bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative quantitative safety profiles of PD-1 and PD-L1 checkpoint inhibitor monotherapies: A Bayesian model-based meta-analysis.
Authors: Shulgin Boris , Smirnova Alexandra , Kosinsky Yuri , Helmlinger Gabriel , Peskov Kirill 
Published: May 2020

e15167 Background: Anti-cancer therapies with immune checkpoint inhibitors (ICIs) are associated with immune-mediated adverse events (imAEs). The objective of this study was to use a Bayesian model-based meta-analysis, to compare safety profiles of PD-1 and PD-L1 checkpoint inhibitor monotherapies. Methods: We performed an exhaustive search through PubMed and TrialTrove databases, ASCO and ESMO abstracts to identify relevant ICI safety data. A Bayesian meta-analysis (BMA) was performed for all-grade and high-grade (Grades 3-4) treatment-related AEs (trAEs) and immune-mediated AEs (imAEs). The analysis was performed for total AEs and individual AEs affecting different organs: dermatological (rash, pruritus), gastrointestinal (diarrhea, colitis), hepatic (AST, ALT), respiratory (pneumonitis), and endocrine (hyperthyroidism, hypothyroidism). Software STAN along with the brms package in R software were used for the BMA. Results: A total of 145 articles were identified, covering 30,737 patients in 153 cohorts treated with anti PD-1 and anti PD-L1 monotherapies. For total all-grade and grade 3&4 trAEs, anti PD-L1 demonstrated lower AE rates vs. anti PD-1 (65% vs. 69% and 12% vs. 16%, respectively). Results were similar for total all-grade and high-grade imAEs (19% vs. 26% and 4% vs. 7%, respectively). The analysis of all-grade individual trAEs showed that anti PD-L1 exhibited lower AE rates vs. anti PD-1 for rash (8% vs. 10.5%), pruritus (9% vs. 12%), diarrhea (8.5% vs. 11%), colitis (1.0% vs. 1.6%), AST (3.0% vs. 5.5%), ALT (3.5% vs. 5.6%), pneumonitis (3.0% vs. 3.9%), hyperthyroidism (0.8% vs. 4.0%) and hypothyroidism (6.0% vs. 8.0%). For grade 3&4 trAEs, differences between anti PD-L1 and anti PD-1 were: 0.6% vs. 1.3% for diarrhea, 0.7% vs. 1.4% for colitis, and 0.9% vs 1.6% for pneumonitis. All-grade imAEs were less frequent for anti PD-L1 vs. anti PD-1 for: rash (6.5% vs. 10%), colitis (1.0% vs. 2.0%), AST (3.5% vs. 3.9%), ALT (2.9% vs. 4.0%), pneumonitis (2.0% vs. 4.0%), hyperthyroidism (2.5% vs. 4.0%) and hypothyroidism (5.5% vs. 9.0%). Similar results were obtained for grade 3&4 imAEs incidences: rash (0.5% vs. 0.9%), diarrhea (0.5% vs. 1.5%), colitis (0.5% vs. 1.1%) and pneumonitis (0.9% vs. 1.4%). Conclusions: Significant differences in trAEs and imAEs rates were shown for anti PD-L1 vs. anti PD-1 monotherapies. Anti PD-L1 demonstrated more favorable safety profiles for total and individual AE rates. Notably, AE rates for pneumonitis and colitis were twice as high for anti PD-1 vs. anti PD-L1 therapies.
Correlation between TMB and MSI in patients with solid tumors.
Authors: ZHAO ZHENG , Li Wentao , Zhang Xing , Ge Minhui , Song Chao 
Published: May 2020

