bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dominant negative PD1 armored CART cells to induce remission in relapsed or refractory non-Hodgkin lymphoma (NHL) patients.
Authors: Pu Chengfei , Huang Liansheng , Su Yang , Ding Tianling , Xiao Xibin , Jin Lina , Cao Zhiyuan , Wu Ting , Chen Tong , Ding Luying , Zhang Xiaohong , Lan Haifeng , Wu Zhao , Xiao Lei 
Published: May 2020

e15028 Background: The chimeric antigen receptor (CAR) T cell treatment has been demonstrated as an effective therapy to treat relapsed/refractory B cell malignancy. However, tumor microenvironment influences and affects the efficacy of CAR T treatment. For example, programmed death ligand 1/2 (PDL1/2) may inhibit the CAR T cells via interaction with up-regulated programmed cell death protein 1 (PD1) after T cells activation, suppressing the tumor-killing capability of the CAR T cells. Thus, blockade of the PD1-PDL1/2 interaction may enhance the anti-tumor efficacy of CAR T therapy. Methods: Here, we generated CAR T expressed an anti-CD19 CAR molecule and a dominant-negative PD1 molecule. Compared with conventional CART cells, these “armored” CART cells showed the enhanced capability of tumor-killing and more “memory-like” phenotypes after multiple-round tumor challenging. These results suggest dominant-negative PD1 molecules may protect CART cells from exhaustion in the tumor microenvironment. Results: Further, we reported the findings of a clinical trial for six relapsed or refractory B-cell non-Hodgkin lymphoma (NHLs) patients treated using our armored CAR T cells. These six patients failed multiple rounds of chemotherapy and radiotherapy. In the clinical trial, the patients were infused with autologous CAR T cells range from1×106/kg to 8×106/kg. PET/CT showed significant tumor shrinkage and SUV max declines in all six patients, and the ongoing responses were monitored. The best overall response rate (ORR)was 100%. Conclusions: The results of these six patients in the clinical trial showed that our armored CAR T cells achieved the significant anti-bulky lymphoma response while causing limited and tolerated cytokine release syndrome and central nervous system toxicity. Thus, dominant-negative PD1 molecules may increase CAR T cells persistence in patients, enhancing the efficacy of CAR T cells for treating blood cancer. Finally, dominant-negative PD1 can be used as a platform technology and may be applied to other adoptive cellular immunotherapies such as TCR-T or TIL in the treatment of solid tumors. We are continuing to monitor current patients and recruit more patients for the clinical trial.
The landscape of gene fusions and the correlation with immunotherapy biomarkers in Chinese patients with advanced solid tumor.
Authors: Liu Wenshuai , Zhou Yifan , Zhang Bei , Bai Yuezong , Wang Yueqi 
Published: May 2020

e15039 Background: Due to the U.S. Food and Drug Administration approval of larotrectinib, a tumor or tissue-agnostic cancer treatment, gene fusions and fusion-driven cancer were identified as indications. Exploration of the gene fusions might be essential in both target therapy and immunotherapy in advanced solid tumor. However, the landscape of gene fusions in Chinese solid tumor patients is poorly reported. Methods: Tissue samples were obtained from 7514 Chinese patients with advanced solid tumor. Genomic alterations were identified via the next generation sequencing (NGS) with a validated commercial 381-cancer-gene panel (panel size over 0.5 MB), including 100 MSI loci. TMB was calculated according to NGS results. Statistical analysis was performed by Fisher exact test using R 3.6.1. Results: There were 162 pathologic or very like pathologic gene fusions observed in 249 (3.31%) patients, covering 30 cancer types. Top frequent fusion genes were ALK (93), RET (32), FGFR2 (26), FGFR3 (13), ROS1 (10), TMPRSS2 (10) and NTRK1 (9). Their main partner genes were EML4 (66/ 93), KIF5B (15/32), BICC1 (5/26), TACC3 (13/13), CD47 (3/10), ERG (9/10) and TPM3 (5/9), respectively. Mostly, only one fusion was detected in one patient. Three patients harbored 3 gene fusions and 35 patients harbored 2 gene fusions, among which 21 patients were observed harboring both fusion and its reciprocal fusion. In the group of patients harboring gene fusions, the prevalence of MSI-H was 4.0% (10/ 249). Especially, the prevalence was significant high (41.2%, 7/ 17) in colorectal cancer patients (P < 0.001). In MSI-H colorectal cancer patients, 4 carried NTRK1 fusions, 2 RET fusions and 1 ALK fusion. And all of them had high tumor mutation burden (TMB). As another immunotherapy response predictor, TMB was low in most solid tumor patients in this study, except for the patients harboring gene fusions involving NTRK1, NTRK2 or STK11, whose TMB-H proportion were 67%, 50% and 33%, respectively. Conclusions: Gene fusions might be associated with MSI-H. In colorectal cancer patients, gene fusions involved either NTRK1 or NTRK2 might be associated with TMB-H, which revealed a potential biomarker for both target and immunotherapy.
Peripheral cytokine as a pan-cancer predictor for immunotherapy with anti-PD-1/PD-L1 antibody.
Authors: Ji Shoujian , Chen Huan , Yang Keyan , Zhang Guanxiong , Zhang Henghui , Xu Jianming 
Published: May 2020

