bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a predictive biomarker and two pharmacodynamic biomarkers to ADG106 treatment, a novel anti-CD137 agonist antibody, in phase I clinical trials.
Authors: Zhang Li 
Published: June 2021

e14505 Background: ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody that mediates anti-tumor activities via unique mechanisms of action. Here we provide safety and efficacy updates from our phase I trials and report the findings of a predictive biomarker and two pharmacodynamic biomarkers which correlate with patients’ clinical responses to ADG106 treatment and demonstrate target engagement, respectively. Methods: Formalin fixed and paraffin embedded (FFPE), blood and plasma specimens were collected from 92 patients enrolled in our phase I trials. We measured expression across a panel of protein biomarkers in FFPE specimens using three highly sensitive detection technologies: multiple immunohistochemical (IHC) staining of protein expression, the BD Multitest 6-color TBNK reagent for profiling immune cell subpopulations, and the MSD-ECL electrochemiluminescence assay for detection of soluble CD137. Objective tumor responses were determined using RECIST v1.1 for solid tumor patients and Lugano classification for lymphoma patients. Results: As of November 30, 2020, ADG106 has demonstrated a favorable safety profile and efficacy in the phase I clinical trials with a disease control rate of 56%. From a retrospective analysis of 28 pretreatment FFPE specimens, we identified a predictive biomarker that correlated with tumor shrinkage upon ADG106 treatment. We identified four biomarker positive specimens from two patients with lymphoma and two with solid tumors. Three out of four biomarker positive patients achieved greater than 30% tumor shrinkage after 3mg/kg or 5mg/kg ADG106 treatment. One biomarker positive patient with stable disease received a low dose ADG106 treatment at 0.5mg/kg during dose escalation. None of the 24 biomarker negative patients showed significant clinical response. A tissue microarray study confirmed expression of this predictive biomarker in a variety of tumor types suggesting a broad indication for ADG106 therapy. Our biomarker studies also demonstrated target engagement with increased NK cell proliferation and soluble CD137 upon ADG106 treatment. Analysis of safety, efficacy, PK and PD data allowed us to select a recommended dose for the upcoming phase II study. Conclusions: We identified a biomarker predictive of response to antitumor CD137 blockade by ADG106, as well as demonstrated the involvement of NK cells in ADG106 mediated anti-tumor activities. In upcoming phase II trials, we plan to enrich for populations expressing this predictive biomarker to demonstrate a clinical benefit to ADG106 therapy further validating early biomarker-based patient stratification. We will also explore the potential of selecting patients for combination treatment with anti-PD-1 therapies. Clinical trial information: NCT03802955.
Gene expression profiling signatures for immunophenotyping of tumor microenvironment using HTG EdgeSeq Precision Immuno-Oncology Panel.
Authors: Jaramillo Melba C. , LaRoche Dominic , Ran Di , Navratil Marian 
Published: June 2021

e14528 Background: Immunotherapy has revolutionized cancer treatment by harnessing the power of the patient’s immune system to fight the disease. While immunotherapies have become increasingly effective, the proportion of patients not responding to immunotherapy ranges between only 20-50%. New breakthroughs in the understanding of the tumor immune biology have led to the development of new, more effective therapies; however, these breakthroughs often hinge on tools that can elucidate the role and abundance of individual components of the patient’s immune system in the tumor microenvironment. Methods: This poster describes the performance of 26 gene enrichment signatures that allow for the measurement of the relative abundance of 23 individual immune and stromal cells in the tumor environment, in addition to providing composite inflammation, stroma and tumor microenvironment scores. These Research Use Only (RUO) signatures are based on gene expression profiling (GEP) data for 1,392 genes implicated in tumor-immune interaction generated using the HTG EdgeSeq Precision Immuno-Oncology Panel (RUO). The signatures were developed and validated using GEP data from 1,073 colorectal, gastric and ovarian cancer formalin-fixed paraffin-embedded (FFPE) tissue specimens. Results: The signature accuracy was independently verified by spiking known numbers of representative immune and stromal cells into an FFPE tissue lysate; the signature outputs were highly correlated to the number of immune and stromal cells present in the sample, with Pearson correlation coefficients ranging from 0.71 to 0.98. In addition, the outputs of some of the signatures were compared to multiple commonly used immunohistochemistry markers of immune cells in 61 non-small-cell lung carcinoma FFPE samples. The results showed a high degree of correlation, with Pearson correlation coefficients of 0.77 and 0.81 for CD4 and CD8, respectively. Conclusions: These immunophenotyping signatures provide a suite of robust tools for the characterization of the tumor microenvironment in order to better understand the tumor immune biology and mechanisms of resistance to immunotherapy. The signature scores can typically be generated from a single section of FFPE tissue using HTG’s extraction-free GEP technology and a fully automated bioinformatic pipeline available in the HTG EdgeSeq Reveal software.
Case series on the safety of mRNA COVID19 vaccines in cancer patients undergoing treatment.
Authors: Haroun Faysal , Alharbi Malak , Hong Alison 
Published: June 2021

