bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of a novel Toll-like Receptor 7 agonist for systemic immunotherapy of cancer.
Authors: Appleman James Richard , Webber Stephen Evan 
Published: May 2019

e14246 Background: While ICPIs (immune checkpoint inhibitors) have fundamentally changed the practice of cancer therapy for tumors arising from many different tissues, ways to increase both response rate and durability are critically needed. On theoretical grounds, combining stimulators of innate immunity with activators of adaptive immunity should lead to better outcomes. We have therefore created a series of novel Toll-like receptor 7 (TLR7) agonists that are intended to be combined with activators of adaptive immunity for the treatment of cancer. We have previously reported a series of unusual properties that must be met for successful drug candidates targeting TLR7 intended for chronic and systemic administration for the treatment of cancer. Methods: Key assays in our testing cascade include: cellular reporter assays and hPBMC assays to evaluate selectivity and potency; characterization in cynomolgus monkeys: appropriate PK with active TLR7 agonist, efficient oral delivery into systemic circulation with prodrugs of the TLR7 agonist, and targeted pharmacodynamic response at relevant oral dose (gating for candidate selection); antitumor activity alone and in combination with other immunotherapeutics in syngeneic rodent tumor models. Results: Appropriate potency at and specificity for TLR7 was achieved early in this discovery program. Furthermore, the PK profile after IV administration met our previously defined criteria. However, oral absorption of candidate prodrugs of two lead molecules was limited. In one class of prodrugs this was due to insufficient lipophilicity; in another class this was a consequence of MDR1 activity. Next-generation candidates have been synthesized; these candidates are expected to have substantially better oral delivery in vivo based upon results in predictive in vitro models. Testing in advanced animal models is in progress. Conclusions: From our original starting point - a relatively weak TLR7 agonist with no oral bioavailability - we have invented a novel series of molecules that are designed to be dosed QOD continuously over a 24-month period to appropriately engage innate immunity at a level that is well-tolerated by the patient while increasing treatment response rate and durability.
Impact of biopsy methodology on biomarker testing in NSCLC in EU5.
Authors: Homer Christophe 
Published: May 2019

e14264 Background: With the increasing number of drug treatments in NSCLC reliant on complementary or companion diagnostics and the evolution of testing methodologies that require larger sample volumes, biopsy remains a gatekeeper to providing adequate sample for biomarker testing and informing treatment decisions. Methods: The Ipsos Global MDx Monitor 2018 Q3 NSCLC EU5 (UK, France, Germany, Italy, Spain) Module: an online multi-stakeholder study involving drug treating physicians (225) and pathologists (81) who answer perceptual questions and report de-identified medical chart data on NSCLC patients (1257) / samples (516), that have undergone at least 1 biomarker test. Study fielded July-September 2018. This abstract reviews pathologist data only. Results: EU5 pathologists (n = 81) state that in 14% NSCLC cases there was not enough sample to carry out any biomarker tests, in 19% cases there was enough sample to carry out some requested biomarker tests and in 67% cases there was enough sample to carry out all biomarker tests. On analyzing NSCLC sample record forms, 83% (421/505) samples from unique patients were from solid samples (FFPE block /Fresh frozen), 14% liquid samples (fluid/cytology) (73/505). Of the 487 NSCLC sample records submitted, 39% biopsies were performed by bronchoscopy (190/487), 25% by Transthoracic Core Needle Biopsy (CNB) (126/487), 16% by Transthoracic Fine Needle Aspiration (FNA) (78/487), 8% by Open biopsy/resection (39/487). Sample sufficiency varies by biopsy methodology; 100% open biopsies/resection (39/39) provided enough sample to carry out all tests ordered - versus 87% for Transthoracic CNB (99/113), 84% for bronchoscopies (155/184), 67% for Transthoracic FNA (49/73). Sample sufficiency varies by sample type; 89% solid samples (357/399) provided enough sample to carry out all tests ordered, 75% liquid samples (49/65). Conclusions: Sample sufficiency and thus ability to test for biomarkers is affected by the biopsy method used to extract the sample, and sample type used for testing (i.e. liquid vs. solid). Sample insufficiency can necessitate a re-biopsy or lead to treatment decisions being taken without the tumour’s full genomic profile at the physician’s disposal.
Coexpression patterns of IDO-1, PD-L1 and EGFR in non-small cell lung cancer.
Authors: Wang Weili , Zhang Chen , Cheng Liang , Jin Jianyue , Kong Feng-Ming Spring 
Published: May 2019