e15169 Background: Both oftumor mutational burden (TMB) and microsatellite instability (MSI) are promising predictive biomarkers for immunotherapy in cancer treatment. However, the association between TMB and MSI with solid tumors was not well investigated especially in East Asian patients. Herein, the relationships for characterizing TMB and MSI in major cancer types were made. Methods: TMB and MSI were measured by 539 genes panel via NGS in tumor tissues. The TMB were calculated as the numbers of synonymous and nonsynonymous mutations, and InDels per megabase in coding regions. MSI was the gain or loss of nucleotides from repetitive DNA and the criteria of MSI-H were defined as above 10% positive of the 195 tested microsatellites sites, and this method was totally consistent with conventional MSI-PCR testing in Research and development sample verification. The relationships between TMB and MSI of 874 patients with solid tumors including 174 patients with liver cancer, 32 patients with bile duct cancer, 54 patients with gastric cancer, 119 patients with colorectal cancer, 27 patients with pancreatic cancer, 32 patients with melanoma, 25 patients with glioma and 411 patients with lung cancer cases were performed by Spearman rank correlation analysis via SPSS v22.0. Results: There was no significant correlation between TMB and MSI in total patients with solid tumors (r = 0.061, p = 0.073). Significantly correlations were observed in patients with colorectal cancer (r = 0.248, p = 0.006) and pancreatic cancer (r = 0.397, p = 0.040). Meanwhile, no significant correlations between TMB and MSI were identified in patients with liver cancer (r = -0.016, p = 0.830), bile duct cancer (r = 0.325, p = 0.070), gastric cancer (r = 0.209, p = 0.130), melanoma (r = -0.057, p = 0.757), glioma (r = 0.009, p = 0.967) and lung cancer (r = 0.015, p = 0.758). Interestingly, total eleven cases were confirmed as MSI high in patients with colorectal cancer, glioma and lung cancer all presented phenotypes of TMB high. Conclusions: We demonstrated the presence of tumor-specific properties correlations between TMB and MSI and provided new insights to use them as biomarkers in immunotherapy. As a retrospective study with a relatively small population, the conclusions of this study needed to be verified with a larger sample.
Comparison of tumor mutational burden across eight types of human cancer.
Authors: Chen Peng , Zhang Cuicui , Meng Zhaoting , Zhang Xing , Ge Minhui , Qin Huijuan 
Published: May 2020

e15170 Background: Tumor mutational burden (TMB) is an impressive predictive biomarker for immune checkpoint inhibitors therapy, and immunotherapy is one of the most promising methods for cancer treatment. However, the profile of TMB in various types of cancers was still poorly understood. Methods: In this study, genomic profiling of DNA was performed using next generation sequencing from a 539 genes panel in tumor tissues. The TMB was defined as the numbers of SNVs including synonymous and nonsynonymous mutations, and InDels per megabase in coding regions of sequenced genome. TMB-H was defined as highest mutation load quintile (top 20%) in each cancer type. The values of TMB of 874 patients were compared among eight main tumor types including 174 patients with liver cancer, 32 patients with bile duct cancer, 54 patients with gastric cancer, 119 patients with colorectal cancer, 27 patients with pancreatic cancer, 32 patients with melanoma, 25 patients with glioma and 411 patients with lung cancer cases by multiple independent samples nonparametric Kruskal-Wallis H test via SPSS v22.0. Results: The median values of TMB in liver cancer, bile duct cancer, gastric cancer, colorectal cancer, pancreatic cancer, melanoma, glioma and lung cancer were 10.29, 8.09, 11.03, 10.29, 5.88, 7.35, 5.88 and 7.35 Muts/Mb, respectively. The cut-off values of TMB-H in corresponding eight solid tumors were 16.18, 19.12, 19.85, 16.18, 10.29, 13.24, 10.29 and 18.38 Muts/Mb, respectively. Based on nonparametric Kruskal-Wallis H test, there were significant differences of median TMB values across eight independent tumor types (χ2 = 26.752, p = 3.693×10−4). Significant differences between patients with colorectal cancer and pancreatic cancer ( p = 0.005) or lung cancer ( p = 0.011) were observed via pairwise comparisons. Conclusions: Our study proved the presence of significant differences across eight cancer types, deepened the knowledge of the cancer-specific of TMB, provided useful information in immunology therapy for East Asian patients with solid tumors. As a retrospective study with a relatively small population, the conclusions of this study needed to be verified with a larger sample.
Integration of TMB and tumor heterogeneity identify an immunologic subtype of melanoma with favorable survival.
Authors: Yang Chunhe , Zhao Guodong , Wang Jianfei , Wang Lingyu , Jin Ge , Lin Rongbo , Yang Yadong 
Published: May 2020