e14562 Background: Millions of vaccines have been administered since Emergency Use Authorization has been granted for two mRNA COVID-19 vaccines (mCV). The Center for Disease Control (CDC) and Prevention recommends that immunocompromised individuals with no contraindications to vaccines may receive an mCV. The CDC suggests that patients receiving cancer therapies should be consulted about the unknown vaccine safety profile and effectiveness. The American Society of Clinical Oncology recognizes that vaccine may reduce the risk of infection for individuals with cancer. Vaccine trials have not actively enrolled immunocompromised or patients on active cancer therapy; therefore, the potential side effects and efficacy of the mRNA vaccines in these individuals are unexplored. Per state guidelines, many patients with cancer undergoing treatment qualify for vaccination however current vaccine uptake in that population is unknown. Data in this specific high-risk population is needed to increase confidence in the vaccine. We explored adverse events (AE) to the mCV in a small cohort of patients undergoing cancer therapy. Methods: Our case series evaluated patients' tolerance to the voluntary but recommended 2 doses of the mCV while on chemotherapy (CX), checkpoint inhibitors (CPI) or tyrosine kinase inhibitors (TKI) at the George Washington University (GWU) Cancer Center in Washington DC. Patient chart review and phone interviews were conducted. Patients had independently signed up for the mCV at the GWU Hospital or through the DC Health Department. Patients were asked if they had experienced any of the commonly reported side effects listed by the CDC or others new symptoms receiving the vaccine. Results: 12 patients had voluntarily received the mCV, all patients were above the age of 65 with a mean age of 72 (66-85). ECOG performance status was 2 or above in 4 patients. 6 patients were receiving single agent CPI, 1 patient was on combination CX and CPI. 2 patients were on oral TKI for EGFR mutated lung cancer. 3 other patients were on combination CX with rituximab, ramucirumab or radiation. In the 2 patients on daily TKI, treatment was not interrupted for the mCV. In the 10 other patients, all but one patient received the mCV at least one week after the last therapy. Both mCV were tolerated without any life-threatening AE or hospitalization. Pain and swelling at the vaccine site were the most common local AE and reported in 7 patients. 6 patients reported systemic AE most commonly myalgia and headaches. Conclusions: This exploratory analysis in 12 patients with cancer undergoing treatment did not uncover any additional SE signals. Larger studies are needed to evaluate AE and efficacy and to guide recommendations for COVID19 vaccination in this patient population.
The incidence of occult endocrinopathies in patients with cancer undergoing immunotherapy in community practice.
Authors: Abdalla Ahmed , Singh Aditi , Gharib Hussein , Huber Benjamin , Malapati Sindhu Janarthanam , Hadid Tarik H. , Kafri Zyad 
Published: June 2021