e14279 Background: Indoleamine-2, 3-dioxygenase (IDO), a well-established immune suppressor, may offset efficacy of immune checkpoint inhibitors (ICIs) such as programmed death receptor ligand-1(PD-L1) by inducing unfavorable tumor microenvironment. The unpredictability of one ICI response may partially due to the concomitant presence of other ICIs. Therefore, increasing interest has been focus on the dual ICIs or the combination of ICIs with conventional treatment modalities such as radiotherapy, chemotherapy as well as target therapy. This study aimed to study the coexpression patterns and significance of IDO-1, PD-L1 and epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC). Methods: Patients with newly diagnosed NSCLC enrolled in three prospective surgery clinical trials were included in this study. The expressions of IDO-1, PD-L1 and EGFR were evaluated by immunohistochemistry (IHC). For positive cases, the percentile score and H-score were generated respectively from two independent pathologists. The descriptive analysis of Crosstab was used to compare the distributions of these biomarkers expression by pathological types. Results: A total of 117 patients (adenocarcinoma -54%, squamous cell carcinoma -32% and others -14%) with pretreatment tissue specimen available for IHC analysis were studied. Of these, 105 (90%) were from lung primary and 12 (10%) from distant metastasis sites. The expressions of IDO-1 (≥ 1%), PD-L1 ((≥ 1%) and EGFR (≥ 90% or intensity = 3) were identified in 43%, 40% and 52% of NSCLC patients. For IDO-1 and PD-L1, coexpression rates were 21% for co-positive and 37% for co-negative. However, there were still 42% patients showed isolated PD-L1 (20%) or IDO-1 expression (22%). The coexpression rates for EGFR and IDO-1 were 21% for co-positive and 26% for co-negative. The coexpression rates for EGFR and PD-L1 were 20% for co-positive and 25% for co-negative. 38% patients had a positive EGFR with either IDO-1 or PD-L1 positive. The expression patterns were not significant associated with clinical factors including pathological types and differentiation grades. Conclusions: IDO-1 and PD-L1 expression patterns may be useful in the selection of NSCLC patients for dual ICIs immunotherapy. The combinations of EGFR target therapy with immunotherapy may benefit some of NSCLC patients. However, testing expression status of EGFR and immune checkpoints becomes essential since majority of NSCLC patients exhibits EGFR positive with IDO-1 or PD-L1 negative patterns.
Breast MRI as a radiomic biomarker of immune enrichment in HER2+ breast cancer.
Authors: Kennedy Laura , Durenberger Grace , Stanton Sasha E. , Vinayak Shaveta , Dintzis Suzanne , Partridge Savannah C. , Gadi Vijayakrishna K. 
Published: May 2019

e14281 Background: Trastuzumab is an important drug in the treatment (tx) of HER2+ breast cancer, but not all tumors are responsive. Immune-enriched tumors have a better response to tx, and a biomarker to identify these tumors would be valuable. Multiparametric functional MRI is a non-invasive technique that can assess the entire tumor without the sampling error of biopsy. In this pilot study, we evaluate breast MRI as a potential biomarker for tumor immune response to trastuzumab. Methods: Women with de novo cT1-2N0 HER2+ breast cancer were enrolled and received paired multiparametric breast MRI examinations (including DWI and DCE sequences) prior to and ~2 weeks after a single dose of trastuzumab, followed by surgery or biopsy (if additional neoadjuvant tx planned). Tumor peak signal enhancement ratio (SER) and mean apparent diffusion coefficient (ADC), reflecting tissue perfusion and tissue cellularity, were determined from the images. Pre- and post-tx tissue were immunologically profiled with TIL counts and an immune-focused RNA gene expression panel. SER and ADC were correlated with TIL and RNA gene expression using Spearman’s rho. Results: To date, 8 women have enrolled and 6 had pre- and post-tx tissue available. The primary endpoint was correlation between SER and ADC measurements with tumor TILs. Secondary endpoints included correlating SER with angiogenesis and inflammation markers and correlating changes in SER and ADC with apoptosis/cell death markers. About half of the patients had TIL-enriched (TIL≥ 50%) tumors at baseline, and after trastuzumab the majority of tumors remained enriched or had an increase in TILs. Results suggest that pre-tx ADC had a negative correlation with TILs by histology and gene expression, although correlations did not reach statistical significance in this small cohort. Results also suggest a strong correlation between pre-tx SER and VEGF-A (r = 0.83) with a trend towards significance (P = 0.10). A decrease in SER post-tx had a strong correlation with an increase in caspase 3 expression (r = -0.85, p = 0.05), which suggested tx effect. Conclusions: Functional MRI may provide a novel biomarker of breast tumor immune response to trastuzumab. Results from additional patients will be available at the meeting.
Frequency of discordance in programmed death ligand 1 (PD-L1) expression between primary tumors and paired distant metastases in advanced cancers: A systematic review and meta-analysis.
Authors: Lee Chia Ching , Tham Ivan Weng Keong , Tan Char Loo , Lum Jeffrey , Tey Jeremy Chee Seong , Soon Yu Yang 
Published: May 2019