e15183 Background: Tumor mutational burden (TMB) has been reported a predictive marker of response to immune checkpoint inhibition (ICI) therapy in previous clinical trials. However, TMB alone is not sufficient to accurately predict immunotherapy benefit. Additional biomarkers are needed for better stratification of immunotherapy sensitive patients. Methods: Here we combined TMB with tumor heterogeneity for evaluating response to ICI treatment. Mutation and clinical data were collected from several melanoma immunotherapy studies, including cohort treated with Ipilimumab and anti-PD-(L)1/anti-CTLA-4 (VanAllen_2015, n = 110; Miao_2018, n = 151) and a cohort treated with Nivolumab (Riaz_2017, n = 60). Tumor heterogeneity was estimated with mutant-allele tumor heterogeneity (MATH) or clone number. Benefit score was defined as ratio between TMB and tumor heterogeneity and the most significant critical values were selected to group patients. Besides, we calculated clonal TMB and investigated its correlation with TMB and tumor heterogeneity. Statistical analyses were performed using R software. Results: Benefit score was tested in several cohorts as a marker of ICI therapy response. In VanAllen_2015 and Miao_2018 cohort, TMB/MATH score significantly improved the performance of stratifying the overall survival (OS) of patients with ICI treatment compared with TMB alone as predictor (p = 0.0068 vs. p = 0.1 and p = 0.028 vs. p = 0.042). In Riaz_2017 cohort, we used clone number to calculate the benefit score due to the unavailability of the raw data. In this cohort, benefit score is also positively associated with higher overall survival (p = 0.056), which outperforms TMB alone with a significance of p = 0.57. Moreover, clonal TMB showed positive correlation with TMB (R > 0.3) and negative correlation with tumor heterogeneity (R < -0.3) in one melanoma cohort (Miao_2018). Conclusions: Tumor heterogeneity, combined with TMB showed superior efficacy in predicting response of ICI therapy. This may further help delineating the mechanisms of immunotherapy in melanoma patients.
Utilizing quantitative multiplex immunofluorescence to characterize paracrine interactions within the tumor-immune landscape of metastatic melanoma.
Authors: Maus Rachel L. , Leontovich Alexey , Moore Raymond , Nevala Wendy Kay , Flotte Thomas J. , Geyer Susan , Guo Ruifeng , Schimke Jill , Dicke Betty Ann , Markovic Svetomir 
Published: May 2020

e15184 Background: Clinical responses to anti-PD1 immunotherapy in patients with metastatic melanoma (MM) remain challenging to predict. This clinical heterogeneity is also reflected in the tumor-immune microenvironment among patients and within a single tumor lesion. With the emergence of multiplex imaging platforms, defining complex phenotypes at single cell resolution has become possible. Here, we sought to objectively quantify paracrine tumor-immune interactions contributing to the variable clinical responses observed in patients receiving anti-PD1 therapy. Methods: Excisional lymph node (LN) biopsies were obtained from treatment-naïve patients with MM who underwent subsequent anti-PD1 therapy. A single 5µm section of LN tissue was used to assess a 42 analyte panel by multiplex immunofluorescence. From 30 LN samples, 418 fields of view (FOVs) were selected resulting in 14,360 high-resolution images of 4 anatomical subregions: tumor core, tumor-immune interface, tumor infiltrate and adjacent immune stroma. Following image processing, we developed an adaptive classification for tumor-centric cellular neighborhoods (TCCN) to identify and quantify critical paracrine interactions within the tumor-immune microenvironment. Results: Stratification based on responsiveness to anti-PD1 therapy resulted in 4 complete responders (CR) and 12 non-responders (NR) at 12-week follow-up. From 126 FOVs, we defined the cellular composition of 197,865 TCCN across patients based on clinical response and LN subregions. Overall, the percentage of TCCN devoid of any T cells, B cells or macrophages was significantly higher in NR compared to CR irrespective of subregion. However, other markers differentiated TCCN based on subregion. Specifically in CR, tumor core regions were enriched for CD8 T cells, while enrichment for B cells and endothelial cells was demonstrated at the tumor-immune interface. Strikingly, tumor infiltrate regions demonstrate robust immune reactivity with enrichment for M1 polarized macrophages, NK cells and B cells in CR compared to NR. Complete data from the 30 patient cohort across 418 FOVs will be presented. Conclusions: Taken together, this data suggests cellular composition of TCCN across subregions of the LN is dynamic within a single metastatic site. In this small cohort, we introduce a formalized stratification to quantify and classify critical paracrine interactions within the immune-tumor microenvironment with the potential to inform clinical responsiveness to therapy.
The role of TGF-β pathway in immune regulation as a potential biomarker of immunotherapy across pan-cancer.
Authors: Yin Yongmei , Liang Yan , Zhao Zhengyi , Zhang Yuzi , Zhao Jing , Cui Longgang , Wang Guoqiang , Bai Yuezong , Cai Shangli 
Published: May 2020

