bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety profile of INT230-6, a novel intratumoral (IT) formulation, during injections into a variety of refractory deep and superficial tumors with evidence of tumor regression and immune activation.
Authors: El-Khoueiry Anthony B. , Thomas Jacob Stephen , Hanna Diana L. , Siu Lillian L. , Azad Nilofer Saba , Whalen Giles Francis , Bender Lewis H. , Walters Ian B. , Olszanski Anthony J. 
Published: May 2019

2602 Background: INT230-6 is comprised of cisplatin (CIS), vinblastine (VIN) and an amphiphilic penetration enhancer which facilitates dispersion throughout tumors and diffusion into cancer cells. In preclinical experiments, INT230-6 led to necrosis and recruitment of immune cells with high rates of complete responses of injected and bystander tumors. This abstract highlights the safety and early pharmacodynamic activity of this approach. Methods: Patients with solid tumors that progressed on all standard treatments were enrolled. Dose escalation occurred by increasing number of tumors injected, loading per tumor, and total dose. INT230-6 was injected once every 2 weeks in multiple lesions for 5 sessions. Patients were monitored for safety and tolerability weekly. Pharmacokinetic(Pk) samples and peripheral blood were collected for flow cytometry and circulating cytokines. Pre and on study biopsies are ongoing. Results: 28 patients (14 unique cancer types) receiving a median of 3 prior treatments were enrolled. Doses from 0.3 ml up to-80 ml of INT230-6 were given into single lesions with some patients receiving a total of 120 mL ( = 9.7mg VIN exceeding the IV VIN dose) without significant systemic absorption or typical cytotoxic adverse events. Pk analysis suggests that systemic exposure of VIN or CIS is ~10% of injected. No DLT’s or drug-related SAE’s reported. The most frequent adverse event was grade 1 or 2 pain at injected site. Superficial tumors showed signs of response including flattening, areas of necrosis and ulceration. Tumor reduction, apparent in in both injected and bystander tumors, may indicate an abscopal effect. An increase > 30% in CD8 T-cells was seen in the blood of 3/9 evaluable patients. Conclusions: INT230-6 was safe and well tolerated in > 100 injections (28 patients) with encouraging activity and pharmacodynamic effects in advanced refractory tumors. Additional analysis of immune cells from on study biopsies will be presented. A new cohort will evaluate combination with an anti-PD1 antibody to understand if local tumor destruction can increase systemic antigen load, increase immune cell recognition and initiate a systemic immune response. Clinical trial information: NCT 03058289.
THOR-707: Using synthetic biology to reprogram the therapeutic activity of interleukin-2 (IL-2).
Authors: Milla Marcos E , Ptacin Jerod , Caffaro Carolina E. , Aerni Hans R. , Ma Lina , Koriazova Lilia , Joseph Ingrid B. , Shawver Laura K. 
Published: May 2019

2603 Background: Recombinant interleukin-2 (rIL-2; aldesleukin) is an approved immunotherapy in melanoma and renal cell carcinoma based on complete durable remissions. The anti-neoplastic properties of IL-2 are mediated by interactions with the beta-gamma chain (IL-2Rβγ) on naïve CD8+ T cells, which lead to their expansion and differentiation into T effector and T memory cells directed against the tumor. However, the widespread use of IL-2 in oncology is limited by interaction with the high affinity IL-2 receptor alpha chain (IL-2R⍺) on regulatory CD4+ T cells (Tregs), which leads to immunosuppression, and on innate lymphoid cells in the vascular endothelium, which leads to eosinophilic recruitment and activation, and the sometimes fatal complication of vascular leak syndrome (VLS). A rIL-2 biased toward IL-2βγ affinity with no IL-2R⍺interaction could fill unmet needs in oncology. Methods: Using a synthetic biology platform, we have engineered THOR-707, a rIL-2 that contains a novel amino acid encoded in the IL-2 gene via a new DNA base pair (X-Y). The novel amino acid serves as a hook for site specific pegylation that extends half-life, blocks IL-2R⍺ engagement and binds to the IL-2Rβγ. Results: In non-human primates, THOR-707 can be dosed to maximize the level of cytotoxic CD8+ T lymphocytes without elevation of VLS-inducing eosinophils. In murine tumor models, THOR-707 induced the expansion of peripheral and intratumoral CD8+ T cells without expansion of suppressive Tregs. Single-agent dose-dependent anti-tumor efficacy was observed in two syngeneic mouse models. In combination with a PD-1 inhibitor, survival of tumor-bearing mice was longer than either agent as monotherapy. Efficacy in tumor models was durable, suggesting activation of CD8+ memory T cell populations. Conclusions: THOR-707 is a reprogrammed, site-directed, singly-pegylated rIL-2 that changes the pharmacologic profile of IL-2, potentially providing a favorable risk-benefit profile. First-in-human studies are expected to begin this year evaluating THOR-707 as monotherapy and in combination with a PD-1 inhibitor. Based on preclinical evidence to-date, THOR-707 may potentially address existing and emerging unmet needs across multiple solid tumors.
AB928, a novel dual adenosine receptor antagonist, combined with chemotherapy or AB122 (anti-PD-1) in patients (pts) with advanced tumors: Preliminary results from ongoing phase I studies.
Authors: Powderly John D. , de Souza Paul L. , Gutierrez Rodolfo , Horvath Lisa , Seitz Lisa , Ashok Devika , Park Adam , Walters Matthew J. , Karakunnel Joyson Joseph , Berry Wade , Rieger Aimee , Garofalo Amanda , Lai Dominic W. , Chaudhry Arvind 
Published: May 2019