e14290 Background: Randomized trials have demonstrated that PD-L1 expression in tumor cells predicts for response to PD-1 or PD-L1 checkpoint inhibitors in advanced cancers. However, the frequency of discordance in PD-L1 expression between primary tumors and paired distant metastases is currently unclear. We aimed to determine the discordance rate of PD-L1 expression between primary tumor and paired distant metastases in advanced cancers. Methods: We searched MEDLINE and EMBASE for eligible studies. We noted the discordance rate (positive-to-negative or vice versa) and performed subgroup analyses based on the PD-L1 expression in primary tumor, locations of primary tumor and distant metastases, positivity thresholds and type of antibody used for testing. We used QUADAS-2 tool to assess the methodologic quality of the included studies. We performed the meta-analysis using the logistic-normal random effects model. Results: We identified 11 eligible studies including 351 cases of lung, colorectal, breast and ovarian cancers. Nine studies were judged to have low risk of bias in their methodological quality. The overall discordance rate in PD-L1 expression between primary tumor and paired distant metastases was 28% (95% confidence interval (CI) = 18-41) with significant heterogeneity among the studies (chi-square test P-value < 0.0001). There was no statistically significant differences in discordance rates between the subgroups: PD-L1-positive (40%, 95% CI = 21-63) vs PD-L1-negative primary tumors (21%, 95% CI = 12-34), lung primary (31%, 95% CI = 14-55) vs colorectal/ breast/ ovarian primary (27%, 95% CI = 19-37), central nervous system metastases (22%, 95% CI = 8-47) vs liver/ lung/ pleural/ peritoneum metastases (34%, 95% CI = 24-46); 1% (23%, 95% CI 16-33) vs 5% positivity threshold (33%, 95% CI 11-68); E1L3N (42%, 95% CI 10-82) vs SP142 antibody (27%, 95% CI 20-36). Conclusions: The discordance in PD-L1 expression between primary tumors and paired distant metastases is close to 30%, which could potentially affect response to immunotherapy. Further works exploring the mechanisms and impact of this discordance are warranted.
Systematic assessment of LCMV based vaccine vectors expressing melanocyte differentiation antigens in human in vitro assays and in mouse melanoma models.
Authors: Flatz Lukas , Cupovic Jovana , Schmidt Sarah , Onder Lucas , Abdou Marie Therese , Fritsche Anna Katharina , Bonilla Weldy , Pop Oltin Tiberiu , Tüting Thomas , Bergthaler Andreas , Orlinger Klaus , Bald Tobias , Ludewig Burkhard , Ring Sandra 
Published: May 2019

e14299 Background: Antibodies blocking the immune checkpoint pathways represent an important milestone in the treatment of patients with metastatic melanoma. However, individuals presenting cold tumors do usually not show a clinical benefit. New cancer vaccine approaches are needed to cover this gap. Methods: A novel replication attenuated vaccine vector based on lymphocytic choriomeningitis virus expressing full length melanocyte differentiation antigens is evaluated in mouse melanoma models and in PBMCs and T cell cultures from melanoma patients. Results: Here, we demonstrate that intratumoral but not intravenous injection of a recombinant propagating LCMV vector expressing the melanoma-associated antigen TRP2 leads to T cell-dependent eradication of established s.c. melanoma. Importantly, intratumoral vaccination shows an abscopal effect on distant lung metastasis and protects from a rechallenge with melanoma. Confocal microscopy and flow cytometry reveal that intratumoral injection of rLCMV vectors reprograms the tumor microenvironment resulting in sustained T cell fitness. In addition, we demonstrate that rLCMV vectors can efficiently transduce human antigen presenting cells. Moreover, in vitro data confirm that rLCMV efficiently induces T cells against various melanoma-associated antigens in PBMCs from melanoma patients. Conclusions: Preclinical assessment of propagating rLCMV vectors shows unique features of this cancer vaccine resulting in a profound and multistep activation of the cancer immunity cycle resulting in eradication of established melanomas in the B16F10 mouse model after one single immunization. Positive proof of principle experiments using PBMCs from melanoma patients suggest a rapid evaluation in clinical trials.
Live-attenuated LCMV-based vector for active immunotherapy of HPV16+ cancer.
Authors: Schmidt Sarah , Bonilla Weldy V. , Pauzuolis Mindaugas , Reiter Andrea , Kleissner Theresa , Oeler Daniel , Stemeseder Felix , Berka Ursula , Kiefmann Bettina , Schulha Sophie , Matushansky Igor , Merkler Doron , Pinschewer Daniel , Orlinger Klaus Karl 
Published: May 2019

