (PMN p = 0.009; NLR p = 0.034) and positively correlated with tumor size (PMN r = 0.344, p = 0.004; NLR r = 0.363, p = 0.003). Conclusions: A relative neutrophilia in NSCLC patients is associated with an inflammatory milieu suggestive of a Th17/Tc17 presence and decreased lymphocyte activation that is reflected within the TME. Further investigation is needed to define the role of NLR as a predictive biomarker and to identify whether neutrophils or Th17/Tc17 T cells could serve as a therapeutic target to improve immunotherapy response in NSCLC.[Table: see text]
A relationship-based approach to improving the clinical trial experience.
Authors: Helou Sarah MacKay , Gadberry Camber W. , Zahara Nicholas , Nickols Claire , Vidhyarkorn Tanya , Otap Daniel , Russell Janice , Piggee Jessica , Scher Catherine , Estrabaut Myriam , Churchill Sarah , Tran San 
Published: May 2019

e14055 Background: The rapidly evolving field of Cancer Immunotherapy (CIT) has mobilized biopharma to develop promising new treatments while at the same time created a need to expedite the pathway of those new therapies from bench to bedside. This race to bring innovative treatments to patients has engendered heightened levels of competition for the attention of and partnership with the best research institutions in the biopharma industry. Methods: Recognizing this reality, Roche created the immunotherapy Centers of Research Excellence (imCORE) Network: a network of leading cancer immunotherapy centers worldwide. The vision of this network was to partner with sites to streamline the operational delivery of the Roche Genentech portfolio while deepening the collective understanding of the science to prioritize and accelerate the most promising new treatment options for our patients. Creation of a network was not a novel idea, but Roche set out to build a network unique to the biopharma industry – one which was relationship-based where the site/sponsor relationship serves as the foundation for driving both collaborative scientific investigations and operational efficiencies in support of Roche’s clinical trials. While the identification and optimization of promising candidate drugs in the preclinical and translational settings are critical first steps in the drug development process, the initiation and operationalization of early phase clinical trials are equally important in the multidimensional cycle of drug development. Results: See Conclusions. Conclusions: This white paper will provide an overview of imCORE’s origins with a focus on the strategic importance of the site-sponsor relationship and the mutual value that is derived from the combined benefits of these relationships and in conducting early clinical trials more efficiently across Roche’s CIT portfolio. Further examination of communication and operational improvement to support the network will be highlighted as key drivers in creating and sustaining meaningful site/sponsor relationships that better facilitate the operationalization of clinical trials and ultimately brings novel therapies to patients in a more efficient manner than in the past.
Effect of mandatory research biopsy requirements on initiation of clinical trials.
Authors: Cheng Jonathan Hin , Tiulim Justin Wayne Wong , El-Khoueiry Anthony B. , Nieva Jorge J. 
Published: May 2019

e14057 Background: There has been an increasing requirement for fresh tumor tissue to enroll in clinical trials in order to look for specific biomarkers. This has been shown to increase screening duration and increase screen failure rates. It was important to corroborate these results in other centers. Methods: This study is a non-randomized retrospective analysis of patients in one subset of patients seen by research nurses who operated in the standard head/neck and lung team not including patients in the phase 1 program. All patients were enrolled in clinical trials from January 16, 2013 to May 28, 2018 at USC Norris Comprehensive Cancer Institute in Los Angeles. Patients who were required to give fresh research biopsies prior to intervention were part of the research biopsy group. Results: In total, 76 patients were analyzed in this study. 33 patients were in the research biopsy group and 43 patients were in the no biopsy group. Trials that required a fresh biopsy had a longer median screening duration (30 vs 14 days) than trials that did not require a biopsy (p < .0001). Conclusions: Our study shows that requiring biopsies prior to clinical trial treatment results in a statistically significant delay in treatment. The informed consent forms that were part of clinical trials involving mandatory research biopsies did not reflect this delay in treatment. However, these delays did not result in a statistically significant decrease in number of days on trial or days until progression of disease.
Tislelizumab, an investigational anti-PD-1 antibody, combined with chemotherapy as first-line treatment for lung cancer in Chinese patients.
Authors: Wang Jie , Zhao Jun , Wang Zhijie , Ma Zhiyong , Cui Jiuwei , Shu Yongqian , Liu Zhe , Cheng Ying , Leaw Shiangjiin , Xia Fan , Wu Yanjie , Liang Liang 
Published: May 2019