2604 Background: AB928, a selective, small-molecule A2aR/A2bR antagonist, potently blocks the immunosuppressive effects of high adenosine concentrations in the tumor microenvironment. Preclinically, combining adenosine receptor inhibition with either chemotherapy or anti-PD-1 resulted in greater tumor control, suggesting AB928 may have additive activity when paired with either of these agents in cancer pts. Methods: Three dose-escalation (3+3 design) studies are assessing the safety, pharmacokinetics (PK), pharmacodynamics, and clinical activity of increasing doses of AB928 (75, 150, 200 mg orally once daily) in combination with: standard pegylated liposomal doxorubicin in triple-negative breast cancer (TNBC) and ovarian cancer (OC); standard mFOLFOX6 in gastroesophageal cancer (GEC) and colorectal cancer (CRC); and AB122 (240 mg every 2 weeks) in various advanced tumors. Following identification of the recommended phase 2 dose of AB928 in combination with chemotherapy or AB122 in dose escalation, the following tumor cohorts may be expanded (15-40 pts/cohort) to further test the combinations: TNBC and OC, GEC and CRC, and renal cell carcinoma. Results: As of 01Feb2019, 9 pts were treated across the 3 studies, and time on treatment ranged from 1-182 days (table). Overall, AB928 combination therapy was well tolerated. Two pts underwent post-baseline disease assessment; both had stable disease. Preliminary data indicate that AB928 PK and adenosine receptor coverage in cancer pts are similar to what was previously assessed in healthy volunteers. AB122 PK and PD-1 coverage are equally unaffected by AB928 co-administration. Updated data, including biomarker data, will be presented at the meeting. Conclusions: Early results showed a favorable safety profile of AB928 combination therapy. All 3 studies are actively recruiting pts. Clinical trial information: NCT03719326; NCT03720678; NCT03629756. [Table: see text]
2D and 3D thermally bioprinted human MCF-7 breast cancer cells: A promising model for drug discovery.
Authors: Campbell Aleli , Philipovskiy Alexander , Heydarian Rosalinda , Varela-Ramirez Armando , Gutierrez Denisse A. , Solis Luis H. , Furth Michael E. , Boland Thomas 
Published: May 2019