e15044 Background: Currently, only a small proportion of cancer patients may benefit from anti-PD-1/PD-L1 immune checkpoint inhibition (ICI), suggesting an urgent need for effective biomarkers. Due to the limited accessibility and heterogeneity of the tissue samples in advanced cancer, predictors as cytokines in the peripheral immune system revealed distinct advantages. Methods: Plasma samples were collected before anti-PD-L1/PD-L1 treatment in two subsets of patients, which comprises 21 esophageal squamous cell cancer (ESCC) patients in the discovery cohort and 61 pan-cancer cases in the validation cohort. A total of 59 immunological factors including cytokines, chemokines, and checkpoints were measured by using a Luminex immunoassay kit. Moreover, tumor infiltrating lymphocytes (TILs) were analyzed using multiplex immunohistochemistry (mIHC) in a subset of tissue samples from the combined cohort. Results: In the discovery cohort of ESCC patients, multiplex Luminex profiling data revealed that soluble PD-L1 and C-C motif chemokine 5 (CCL5/RANTES) were significantly upregulated in patients with clinic benefit at baseline. We therefore tested the predictive and prognostic value of the two peripheral factors, along with their combined signature, “the 2-cytokine signature”. In specific, the signature-high subgroups displayed remarkably increased disease control rate (DCR) and prolonged survival, versus that of the lower subgroups (p < 0.05 for all comparison). More importantly, in the pan-cancer validation cohort, the three signatures exhibited a strong predictive value as well (PD-L1, AUC = 0.71; CCL5/RANTES, AUC = 0.71; the 2-cytokine signature, AUC = 0.72; p < 0.05 for all comparison). Notably, the 2-cytokine signature revealed significant stratification power for overall survival (HR = 0.431, p < 0.05) and progression free survival (HR = 0.423, p < 0.01). Intriguingly, further quantitative analysis of the local tumor microenvironment by mIHC assays revealed a positive correlation between the levels of the 2-cytokine signature and NK cell infiltration. Conclusions: A combined peripheral signature comprising CCL5/RANTES and soluble PD-L1 appears to be an effective pan-cancer biomarker to identify patients who may benefit from anti-PD-1/PD-L1 monotherapy. Further analysis indicated a link between higher peripheral signature and enrichment of NK cells in the local microenvironment. Therefore, peripheral immunological features may play an essential role in guiding patient selection for ICI immunotherapy.
Predicting the efficacy of nivolumab combined with radiation therapy by longitudinal liquid biopsy with artificial intelligence for patients with metastatic breast cancer (translational research of the KBCRN-B-002 trial).
Authors: Kawaguchi Kosuke , Takada Masahiro , Kotake Takeshi , Yoshimura Michio , Uozumi Ryuji , Kataoka Masako , Koyama Takahiko , Tokumasu Reitaro , Kato Hironori , Yoshibayashi Hiroshi , Suwa Hirofumi , Tsuji Wakako , Yamashiro Hiroyasu , Kataoka Tatsuki R , Ishiguro Hiroshi , Parida Laxmi , Morita Satoshi , Toi Masakazu ,   Kyoto Breast Cancer Research Network (KBCRN)
Published: May 2020