e15187 Background: The transforming growth factor beta (TGF-β) signaling pathway has been reported to be involved in both tumor suppression and tumor promotion. However, the role of TGF-β pathway in immune regulation for cancer patients and its influences on immunotherapy efficacy have not been systematically investigated. Methods: Available data of whole-exome sequencing, mRNA expression, baseline characterization and prognosis information of 10,912 pancancer patients were adopted from The Cancer Genome Altas (TCGA) to explore the role of TGF-β pathway in immune regulation. Formalin-fixed, paraffin-embedded tissue samples from 6,717 Chinese patients with over 17 tumor types were assayed by next-generation sequencing with a panel with 381 cancer related genes as a validation cohort (3DMed cohort). Datasets from the public MSK cohort (N = 1,610) was used to explore the association of TGF-β pathway in patient survival. Results: The highest prevalence of single nucleotide variation (SNVs) in TGF-β pathway fell in digestive system tumors in both TCGA and 3DMed cohorts, including colon adenocarcinoma pancreatic adenocarcinoma, rectum adenocarcinoma, and stomach adenocarcinoma. TGF-β pathway SNVs was significantly correlated with high microsatellite instability, high tumor mutational burden (TMB-H) status and high neoantigen burden (TNB-H) ( p< 0.001) across all tumor types. Notably, the correlation of pathway alternation and TMB or TNB remained significance in microsatellite stable patients ( p< 0.001). Alternations of the pathway genes were associated with significant different expression patterns of immune-related genes such as the up-regulation of CD28, CD40, and CCL5, etc. Consistently, significant higher levels of CD8 ( p< 0.001), dendritic cells ( p< 0.001), and neutrophil cells ( p< 0.001) were observed in the pathway mutated samples. Patients with TGF-β pathway mutations exhibited significant worse prognosis than the wild-type patients regardless of interventions (overall survival, HR 1.20, 95% CI 1.08-1.33; p= 0.001). However, when treated with immune checkpoint inhibitors, superior survival benefit was observed in patients in the mutation group versus the wild-type group (overall survival, HR 0.73, 95% CI 0.61-0.88; p= 0.001). Conclusions: Our study has provided clues for the role of TGF-β pathway in immune regulation in patients with solid tumors and revealed the potential predictive role of TGF-β pathway alternation in cancer immunotherapy.
Potential use of IL-7 and IL-15 for ex vivo generation of LAK.
Authors: Filippova Svetlana Yu. , Kit Oleg I. , Sitkovskaya Anastasia O. , Zlatnik Elena Yu. , Novikova Inna A. , Vashchenko Larisa N. , Kechedzhieva Emma E. , Dashkova Irina R. , Ausheva Tatiana V. , Andreiko Elena , Saforyan Natalya S. , Vladimirova Liubov Yu 
Published: May 2020

e15201 Background: A review of scientific literature has shown that IL-2 is most often used for the LAK generation, while the potential of other NK-stimulating interleukin cells remains poorly understood. In this study, we investigated the effect of IL-7 and IL-15 on ex vivo LAC generation. Methods: A fraction enriched in NK cells was isolated by magnetic cell sorting with the NK Cell Isolation Kit (#130-092-657, Miltenyi Biotec, Germany) from PBMC in 11 patients with stage II-III breast cancer without treatment. Cells were introduced into a 6-well 3x105 plate in RPMI medium (Gibco, USA) supplemented with 10% FBS (Gibco, USA). Cytokines 40 ng/ml were added to the wells in 6 variants: 1) IL-15; 2) IL-2; 3) IL-7; 4) IL-15+IL-7; 5) IL-15+IL-7+IL-2; 6) control without cytokines. Cells were cultured at 5.0% CO2 and 37°C. Cells were counted with a hemocytometer daily for 5 days and on days 8, 9 and 10 of cultivation. Results: The number of NK cells in control samples gradually decreased: by 2 times on day 5 and by 3 times on day 10. On day 5, the number of NK cells was 1.5 times higher than in the control when cultured with IL-2, and 1.4 times higher when cultured with IL-7+IL-15. After 9 days, a statistically significant increase in the number of cells, compared to the control sample, was observed with the addition of IL-2 (1.6 times); IL-15 and IL-7+IL-15 (1.5 times). On day 10, significant differences from the control were found in most samples: the number of cells was higher in samples cultured with IL-2 and IL-7+IL-15 (1.9 times) and with IL-15 and IL-2+IL-7+IL-15 (1.7 times). IL-7 alone led to a gradual decrease in the number of cells, and on days 8, 9 and 10 it was lower than in the control samples. Conclusions: In general, the introduction of cytokines into the samples enriched with NK cells contributed to the preservation of this subpopulation on days 5-10 of cultivation. However, the use of IL-7 and IL-15, both alone and in combination, did not lead to a significant increase in LAK compared to the use of IL-2.
Proteome-wide biomarker quantification and target screening.
Authors: Quan Qimin , Geanacopoulos John , Ritchey Joshua , Clenow Mark , Wilkinson Joe , Boyce John 
Published: May 2020