2605 Background: Breast cancer (BC) is the second leading cause of cancer death following lung cancer. Bioprinting, the use of computer aided process to print biological living and non-living material to create patterns in 2D or 3D structures, is a novel technique that has been proposed to be used to develop tissue engineered solutions for a wide array of clinical applications, e.g., skin grafting. We investigate here if bioprinted breast cancer cells show some of the hallmarks of cancer tissues, and thus may represent good in vitro models for drug discovery. Methods: For this study, MCF-7 BC cells were cultured, stained, counted and turned into a bioink solution by suspending in phosphate buffered saline solution. The cells were bioprinted over a 96-well plate and pre-incubated for 18 hours in DMEM and RPMI media with 10% Fetal Bovine Serum and Charcoal Stripped Serum, respectively. After 18 hours of incubation the media was supplemented with Tamoxifen at 5µM, 10µM, 50µM, 90µM and 110µM concentrations. Cytotoxicity was measured 24 hours post-treatment using a differential nuclear staining assay and an INCell 2000 bioimager system. Results: Bioprinted cells exposed to high concentrations of Tamoxifen (90 µM and 110µM) exhibited a viability of 8.2% and 10.8%, respectively. Whereas viability of manually seeded cells at those concentrations was 0.11% and 0.05%. Viability of negative and positive controls was at 7.6% and 97.0% for the bioprinted samples and for the normally seeded cells was 4.9% and 98.8% respectively. Conclusions: In our study, we have established a novel 2D/3D breast tumor model applying bioprinting technology for drug discovery. The higher cell viability of MCF-7’s at high concentrations of Tamoxifen could be attributed to the hormesis effect and activation of chaperone proteins, e.g., HSP70 and HSP90, possibly caused by bioprinting. We hypothesize that bioprinted MCF-7 cells also show increased levels of chaperone proteins, which may in a way mimic their in vivo behavior. In this novel in vitro 2D/3D model, the bioprinted cells show a more biological relevant behavior than normally cultured cells. Insights into the cell behavior after bioprinting may elucidate how to build improved in vitro models for BC research.
Gut microbiota and clinical outcomes treated with nivolumab in Chinese non-small cell lung cancer.
Authors: Lu Shun , Jing Yueping , Xia Liliang , Li Ziming , Yao Chengcheng , Wang Ying 
Published: May 2019

2614 Background: Gut microbiome affecting responses to immune checkpoint inhibitors (ICIs) against non-small cell lung cancer (NSCLC) has been investigated in western population. However, considering genetic variation, this phenomenon remains in vague in east-Asian NSCLC population. The study is designed to explore the relationships between gut microbiome and clinical outcomes treated with anti-PD-1 blockade in Chinese patients. Methods: 37 NSCLC patients received the treatment of Nivolumab were enrolled in the study from the clinical trials CheckMate870 (NCT03195491). Fecal samples were collected at the starting point, every time point performing clinical evaluation and that with disease progression. 16s sequencing was applied to assess the gut microbiota characteristics. Peripheral immune profiles were determined by multi-color flow cytometry in parallel. Results: When subgrouping patients into responders (R) and non-responders (NR) groups according to the clinical response assessed by RECIST1.1, patients in R group harbored higher diversity of gut microbiome at the starting point with consistent composition along the treatment. Analyzing progression-free survival (PFS) according to RECIST 1.1, patients with higher microbiome diversity had significantly prolonged PFS when compared to those with low diversity. Compositional difference was observed between two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium logum, Prevotella corpri in R group whereas Ruminococcus_unclassified in NR group. Analysis of systemic immune responses using multi-color flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had more frequencies of memory CD8+ T cell subset in the periphery in response to anti-PD-1 therapy. Conclusions: Our results report the strong correlation between the gut microbiome diversity and the responses to anti–PD-1 immunotherapy in Chinese NSCLC patients regardless of genetic variation between Western and Chinese population. Patients with a favorable gut microbiome (such as high diversity) have enhanced immune responses mediated by effector T cell function in the periphery. These findings thus provide important implications for the prediction and the evaluation of anti-PD-1 immunotherapy against NSCLC.
Tissue immune response in epithelial ovarian carcinoma.
Authors: Henriksen Jon , Donskov Frede , Waldstrøm Marianne , Hjortkjær Mette , Petersen Christina Braad , Thomsen Caroline Brenner , Jakobsen Anders Kristian Moeller , Steffensen Karina Dahl 
Published: May 2019