e15046 Background: Advances in immuno-oncology (IO), i.e., programmed cell-death protein 1 (PD-1) inhibitors, are revolutionizing cancer treatment by offering hope for a cure. However, the benefit of IO agents in metastatic breast cancer (MBC) remains limited. For immunotherapy to be successful, it is essential to understand the tumor immune contexture. Systemic immune alterations, such as the signature of peripheral blood mononuclear cells (PBMC) and cytokine expression, are one of the hallmarks of successful immunotherapy in MBC. The abscopal effect induced by radiation therapy (RT) is known to be a modulator of systemic immune alterations, and the abscopal effect is considered as a systemic anti-tumor immune response. In this study, we integrated time series multi-omics data in order to identify alteration of the immune signatures after RT combined with nivolumab, a PD-1 inhibitor, using a longitudinal liquid biopsy with artificial intelligence. Methods: This study was conducted as translational research, part of the KBCRN-B-002 trial, which is a multicenter phase Ib/II study evaluating the safety and efficacy of nivolumab in combination with RT in patients with HER2-negative MBC (UMIN: UMIN000026046). Twenty-nine patients were included in the translational analysis set. The multi-omics data included data from RNAseq, mass cytometry (CyTOF) and multiple cytokines, using PBMC, serum and plasma. We collected time series data, which covered the baseline, two weeks after starting therapy, four weeks after starting therapy and the timing of progressive disease. For integrated analysis of the multi-omics data, a machine-learning method was developed. Results: Our integrated analysis (involving a longitudinal liquid biopsy and machine-learning method) identified an apparent cluster of responder groups and alteration of the systemic immune signatures. Single-cell analysis using CyTOF results including the signature of the immune cell composition, effector immune cells and immune suppressor cells. Conclusions: Our method clustered responders well and identified candidates of the systemic immune signatures for actionable hallmarks of RT combined with IO agent by a longitudinal liquid biopsy. Clinical trial information: NCT03430479 .
Association of dynamic changes of methylated SFRP2 in ctDNA with prognosis in advanced gastric cancer.
Authors: Haijiao Yan , Ge Kele , Chen Wenyu , Mao Xizheng , Li Xiaodong , Xiao Mingzhe , Liu Wensong , Wu Jun 
Published: May 2020

e15051 Background: Secreted frizzled-related protein 2 (SFRP2) is a tumor suppressor gene and its hyper methylation could cause its inactivation and promote cancer development. However, whether methylated SFRP2 (mSFRP2) in ctDNA could serve as prognostic biomarker for patients with gastric cancer has not been thoroughly studied. Methods: Stage III or IV gastric cancer patients treated with systemic chemotherapy in the Third Affiliated Hospital of Soochow University from 2015 to 2017 were included. The mSFRP2 before and during chemotherapy were dynamically detected from ctDNA by digital polymerase chain reaction-based technologies. Results: In total, 121 patients were enrolled, with 63 in stage III and 58 in stage IV. Baseline median mSFRP2 was higher in stage IV than stage III (64 VS 18 copies/ng, P < 0.001). In stage III GC, the top 50% mSFRP2 population had shorter median disease-free survival (DFS, 11.0 months VS NR; HR, 13.05; 95% CI, 3.05-55.95;) and overall survival (OS, 17.0 months VS NR; HR, 7.80; 95% CI, 1.81-33.60). Similar results were observed in stage IV GC that the median progression-free survival (PFS, 4.0 VS 7.0 months; HR, 2.74; 95% CI, 1.58-4.78) and OS (12.0 VS 16.0 months; HR, 3.14; 95% CI, 1.67-5.92) was shorter in patients with top 50% mSFRP2. During the dynamic monitor along treatment, elevated mSFPR2 was associated with worse PFS (5.0 VS 7.0 months; HR, 2.17; 95% CI, 1.25-3.76) and OS (12.0 VS 15.5 months; HR, 3.51; 95% CI, 1.94-6.35) in stage IV patients. Conclusions: Our study shows the association between SFRP2 methylation and its dynamic change and prognosis in patients with gastric cancer. Our results provide a potential biomarker in ctDNA for prognosis and dynamic monitoring in patients with gastric cancer.
Characterization of the immune tumor microenvironment of HER2-positive breast cancer following treatment with entinostat and immune checkpoint inhibition.
Authors: Roussos Torres Evanthia T. , Sidiropoulos Dimitrios N , Davis-Marcisak Emily , Kagohara Luciane Tsukamoto , Connolly Roisin M. , Stearns Vered , Jaffee Elizabeth M. , Fertig Elana J. 
Published: May 2020