e14571 Background: Immune checkpoint blockade (IO) can induce inflammation of the pituitary, thyroid or adrenal glands. This usually results in non-specific symptoms such as headache, low-energy, nausea and vomiting, which can be difficult to differentiate from symptoms associated with cancer and therapy-related symptoms. Therefore, the exact incidence of endocrinopathies is exceedingly difficult to estimate in community practices. Also, the variable methods of assessment, diagnosis, and monitoring used in different clinical trials make it challenging to precisely measure the incidence of endocrinopathies. Methods: This is a single-center retrospective chart review of patients diagnosed with cancer receiving immunotherapy for cancer treatment who had routine hormone levels checked during their treatment. Data collected includes tumor types and the types of IO agents used. Laboratory data collected included thyroid-stimulating hormone (TSH), testosterone level, follicular stimulating hormone (FSH), luteinizing hormone (LH), cortisol levels. Results: In total, 75 patients were included in the study. The primary indication for IO was lung cancer in 43 patients (57%), genitourinary tumors (12%), melanoma (12%) and head & neck cancers (5.3%). Single-agent nivolumab (39 patients) was the most common IO agent used followed by single-agent pembrolizumab (22 patients), ipilimumab (11 patients), atezolizumab (3 patients), avelumab (1 patient) (There was one patient who got nivolumab initially and then pembrolizumab). Nine patients were treated with ipilimumab/nivolumab combination. The mean number of cycles received was 9.1. The total number of patients who developed at least one abnormal hormone level was 57(76%), with 33 out of 74 (45%) patients had at least one abnormal TSH, 29 out of 44 (66%) patients had at least one abnormal testosterone level, 10 out of 49 (20.4%) patients had at least one abnormal FSH and/or LH level, 36 out of 52 (69%) patients had at least one abnormal cortisol level. The mean number of days from starting IO to develop the first abnormal laboratory result was 106 days. Conclusions: The incidence of endocrinopathy was significantly high in patients receiving IO in this study, which is higher than what is reported in previous clinical trials. This could be due to frequent testing in asymptomatic patients and strict laboratory cut-off values which is not always clinically meaningful. This finding may highlight the importance of routine monitoring of the endocrine function during IO treatment. Routine measurement of hormone levels can detect asymptomatic endocrinopathy which may warrant further work-up and treatment. These findings should be validated in a larger prospective study.
Antitumor efficacy of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone in lung cancer xenografts.
Authors: Lukbanova Ekaterina A. , Goncharova Anna S. , Volkova A. V. , Mindar M. V. , Zaikina Ekaterina V. , Khodakova D. V. , Shevchenko Alexey N. , Filatova Elena V. , Khomutenko Irina A. , Shvyrev Dmitry A. , Sayapin Yuriy A. , Gusakov Evgeniy A. , Lazutin Yuriy N. 
Published: June 2021

e15008 Background: Lung cancer is the most common cancer worldwide. The efficacy of chemotherapy for this tumor does not exceed 40%. Moreover, all cytotoxic agents cause many side effects. The search for new substances with an antitumor effect seems to be relevant. Tropolone alkaloids, which are seven-membered non-benzenoid aromatic compounds, are promising inhibitors of tumor growth. The purpose of the study was to evaluate the antitumor efficacy of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone in subcutaneous xenografts of lung cancer A549 cells in immunodeficient Balb/c Nude mice. Methods: The study was performed on a PDX model of lung cancer created by subcutaneous injection of A549 cell suspension, 5x106 cells in 0.2 ml of a solution of serum-free nutrient medium 199 and Matrigel (1:1). Animals were equally divided into 5 groups (each n = 5). Experimental groups 1, 2, 3 and 4 received 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone at doses of 0.0055, 0.055, 0.55 and 2.75 mg/g, respectively; the control group received 1% starch gel. The dynamics of the growth of a subcutaneous xenograft was evaluated by measuring tumor nodes. The volumes of tumor nodes were calculated using the Shrek’s formula for the ellipsoid: V = a×b×c×p/6, where V is the tumor volume (mm3), and a, b, c are the maximum dimensions of the ellipsoid in three planes (mm). The data were statistically analyzed using the Exel and Medstatistic progams. Results: The dynamics of subcutaneous xenograft growth in groups 1, 2, 3 and 4 significantly differed from the control group (p = 0.023). The average tumor volumes on the 39th day after the implantation in the control group and in experimental groups 1, 2, 3 and 4 were 1159.2, 895.3, 565.8, 80.7 and 76.7 mm3, respectively. The inhibition of tumor growth (ITG) was in direct proportion to the dose of the administered substance. Lower ITG(%) (32.4, 23.2 and 10.3% in experimental groups 2, 3 and 4, respectively) was associated with lower concentrations of О154 (0.55 mg/g, 0.055 mg/g and 0.0055 mg/g, respectively). Conclusions: The study demonstrated statistically significant differences in xenograft volume indices in all experimental groups compared to the control group.
Phase Ib/II study of capecitabine 7/7 schedule with neratinib in patients with HER2-positive metastatic breast cancer (MBC).
Authors: Wang Rui , Singh Jasmeet Chadha , Wong Serena Tsan-Lai , Lake Diana , Iyengar Neil M. , D'Andrea Gabriella , Brockway-Marchello Julia P. , Kaba Asta , Traina Tiffany A. , Robson Mark E. , Dang Chau T. 
Published: June 2021