2625 Background: Epithelial ovarian cancer (EOC) is a highly malignant disease with a fatal outcome for most patients. During recent years immunological mechanisms have proven important in relation to the treatment and prognosis of cancer, but within EOC the knowledge is still sparse. Understanding the importance of immune markers to the prognosis of ovarian cancer is essential for the future treatment of EOC. The aim of the present study was to investigate the prognostic impact of intratumoral PDL-1 expression, T cells, neutrophil granulocytes (NG) and Natural Killer (NK) cells in a population based cohort. Methods: All patients diagnosed with ovarian cancer in Denmark in 2005 were included in the study. Immunohistochemical staining was performed on tumor tissue from 412 patients. Antibodies for PD-L1, T cells (CD8), NG (CD66b), and NK cells (CD57) were used. Cell densities were analyzed using a digital image analysis method. The primary endpoint was overall survival (OS). Results: In high grade serous carcinoma (HGSC) the median OS in patients with a high level of tumor infiltrating T cells was 37 vs 25 months in patients with a low level(p = 0.0008). Multivariate analysis showed a hazard ratio (HR) of 0.72 (p = 0.020). The median OS in patients with a high level of tumor infiltrating NK cells was 45 vs 29 months in patients with a low level (p = 0.0310). Multivariate analysis showed a HR of 0.67 (p = 0.041). PD-L1 and NG had no statistically significant impact on OS. Only T cells showed prognostic significance across histological subtypes with a HR of 0.72 (p = 0.007) in favor of a high density of T cells. Conclusions: The present population based study demonstrated prognostic importance of tumor infiltrating T cells and NK cells in HGSC. Neither PD-L1 nor NG held prognostic significance.
The consensus Immunoscore adapted to biopsies in patients with locally advanced rectal cancer: Potential clinical significance for a “Watch and Wait” strategy.
Authors: El Sissy Carine , Kirilovsky Amos , Van Den Eynde Marc , Romero Alfredo , Marliot Florence , Lagorce Christine , Bibeau Frédéric , Iseas Ilma Soledad , Roca Enrique Luis , Vaccaro Carlos Alberto , Tougeron David , Carvalho Carlos Torres , Figueiredo Nuno , Perez Rodrigo O , Habr Gama Angelita , Scripcariu Viorel , Gerard Jean-Pierre , Galon Jerome , Zeitoun Guy , Pages Franck 
Published: May 2019

2628 Background: We investigated whether an adaptation to rectal biopsies of the recently validated consensus Immunoscore, could predict the response to neoadjuvant treatment and delineate clinical responders that could benefit from a “Watch and Wait” (W&W) strategy with acceptable outcomes. Methods: Initial biopsies from 273 patients with locally advanced rectal cancer (LARC) treated by neoadjuvant chemoradiotherapy (nCRT) followed by Total Mesorectal Excision (TME), were immunostained for CD3+ and cytotoxic CD8+ T cells and quantified by digital pathology to determine the Immunoscore within pre-treatment Biopsy (ISB). Expression level of 44 immune related genes post-neoadjuvant treatment was investigated by Nanostring technology (n = 64 patients). Results were correlated with response to neoadjuvant treatment, disease free survival (DFS) and time to recurrence (TTR). Prognostic performance of ISB was finally assessed in 73 LARC treated by W&W strategy. Results: ISB Low, Intermediate and High were respectively observed in 23.3, 50.4 and 26.3 % of the cohort. ISB was positively and significantly correlated with the response to nCRT, as evaluated by Dworak classification (P = .0034), ypTNM (P = .0003), down-staging (P = .0014), and neoadjuvant rectal (NAR) score, (P < .0001). ISB status was also positively associated with the degree of local immune activation post-neoadjuvant treatment. ISB High patients were at low risk of relapse, with 5-year DFS rates of 81.1 % (CI, 71.3-92.1 %) as compared to 57.8 % (CI, 45.9-72.9 %) in ISB low patients. In multivariate analysis, ISB was the only significant parameter at presentation associated with DFS (High vs Low: P = .001). Among W&W patients, significant difference was observed for TTR according to ISB status (High vs Low: P = .025). Conclusions: ISB could provide a reliable estimate of the response to nCRT and risk of recurrence in LARC patients' treated by TME or W&W strategy.
A multiplex immunofluorescence assay to assess immune checkpoint inhibitor-targeted CD8 activation and tumor colocalization in FFPE tissues.
Authors: Navas Tony , Fino Kristin , Fung King Leung , Cutuli Facundo , Kinders Robert J. , Sharma Aditi , O'Sullivan-Coyne Geraldine , Chen Alice P. , Hecht Toby Tucker , Doroshow James H. , Parchment Ralph E. 
Published: May 2019