e15061 Background: HER2+ breast cancers are known to be less-immunogenic and associated with low response rates to immune checkpoint inhibitors (ICIs). A combination of immunosuppressive signals that prevent cytotoxic T cells from infiltrating the tumor microenvironment (TME) and, low tumor antigen expression, contribute to immunotherapy resistance in this population. Epigenetic modulators can both reexpress tumor antigens and rewire the immunosuppressive environment. We previously used a histone deacetylase inhibitor, entinostat (ENT), in combination with ICIs to reverse the immunosuppressive TME and increase tumor antigen expression in a NeuN HER2+ mouse model of breast cancer. Our results showed that ENT in combination with anti-PD-1, anti-CTLA-4, provided a significant survival benefit compared to either treatment alone. Methods: This current study employs single cell RNA-sequencing on whole tumor samples from mice treated with ICIs and entinostat to investigate the role of epigenetic inhibitors in rewiring the expression of tumor antigens and the cellular landscape of the TME. We generate single cell data over 54,000 cells from 20 tumors treated with entinostat alone or in combination with anti-PD1 and anti-CTLA4 and their combination. Results: Analysis of cells in the TME identifies consistent proportion of monocytes, macrophages, T-cells, Myeloid Derived Suppressor Cells (MDSCs) and Cancer Associated Fibroblasts (CAFs) before and after treatment. Differential expression analysis within the cell types identifies distinct subpopulations and we explore those that are either proportionally higher or lower in each treatment group. Notably, pathway analysis on differentially expressed genes of each cell type identified that combination entinostat and checkpoint treatment increased T cell activation, leukocyte proliferation, myeloid leukocyte and neutrophil migration, and decreased Wnt signaling and histone modifications in tumor cells. These results are being corroborated in patient samples from a parallel clinical trial to provide translational relevance. Conclusions: Our current work provides insights into the transcriptional network within a breast tumor after treatment with ENT+ICIs. We predict our findings will bring us closer to identifying additional therapeutic targets and ultimately improve survival rates of patients with less-immunogenic tumors.
Association of body mass index (BMI) with clinical efficacy of immune checkpoint inhibitors (ICI) in advanced cancer patients: A retrospective analysis.
Authors: Moreira Raphael Brandao , Fernandes Mauricio , Monteiro Mariana Ribeiro , Luiz Francine , Simplicio Erika , Andrade Perla de Mello , Batista Mayara , Lima Letycia , Silva Astrid , Nunez Juliana , Freitas Daniele , Araujo Luiz H. , Aguiar Pedro Nazareth 
Published: May 2020

e15066 Background: Obesity is linked to an increased risk of cancer development. The excess of body fatness seems to be associated with alterations in hormonal, metabolic and inflammatory pathways, that may lead to activation of the carcinogenesis process. Previous studies suggested this obesity pro-inflammatory state could improve ICI clinical efficacy. Methods: Baseline characteristics and clinical outcomes were retrospectively collected from advanced cancer patients of any primary site, and treated with ICI in our institution. The BMI was determined for all pts and categorized into 2 groups: obese (BMI≥30) and non-obese (BMI < 30). Primary outcomes were the association of BMI category with overall survival (OS) and progression free survival (PFS) assessed by log-rank statistic, and both were stratified by sex, age, treatment agent and primary tumor site using the Cox-regression. Secondary outcome was the association of BMI with objective response rate (ORR). Results: We collected data from 448 advanced cancer pts - 192 (43%) as normal weight, 159 (36%) as overweight, 78 (17%) as obese and 19 (4%) as underweight. A total of 370 pts (83%) were included in the non-obese group (BMI < 30) and 78 (17%) patients in the obese group (BMI≥30). The majority of pts (387 - 84%) received anti-PD-1/anti-PD-L1; 128 pts (28%) were treated at 1st line and 200 pts (44%) at 2nd line. The obese group experienced longer mOS than the non-obese group - 21.8 months (95% CI NR - NR) vs. 14.9 months (95% CI 8.3 -21.5); HR = 0.82, (95% CI 0.57-1.18, P = 0.28). However, this was not statistically significant and even after stratification. The obese group had an inferior mPFS than the non-obese group - 4.7 months (95% CI 3.8- 5.7) vs. 5.3 months (95% CI 3.45-7.15); - HR = 0.99, (95% CI 0.76 -1.30), P = 0.95. There was no significative difference in mPFS and ORR according to BMI. Conclusions: Although study did not report an improved OS among high BMI pts treated with ICI, our results suggested a trend in survival benefit. The BMI should be explored as a stratification variable in the design of prospective trials with advanced cancer pts and ICI treatment.
Effect of concurrent beta-blocker use in patients receiving immune checkpoint inhibitors for advanced solid tumors.
Authors: Patel Vaibhav G. , Qin Qian , Wang Bo , Gogerly-Moragoda Mahalya , Mellgard George , Zhong Xiaobo , Parikh Anish B , Leiter Amanda , Gallagher Emily J. , Oh William K. , Galsky Matt D. , Tsao Che-Kai 
Published: May 2020