e14303 Background: Active immunization against cancer requires the induction of exquisitely potent tumor-specific CD8+ T cell (CTL) responses, which can be repeatedly boosted and reactivated. Hookipa Pharma engineered a replication-attenuated viral vector platform (TheraT) based on the arenavirus lymphocytic choriomeningitis virus (LCMV), which meets these aforementioned criteria. Here, we present a preclinical data package of Hookipa´s lead immunotherapy product HB-201, targeting HPV16-driven cancer. Methods: TheraT-E7E6 encodes a highly immunogenic, non-oncogenic version of the human papilloma virus 16 (HPV16) oncoproteins E7 and E6. Results: Attenuation and safety of TheraT-E7E6 were demonstrated by i) rapid viral clearance after systemic administration of the vector and ii) reduced neurovirulence in mice.TheraT-E7E6 can be administered intravenously as systemic therapy or intratumorally as local therapy with an abscopal-like effect. Treatment was shown to induce substantial CD8+ T cell expansion and high frequencies of E7- and E6-specific CTL responses with a balanced effector / central memory profile. These responses were boosted and reactivated upon TheraT-E7E6 re-administration. TheraT-E7E6 eradicated palpable tumors in a syngeneic mouse TC-1 tumor model of HPV-driven cancer. Even in mice with large tumors (~300mm3) TheraT-E7E6 afforded significant tumor control and improved survival, with high frequencies of E7-specific CTLs persisting for several weeks. Animals which cleared the tumor after TheraT therapy were long term protected from tumor re-challenge. Furthermore, TheraT is efficacious in checkpoint inhibitory refractory models and can also synergize in combination with checkpoint inhibitors (CPIs). Conclusions: In conclusion, replication-attenuated TheraT-E7E6 is safe, highly immunogenic and shows excellent therapeutic efficacy as mono- or combination therapy in a preclinical model of HPV-induced cancer. Clinical trials for the treatment of HPV16+ cancers will be initiated in 2019.
A phase I study of the safety and immunogenicity of a multi-peptide personalized genomic vaccine in the adjuvant treatment of solid tumors and hematological malignancies.
Authors: Blazquez Ana , Rubinsteyn Alex , Kodysh Julia , Finnigan John Patrick , Marron Thomas Urban , Meseck Marcia , O'Donnell Timothy , Hammerbacher Jeffrey , Donovan Michael J. , Mahajan Milind , Miles Brett A. , Irie Hanna , Tiersten Amy , Tewari Ashutosh , Parekh Samir S. , Nair Sujit , Galsky Matt D. , Schadt Eric E. , Friedlander Philip Adam , Bhardwaj Nina 
Published: May 2019