2629 Background: Immune checkpoint inhibitors promote antitumor immune responses by enhancing T-cell activity. Measuring the pharmacodynamic effects of these drugs is challenging, as it requires assessing both immune cell and cancer cell populations. To evaluate T cell activation in tumor tissue from patient biopsies, we developed a robust multiplexed immunofluorescence assay. Methods: Our assay uses novel oligo-conjugated antibodies (Ultivue) for simultaneous quantitation of TCR activation (phospho-CD3zeta), immune checkpoint signaling via PD-1 (p-SHP1/p-SHP2), and the net stimulation/inhibition resulting from the integration of these two pathways in CD8 cells (p-ZAP70), while also providing the proximity of CD8 cells to tumor tissues, identified by β-catenin. The method was clinically validated using custom tissue microarrays (TMA) containing tumor biopsies of 3 different histologies (CRC, NSCLC, and breast). Results: From a total of 192 tumor core biopsies, 20/64 NSCLC, 9/64 CRC, and 3/65 breast TMA cores were found to have a significant number of CD8+ tumor infiltrating lymphocytes (TILs) at baseline ( > 50 cells in the examined section). In 18 of the 20 NSCLC cores, ≥50% of CD8 cells both inside and outside of the tumor were activated (CD3z-pY142+). In 6/9 CRC cores, ≥50% of CD8+ cells inside tumor tissues were activated, and in 4/9 CRC cores, ≥50% of CD8+ cells in stroma were activated. In 2/3 breast tumor cores, 90% of CD8+ cells inside tumor tissues were activated; in the remaining core, 90% of CD8+ cells in stroma were activated. Interestingly, all 192 cores had minimal to no expression of activated Zap70 (pY493) in CD8+ cells. Conclusions: Depending on tumor histology, baseline biopsy samples may contain variable numbers of activated CD8+ TILs (CD3z-pY142+), which may reside inside or outside of tumor regions and express very low levels of Zap70-pY493. Anti-PD-1 therapy is predicted to enhance T-cell cytotoxic activity, as demonstrated by an increased number of TILs and elevated Zap70-pY493 expression. This assay is being used for pharmacodynamic evaluations in ongoing immunotherapy clinical trials. Funded by NCI Contract No HHSN261200800001E.
Tumor mutational burden (TMB) and PD-L1 expression as predictors of response to immunotherapy (IO) in NSCLC.
Authors: Castellanos Emily , Snider Jeremy , Ali Siraj Mahamed , Backenroth Daniel , Albacker Lee A. , Murugesan Karthikeyan , Li Gerald , Frampton Garrett M. , Alexander Brian Michael , Carson Kenneth Robert 
Published: May 2019

2630 Background: PD-L1 expression and TMB, as a proxy for neoantigen burden, have been correlated with response to IO in advanced NSCLC (aNSCLC) clinical trials, but their combined utility is unclear. We assessed TMB and PD-L1 as predictors of response in aNSCLC patients (pts) after IO monotherapy in a real-world setting. Methods: Pts had a diagnosis of aNSCLC, comprehensive genomic profiling of 186-315 genes/1.1 megabase (Mb), PD-L1 testing of pre-IO specimens, and were treated in the Flatiron Health network (1/2011 - 6/2018). Clinical characteristics and real-world tumor response (rwTR) were obtained via technology-enabled abstraction of clinician notes and radiology/pathology reports, and linked to genomic data in the Flatiron Health-Foundation Medicine Clinico-Genomic Database. A general additive model examined the predictive value of TMB (as continuous measure) and PD-L1 level on rwTR. A reduced PD-L1-only model was compared to the full model using Akaike Information Criterion (AIC). rwTR predictions at representative TMB and PD-L1 levels were calculated. Results: Of 426 pts, PD-L1 expression was high (≥50%) in 140, low (1-49%) in 123, and negative (<1%) in 163. Median TMB was 9.6 mut/Mb (IQR 4.4 - 14.8) overall, 11.3 in responders and 8.7 in non-responders. TMB did not correlate with PD-L1 level (Kruskal-Wallis p=0.29). The TMB + PD-L1 model had superior prediction of rwTR than the PD-L1 model, as assessed by lower AIC score. In the combined model, higher TMB and PD-L1 levels were each associated with higher rwTR likelihood (Table). Predicted rwTR probability, % (95% CI), by TMB and PD-L1 in line 1. Conclusions: TMB and PD-L1 expression are independent markers that, when combined, have increased predictive power for response to IO. High TMB + low/neg PD-L1 behaved similarly to low TMB + high PD-L1, and high TMB + high PD-L1 predicted the highest rwTR. Investigation of these biomarkers as complementary predictors of progression and overall survival is ongoing.[Table: see text]