e14067 Background: Tislelizumab, an investigational anti-PD-1 antibody, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports showed tislelizumab was generally well tolerated and had antitumor activity in patients (pts) with advanced solid tumors; 200 mg IV Q3W was established as the RP2D. Methods: This phase 2 clinical trial (NCT03432598) assessed tislelizumab (200 mg Q3W) with platinum (plt)-based chemotherapy (Q3W) as first-line treatment for Chinese pts with advanced lung cancer. All pts received tislelizumab + plt doublet (4–6 cycles) until disease progression. Nonsquamous (nsq) NSCLC pts received pemetrexed (PMX) + plt (4 cycles) followed by PMX maintenance; squamous (sq) NSCLC pts received A) paclitaxel (PXL) + plt or B) gemcitabine + plt; SCLC pts received etoposide + plt. Tumor response (RECIST v1.1) and safety/tolerability were evaluated. PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Results: As of 15 Oct 2018, 54 pts (median age 61 yr; 74% male; 72% current/former smokers; 31% with ≥10% PD-L1 expression on tumor cells) received tislelizumab; 24 pts remain on treatment. Confirmed PR was observed in 36 pts and most occurred within the first 2 assessments. Other efficacy estimates (eg, PFS) are maturing. Grade ≥3 AEs occurring in > 15% of pts were decreased neutrophil counts (n = 25) and anemia (n = 9); immune-related AEs occurring in ≥2 pts were decreased triiodothyronine, hyperthyroidism, hypothyroidism, and pyrexia (n = 2 each). One sq-NSCLC pt ( A) experienced fatal myocarditis/myositis after 1 cycle; other AEs resolved with tislelizumab interruption (n = 30), discontinuation (n = 4), or other appropriate treatment. Conclusions: Tislelizumab in combination with standard of care plt-based chemotherapy was generally well tolerated and demonstrated antitumor activity. Clinical trial information: NCT03432598. [Table: see text]
Burden of copy number alterations predicts outcomes in immune checkpoint blockade treated gastrointestinal cancer patients.
Authors: Lu Zhihao , Chen Huan , Li Shuang , Jiao Xi , Wu Lihong , Zhang Henghui , Shen Lin 
Published: May 2019

e14068 Background: Despite the great achievements made in immune checkpoint blockade (ICB) in cancer therapy, how to identify patients who may benefit from ICB still remains one of the central questions, especially in gastrointestinal (GI) cancer. Methods: To address this, we analyzed FFPE tumor specimens from 73 patients with metastatic GI cancers who were treated with ICB. All patients were randomly assigned into discovery (60%) and validation (40%) cohorts. Overall, tumor mutation burden (TMB) and copy number alterations (CNAs) were determined by using the whole-exome sequencing platform. FFPE samples of 65 patients were analyzed via a multiplex RNA immune oncology sequencing panel. Results: Here we show that lower burden of copy number alteration (CNA) was observed in responders to immunotherapy in both discovery and validation cohorts. More importantly, lower burden of CNA in GI cancers were associated with improved objective response, clinical benefit and overall survival. Efficacy also correlated with the higher TMB. Of note, a combinatorial biomarker of TMB and burden of CNA may better stratify responders from patients received immunotherapy. In addition, patients with lower burden of CNA revealed increased IFNγ and expanded immune signatures in our GI patient cohort and TCGA cohorts as well. Conclusions: Our results suggest that burden of CNA may expand the predictive and prognostic value of genomic determinants in identifying potential responders with GI cancer to immune checkpoint blockade therapy.
Review of therapeutic approaches for B-cell malignancies with immune checkpoint blockade and chimeric antigen receptor t-cell therapies: Development, benefits, and limitations.
Authors: Hays Priya 
Published: May 2019

e14069 Background: Immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR) T-cell therapies have emerged as approaches to treat B-cell malignancies. Methods: PubMed/NCBI/MEDLINE databases were accessed with keywords "immune checkpoint inhibitors and B-cell malignancies" "CAR T-cell and B-cell malignancies", and various permutations including "clinical data" "toxicities", "reviews", "quality of life", and "adverse effects". Results: The first-in-class approved immune checkpoint inhibitor was ipilimumab, which is a fully humanized mAb that blocks the immunosuppressive signal by cytotoxic T-lymphocyte antigen. Thereafter, nivolumab was also approved for use in the treatment of Hodgkin's lymphoma in 2016. In phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma received the anti-PD-1 monoclonal antibody nivolumab. Eighty-one patients were treated and drug-related adverse events occurred in 51 (63%) patients. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma and other hematologic malignancies. Clinical trial results describing CD19-targeted CAR T-cell therapy of patients with relapsed B-ALL were published in 2015. In this study, all five patients treated with CAR T cells achieved minimal residual disease negative complete remission. Updated results describing the treatment of 16 patients with relapsed or refractory B-ALL treated with CAR T cells were published: the overall CR rate in this trial was 88% and 12 of 14 patients were classified as minimal residual disease negative. 44% of these patients went on to standard-of- care allogeneic hematopoietic stem cell transplant. Initial studies also reported potent anti-leukemic effects of CD19 CAR T cell therapy in three patients with refractory chronic lymphocytic leukemia where two of the three patients achieved MRD-CR. Infused CAR T cells proliferated up to 10,000-fold and persisted in recipients for at least 6 months and shown to retain antitumor activity after six months. Costs for CAR T-cell therapies remain exorbitant, reaching over $1M (USD) per patient. Conclusions: Clinical data reveal safety and efficacy, and also associated toxicities for both approaches.