e15205 Background: Existing drug development programs are represented by only a few hundred protein targets. A large subset of the ~20,000 proteins encoded by the human genome remain undiscovered. Proteome-wide “druggability” screening may lead to new targets for therapeutics. Methods: The NanoMosaic platform is a digital immunoassay technology that achieves sub-pg/ml level sensitivity, whole-proteome level multiplexing capability, and 7 logs of dynamic range. The platform overcomes the sensitivity and dynamic range limitations of traditional protein arrays and mass spectrometry. Results: The NanoMosaic technology is powered by silicon nanoneedle biosensors that are densely integrated on a plate and manufactured with CMOS-compatible nanofabrication processes. Each nanoneedle is a label-free biosensor, functionalized with capture antibodies. Its scattering spectrum changes when an antigen binds to its surface. Each analyte specific sensing area consists a total of ~23k nanoneedles divided into a digital region (~20k nanoneedles) and an analog region (~3k nanoneedles). The digital nanoneedles provide the single molecule sensitivity. Therefore, at ultra-low concentration when antigens that are captured by the nanoneedles follow Poisson statistics, the number of antigens can be quantitated by counting the presence or absence of color changes of individual nanoneedles in a binary fashion. As the protein concentrations increase, the binding event counts increase accordingly and achieve saturation when all nanoneedles capture more than one protein. Above the digital saturation concentration, an adjacent section of analog nanoneedles perform quantitative analysis based on the level of color change, thus providing a wider dynamic range up to 1ug/ml. Ultrahigh level multiplex can be achieved by parallelizing the detection in a microarray format without loss of the sensitivity and dynamic range. A 20,000-plex proteome-wide study can be achieved with a total of 5 billion nanoneedles on a ~70mm by 70mm chip. Conclusions: In conclusion, proteome-wide biomarker quantification and target discovery can be performed on the NanoMosaic platform at higher sensitivity, wider dynamic range, lower cost and higher throughput than is currently possible by mass spectrometry or traditional immunoassays.
AVIDIO as a novel oncolytic immunotherapy platform for the treatment of colorectal cancer.
Authors: Almassian Bijan , Madina Bhaskara R , Chen Ju , Ye Xiaoyang , Krady Marie M , Ma Xianyong , Yarovinsky Timur O , Mason Stephen W , Nakaar Valerian , Wang Kepeng 
Published: May 2020

e15210 Background: Colorectal cancer is the third deadliest of all cancers causing more than 50,000 deaths per year in the U.S. Oncolytic viruses have seen limited use for the treatment of cancers, and further improvement of these methods with immune-modulating activities may prove crucial for the effectiveness of these agents in the treatment of human malignancies. To this end, we developed an artificial virus for infectious diseases and immuno-oncology (AVIDIO) platform that employs virus-like vesicles (VLV) for both the delivery of immunomodulatory agents to tumors and oncolytic activity. Methods: The AVIDIO platform is comprised of in vitro evolved RNA-dependent RNA polymerase from an alphavirus, Semliki forest virus, and envelope glycoproteins from vesicular stomatitis virus, which together form VLVs. Both unarmed VLVs and VLVs armed with the p35 subunit of IL-12 (VLV-IL12p35), an immunomodulatory cytokine that can induce Th1-mediated immunity, were tested for oncolytic activity against various cancer cell lines, including MC38 colorectal cancer cells, in vitro. Using the MC38 syngeneic murine tumor model, we evaluated the antitumor activity of VLV-IL-12p35 in vivo. We used tumor growth measurements and analyses of tumor-infiltrating cells after consecutive treatments with VLV-IL-12p35 to monitor its antitumor and immunomodulatory activities, respectively. Results: VLV-IL-12p35 showed robust oncolytic activity against MC38 cells in vitro, killing over 80% of cells within 24 h. Treatment of intradermal MC38 tumors by intra-tumoral delivery of VLV-IL-12p35 resulted in more than 65% suppression of tumor growth within 2 weeks ( p< 0.05). VLV-IL-12p35-treated tumors also harbored significantly more CD8+ T cells, IFN-gamma-producing CD4+ T cells, and reduced numbers of Foxp3+ regulatory T cells. Conclusions: Our results show that VLV-IL-12p35 derived from the AVIDIO platform has oncolytic activity in vitro and antitumor and immunomodulatory activities in vivo. Therefore, AVIDIO is a promising platform for the delivery of immunomodulatory agents to tumors. Further optimization of the platform, including the addition of other immunomodulatory agents, is in progress to advance the AVIDIO platform to clinical applications for colorectal cancer.