e15068 Background: Stress-induced adrenergic signaling suppresses the immune system. In animal model systems, pharmacological beta-blockade stimulated CD8+ T-cell activity, and further, it improved clinical activity of immune checkpoint inhibitors (ICI) in inhibiting tumor growth. Herein, we investigate the effect of beta blockers (BB) on clinical outcomes of patients receiving ICI in advanced solid tumors. Methods: We retrospectively evaluated patients with solid tumors treated with at least 2 doses of ICI at our institution from December 2010 to April 2017. The primary outcome was disease control rate (DCR), as defined by radiographic complete response, partial response, or stable disease, by RECIST 1.1 criteria. The primary predictor was use of BB (β1-selective BB vs. no BB; non-selective BB vs no BB). The primary predictive variable was analyzed using multivariate logistic regression model controlling for several parameters including patient demographics, co-morbidities, ECOG performance status, and tumor type and location of metastases. All tests were two-sided at the significant level of 0.05. Results: We identified 298 evaluable patients with median age of 66.5 (31-95). Of these patients, 200 (67%) did not use BB, 75 (25%) used β1-selective BB, and 23 (8%) used non-selective BB. In multivariate analysis, use of β1-selective BB was significantly associated with improved DCR compared to no BB (ORR 2.43, 95% CI 1.31-4.51, P = 0.005), while use of non-selective BB was not associated with improved DCR (ORR 1.71, 95% CI 0.65-1.47, P = 0.27). Conclusions: The concurrent use of BB may enhance the clinical activity of ICI, particularly β1-selective BB. Our findings warrant further investigation to understand the interaction of β1- and β2-adrenergic signaling and antitumor immune activity, and potentially explore a combination strategy of ICI and BB.
The clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors.
Authors: Yuan Min , Fang Juemin , Zhu Zhongzheng , Mao Wei , Wang Hui , Liu Weixing , Qian Hong , Wu Jianguo , Guo Xianling , Xu Qing 
Published: May 2020

e15081 Background: Anlotinib (AL3818) is a novel multi-target tyrosine kinase inhibitor (TKI) for tumor angiogenesis and tumor cell proliferation. Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We reported results from the clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors. Methods: 21 patients with advanced lung, gallbladder, endometrial, gastric, pancreatic, penile cancers and melanoma were treated since January 2019. Patients received a combination of anlotinib (12mg) once daily on day 1 to day 14 (21 days as a course) plus anti-PD-1 antibodies every 3 weeks until progression or unacceptable toxicity. Radiologic imaging was performed every 6 weeks for the first year of therapy. Results: Among 21 enrolled patients, 11 tumor types were represented, with lung, gallbladder, endometrial cancers and sarcoma being the most common.Most patients had received prior systemic therapy for metastatic disease (76.2%). The objective response rate (ORR) was 19.1%, including one complete responses (CR) (4.8%) and three partial responses (PR) (14.3%) and a disease control rate (DCR = CR+PR+SD) of 81.0% (17 of 21). One CR and three PRs have lasted 4, 4, 5 and 8 months, respectively. Thirteen patients (61.9%) had stable disease (SD) that lasted 1.5 to 13 months. Treatment-related adverse events occurred in 12 patients (57.1%). Three patients (14.3%) had grade 3 treatment-related adverse events. There were no grade 4 and 5 treatment-related adverse events. Grades 3 toxicities included hand-foot syndrome (n = 1) and hypertension (n = 2). Conclusions: anlotinib can be administered combined with anti-PD-1 antibodies with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomized trial.