e15016 Background: Neratinib (N) is a potent irreversible inhibitor of HER1, HER2, and HER4. Capecitabine (X) at optimal dose of 7 days on and 7 days off schedule (7/7) is well-tolerated with low rates of ≥ grade (G3) diarrhea. Methods: We conducted phase Ib/II study of N with X (7/7) with loperamide and colestipol prophylaxis in patients (pts) with pretreated HER2+ MBC (NCT03377387). Eligible pts had normal left ventricular ejection fraction (≥ 50%), any and < 4 prior chemotherapy-based treatments in phase Ib and II, respectively. Primary endpoint of phase Ib is maximum tolerated dose (MTD) and phase II is response rate. Secondary endpoints are safety, tolerability, and progression-free survival. Exploratory endpoint is to quantify cell-free DNA (cfDNA), correlating with response. Phase Ib follows traditional 3+3 design with 4 dose levels. In phase II, if > 3/9 respond, study is expanded to 24. If > 10/24 respond, study is deemed successful. Results: As of 2-4-2021, 10 pts were enrolled in phase Ib. 4 pts were treated at dose level 1 (X at 1500 mg BID at 7/7 and N at 240 mg daily); 2/4 pts experienced with G3 diarrhea during cycle 1. Six pts were treated at dose level -1 (X at 1000 mg BID 7/7 and N at 240 mg daily); 1 (17%) developed G3 diarrhea. The MTD is X at 1000 mg BID 7/7 and N at 240 mg daily. Twenty-two of 24 pts have been enrolled in phase II. Of 22 pts, data show 6 with partial response, 8 with stable disease, 3 with progressive disease, and 5 have not been assessed radiographically. Overall, 6/22 (27.3%) and 1/22 (4.5%) had all G and G3 diarrhea, respectively. Other significant toxicities at MTD included G2 hand foot syndrome (n = 1, 4.5%), G1 fatigue (n = 1, 4.5%) and G1 nausea (n = 4, 18%). Conclusions: The MTD is X at 1000 mg BID at 7/7 and N at 240 mg daily. This combination is safe and well tolerated with G3 diarrhea rate of 4.5%, which is significantly lower than the X 14/7 schedule in NALA study. The phase II portion of the study is near completion and updated result will be presented. Analysis of cfDNA, to correlate with response for phase II portion, is ongoing. Clinical trial information: NCT03377387.
Anti-tumor activity of SKLB-0322, a novel EZH2 covalent inhibitor, in ovarian cancer.
Authors: Zhu Yongxia , Chen Xinyi , Zhang Qiangsheng , Shi Lihong , Yu Luoting , Xiao Hongtao 
Published: June 2021

e15052 Background: Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) that regulate downstream target genes expression, and then promotes tumor cell proliferation, metastasis and drug resistance. EZH2 also performs some functions in a PRC2-independent manner. Most of reported EZH2 inhibitors are S-adenosyle-methionine (SAM)-competitive inhibitor, and are less selective for EZH2 close homolog EZH1, which resulted in safety concerns and insufficient efficacy. To obtain irreversible EZH2 inhibitor, a novel covalent inhibitor was developed and characterized. Methods: SKLB-0322 and its derivatives were designed, synthesized and confirmed as EZH2 covalent inhibitor by us. The anti-tumor activities of SKLB-0322 were investigated by MTT assay, flow cytometry, and western blot assay. The reversible analog of SKLB-0322 (SKLB-0322’) was used as negative control. Results: SKLB-0322 inhibited EZH2 methyltransferase activity with nanomolar potency, while the inhibitory activities of SKLB-0322’ was reduced. The mass spectrometry (MS) analyses revealed that SKLB-0322 could efficiently forms a single modified covalent adduct. SKLB-0322 displayed noteworthy potency against ovarian cancer cell lines at low micromolar level and reduced the expression level of H3K27me3 in a concentration-dependent manner, which was about 5-fold more active than the reversible negative control SKLB-0322’. Besides, SKLB-0322 caused G2/M phase cell cycle arrest in A2780 and PA-1 cells. Furthermore, SKLB-0322 induced A2780 and PA-1 cell apoptosis in a time- and concentration- dependent manner. Conclusions: Our data clarified that SKLB-0322 is an EZH2 covalent inhibitor for ovarian cancer therapy which is worthy of further evaluation.
Inhibitory effect of lignans from Ailanthus altissima on proliferation of human lung cancer cells and its mechanism.
Authors: Wang Yu , Wang Siming , Wu Yibing , Dong Mei , Ni Zhiyu 
Published: June 2021