e14307 Background: Mutation-derived tumor antigens (MTAs) arise as a direct result of somatic variations that occur during carcinogenesis and can be characterized via genetic sequencing and used to identify MTAs. We developed a platform for a fully-personalized MTA-based vaccine in the adjuvant treatment of solid and hematological malignancies. Methods: This is a single-arm, open label, proof-of-concept phase I study designed to test the safety and immunogenicity of Personalized Genomic Vaccine 001 (PGV001) that targets up to 10 predicted personal tumor neoantigens based on patient’s HLA profile (ClinicalTrials.gov: NCT02721043). Results: Patients who completed vaccination with PGV001_002 (head and neck squamous cell cancer) received 10 doses of vaccine comprising 10 long peptides (LP) combined with poly-ICLC (toll-like receptor-3 agonist) intradermally. Vaccine-induced T-cell responses were determined at weeks 0 and 27 (before and after treatment, respectively), ex vivo by interferon (IFN)-g enzyme-linked immunospot assay and after expansion by intracellular cytokine staining. Overlapping 15-mer peptides (OLPs) spanning the entirety of each LP and 9-10-mer peptides corresponding to each predicted class I epitope (Min) were pooled. Ex vivo responses to these peptide pools were undetectable at week 0 but were evident at week 27 against 2 OLPs out of 10 (20%) and in 5 Min out of 10 (50%). After in vitro expansion, neoantigen-specific CD4+ and CD8+ T-cell responses were found in 5 out of 10 pooled peptides (50%). 7 out of 10 (70%) epitopes elicited polyfunctional T-cell responses (secretion of INF-g, TNF-a, and/or IL-2) from either CD4+ or CD8+ T cells. Conclusions: The PGV001 vaccine in our first patient showed both safety and immunogenicity, eliciting CD4+ and CD8+ responses to the vaccine peptides. As we enroll additional patients in this clinical trial, and perform deeper phenotyping of their tumor-reactive T cells, we will learn the determinants necessary for the successful generation of MTA-based vaccines, while informing future immunotherapeutic approaches and rational combinations. Clinical trial information: NCT02721043.
Role of metabolic reprogramming toward fatty acid oxidation on tumor lymph node metastasis.
Authors: Lee Choong-kun , Jeong Seung-hwan , Jang Cholsoon , Bae Hosung , Kim Yoo Hyung , Park Intae , Kim Sang Kyum , Koh Gou Young 
Published: May 2019

e14501 Background: Metastasis of tumors to lymph node (LN) is a strong predictor of cancer patient mortality and determinant of disease progression and treatment options. Despite the clinical significance of tumor LN metastasis, the mechanisms underlying this process remain largely unexplored. Methods: We used comparative transcriptomics and metabolomics analyses of the primary tumor and LN micro- and macro-metastatic tumors from B16F10 murine melanoma model. B16F10 melanoma footpad implantation model and MMTV-PyMT spontaneous breast cancer genetic mouse models were analyzed in vivo. We also investigated the LN-metastatic tumors from sentinel LNs in 21 patients with melanoma. Results: We found that tumor cells undergo dramatic metabolic reprogramming towards fatty acid oxidation (FAO) for successful LN metastasis. Mechanistically, transcription co-activator YAP is selectively activated in LN metastatic tumors, leading to stimulation of FAO gene programs. Pharmacological inhibition of FAO or genetic ablation of YAP in tumors markedly suppressed LN metastasis. Unexpectedly, metastatic tumors highly stimulated the bile acid synthesis pathway upon arrival at the LN, and these bile acids activated YAP of tumor cells via nuclear vitamin D receptor. Lastly, YAP activation in the metastatic LNs of melanoma patients was reversely correlated with distant metastasis–free survival. Conclusions: This study propose that inhibition of FAO or YAP signaling to prevent the metabolic reprogramming of metastatic tumors offers a potential therapeutic strategy for mitigating tumor LN metastasis.
The relationship between mesenchymal stem cells, monocyte-macrophages, endothelial progenitor cells, and prognosis of hepatocellular carcinoma.
Authors: Yan Kun 
Published: May 2019

e14507 Background: This experiment is designed to investigate the clinical correlation between mesenchymal stem cells, macrophages, endothelial progenitor cells and hepatocellular carcinoma, furthermore to assess their diagnostic value. Methods: A prospective cohort study was conducted to collect patients who admitted to the Department of General Surgery, Second Affiliated Hospital of Xi'an Jiaotong University. The peripheral blood samples of patients with hepatocellular carcinoma (HCC) who diagnosed by pathology from September 2014 to August 2016 were collected. The mesenchymal stem cells, macrophages and endothelial progenitor cells (EPCs) were analyzed by flow cytometers. Results: There was no correlation between hepatocellular carcinoma and peripheral blood mesenchymal stem cells (p > 0.05), and there was correlation between hepatocellular carcinoma and macrophages and endothelial progenitor cells (p < 0.01). The positive correlated coefficient is 0.938 in macrophages, and the negative correlated coefficient is -0.835 in the endothelial progenitor cells. Conclusions: The differentiated pathways of mesenchymal stem cells in hepatocellular carcinoma play key roles in the progression and prognosis of hepatocellular carcinoma.