e15059 Background: Plants are thought to contain compounds that inhibit the proliferation of cancer cells in vitro, and many attempts have been made to isolate anti-cancer drugs from plants. Ailanthus altissima is a family of Simaroubaceae, the bark is gray to grayish-black, because of the smell of the gland patches at the base of the leaves. 3,5,3-trimethoxy-8,1-neoligna-4,2,7,9,9-pentol (TNP) isolated from Ailanthus altissima. Methods: (1) Apoptosis was detected by flow cytometry: the cells were incubated with 10 mmol/L TNP for 24 h, and the cells were collected. The cell concentration was adjusted to 5×105 ̃ 5×106/ L. While propionate iodide was added for DNA fluorescence staining (Propidium Iodide, PI: 50 mg/L，triton-x100 1.0%). (2) The changes of p53, Bax and caspase-3 were detected by Western blot. The cells were cultured in 10 μmol/L cisplatin and TNP medium for 24 hours. Image J image analysis software is used for semi quantitative analysis. The data were expressed by mean standard deviation, and the mean values of each group were compared by analysis of variance and the least significant difference. There was a significant difference in P< 0.05. (3) A549 cells were treated with 10 μmol/L cisplatin and TNP. A549 cells were incubated with cisplatin and TNP, and then treated with solvent control (final concentration 0.1% dimethyl sulfoxide) with or without caspase inhibitor for 48 hours The OD value was determined by MTT method. Cell survival rate (%) = (OD value of control group /OD value of control group) 100%. Results: (1) The reverse effect of caspase inhibitor on the proliferation of A549 cells: the cell survival rates of A549 cells treated with 0.1, 1 and 10 μmol/L cisplatin and TNP were 96.11%, 72.36%, 27.57% and 71.42%, 28.97% and 4.34% respectively. The survival rate of A549 cells incubated with cisplatin and TNP 20 μmol/L increased to 100.00%, 81.92%, 57.54% and 85.69%, 48.57% and 16.95% respectively. Caspase inhibitor reversed the inhibitory effect of TNP on A549 cells. (2) The effect of TNP on apoptosis of A549 cells: after treatment with 10 μmol/L TNP for 24 h, the apoptosis rate of A549 cells was (24.01)%, which was significantly higher than that of the blank control group (6.79)% ( P< 0.05). (3) The results showed that the up regulation of p53, Bax and caspase-3 protein by TNP was 10 μmol/L. Conclusions: TNP can induce apoptosis of human lung cancer cell line A549, and it can up regulate the expression of p53, Bax and Caspase-3, which may be one of the mechanisms of TNP inducing apoptosis of A549 cells. The experiment also proves that caspase inhibitor can reverse the effect of TNP. TNP inhibits the proliferation of A549 cells.
Genetic alterations in MSS and TMB-H Chinese colorectal cancer patients.
Authors: Ren Shuangyi , Guo Taiyan , You Xia , He Qianru , Zhang Qin , Qi Chuang 
Published: June 2021

e15524 Background: Efforts by previous study had provided molecular profile of MSS & TMB-H gastrointestinal (GI) cancers, however, Asian patients were underrepresented in this study. We aim to investigate specific molecular features of Chinese MSS & TMB-H colorectal cancer patients. Methods: FFPE tumor samples from 249 Chinese colorectal cancer patients with MSS & TMB-H (Chinese cohort) were sequencing using a panel targeting 539 cancer-related genes of the human genome. Genomic data from our cohort was compared with publicly available data from 508 MSS & TMB-H colorectal cancer patients from the TCGA dataset (TCGA cohort). TMB was calculated on the two cohorts following the same criteria. TMB-H was defined as the top quartile of all TMB values. Results: In total, 48 (19%) MSS & TMB-H patients were found in Chinese cohort, and 55 (10%) were found in TCGA cohort. Based on the analysis of the genetic alteration profile from our cohort, in MSS & TMB-H colorectal cancer patients, APC (85%), TP53 (81%), KRAS (44%), and LRP1B (378%) as the most commonly altered genes. In TCGA cohort, TTN (84%), APC (80%), TP53 (64%), SYNE1 (51%), and MUC16 (51%) as the most commonly altered genes. On the other hand, the most difference genes between MSS & TMB-H group and MSS/TMB-L group in TCGA cohort were TNN (84% vs. 52%; p = 0.000008), SYNE1 (56% vs. 24%; p = 0.000003), MUC16 (51% vs. 23%; p = 0.00006), FAT4 (47% vs. 16%; p = 0.000002), RYR2 (44%vs. 16%; p = 0.00001). Compared with TCGA cohort, LRP1B (38% vs. 13%; p = 0.0005), TCF7L2 (33% vs. 8%; p = 0.00003), SPTA1 (29% vs. 6%; p = 0.00005), PREX2 (19% vs. 3%; p = 0.0006) were the most difference genes between MSS & TMB-H group and MSS/TMB-L group in Chinese cohort. Conclusions: Our study contributes to the understanding of specific genetic alterations harbored by MSS & TMB-H colorectal cancer patients that could potentially be developed as markers of precision medicine.