bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT047: Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous Pembrolizumab in high grade nonmuscle invasive bladder cancer
Authors: Alanee Shaheen , Zawahry Ahmed El , Sana Sherjeel , McVary Kevin , Robinson Kathy , Rao Krishna A. 
Published: August 2019

Abstract
PURPOSE: A phase I trial of intravesical bacillus Calmette-Guérin (BCG) in combination with systemic pembrolizumab was conducted in patients with high grade non-muscle invasive bladder cancer who had persistent or recurrent disease after failing treatment with at least 2 courses of intravesical therapy (one of which had to contain BCG) or BCG followed by maintenance BCG. The primary objective was to determine the safety of this combination. Secondary end points included response to treatment at 19 weeks (end of treatment) and 3 months post treatment.
MATERIALS AND METHODS: A total of 9 patients with recurrent/persistent high-grade non-muscle invasive bladder cancer after at least two courses of intravesical therapy or one course of BCG treatment followed by one course of maintenance BCG were enrolled in the study. Six doses of pembrolizumab were given every 3 weeks over 16 weeks given concurrently with 6 weekly doses of BCG beginning at week 7. Patient safety was evaluated during and for 30 days following pembrolizumab treatment. Preliminary combination efficacy was determined at 19 weeks using cystoscopy. Bladder biopsy was performed in patients with suspicious lesions.
RESULTS: The combination of BCG and pembrolizumab was well tolerated at both 100mg and 200mg fixed doses. Fatigue and cystitis-type symptoms (burning, spasm, urgency, sensitivity, and frequency) were the most common adverse events and all cases were either grade 1 or 2. Two patients died during the trial period. One patient died due to progression of low grade upper urinary tract transitional cell carcinoma. The other patient died after cystectomy (for progressive disease) due to causes unrelated to the trial treatment. Of the 9 patients treated, 6 (78%) had no evidence of disease in the bladder and 1 had a mixed response (progression in the upper urinary tract only) at 19 weeks (end of treatment) while 5 (56%) remained disease-free at the 3 month follow up.
CONCLUSIONS: The combination of BCG and pembrolizumab was well tolerated with subjects exhibiting the expected adverse effects associated with the use of both medications. Intravesical BCG and pembrolizumab may have clinical activity in non-muscle invasive bladder cancer recurring after repeated intravesical therapy. .A phase III trial is now open and enrolling in the United States and other countries (NCT03711032).
Citation Format: Shaheen Alanee, Ahmed El Zawahry, Sherjeel Sana, Kevin McVary, Kathy Robinson, Krishna A. Rao. Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous Pembrolizumab in high grade nonmuscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT047.
Abstract CT064: Intranasal brain delivery using NEO100 for recurrent glioblastoma
Authors: Chen Thomas C. , Wagle Naveed , Peereboom David , Taylor Lynne 
Published: August 2019

Abstract
NO CHANGES TO ORIGINAL ABSTRACT
NEO100 is a GMP quality, purified perillyl alcohol (POH) which has been undergoing clinical trials under IND approval (144,595) entitled "Open label, Phase I/IIa dose escalation study of safety and efficacy of NEO100 in recurrent grade IV glioma." It was granted orphan drug and fast track status by the FDA. Inclusion criteria include temozolomide failure, bevacizumab naïve, tumor less than 3x3 cm, and Karnofsky score greater than or equal to 60. Patients were enrolled from University of Southern California (USC), Cleveland Clinic, and University of Washington. Total number of patients to be enrolled for Phase I is 12 with four dose escalating cohorts of 3 patients per cohort. The remaining 31 patients would be enrolled after maximal tolerated dosage (MTD) for Phase IIa. The delivery is intranasal via a nasal nebulizer using the concept of nasal brain delivery via the olfactory and trigeminal nerves for delivery to the brain and tumor. To date, 8 patients have been enrolled. Cohort 1 received 96 mg/dose qid, Cohort 2 received 144 mg/dose qid, cohort 3 received 192 mg/dose qid, and cohort 4 will receive 288mg/dose qid. No toxicities were detected. Inhalation was very well tolerated. The duration of the trial is for 6 months. To date, 3 patients have not shown evidence of progression for greater than 6 months (one patient 1 year (cohort 2), one patient 7 months (cohort 3), one patient 6 months) (cohort 3). This is the first FDA approved trial for intranasal delivery to malignant gliomas. Although preliminary, we are encouraged by the progression free survival of 3/8 patients in this dose escalation trial.
Citation Format: Thomas C. Chen, Naveed Wagle, David Peereboom, Lynne Taylor. Intranasal brain delivery using NEO100 for recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT064.
Abstract CT148: Small molecule immune-modulator icaritin: Safety, durable survival and inflammation-immune biomarkers in advanced hepatocellular carcinoma
Authors: Qin Shu-Kui , Li Qing , Xu Jianmin , Liang Jun , Cheng Ying , Li Shu , Zheng Limin , Ye Bin , Meng Kun , Sun Yan 
Published: August 2019

Abstract
Objectives: Hepatocellular carcinoma (HCC) was characterized with high heterogeneity and immune “tolerogenic”. Despite of immune checkpoint inhibitors have demonstrated promising results with improved overall survival. Novel small molecule-based immune therapies with high safety profiles might be particularly needed for advanced HCC patients. The purpose of this Phase II study is to explore the safety, clinical activities and treatment associated inflammation-immune biomarkers of icaritin in advanced HCC.
Methods: Major eligibility criteria include histologically confirmed unresectable, HCC patients with Child-Pugh Class A or B liver function. Total of 70 advanced HCC patients were enrolled and administrated with 600 mg b.i.d. Primary endpoints were TTP, and secondary endpoints were safety, OS, and DCR. Local disease control was defined as no progressive disease (PD) by RECIST. Kaplan-Meier analysis was utilized for OS assessment. Inflammation-Immune biomarkers NLR, PLR, cytokines, baseline expression of checkpoint/immune gene panel including PD-L1/L2, TIM3, IDO, HLA were evaluated by Nanostring and NGS technologies, retrospectively.
Results: There was no ≥ grade III drug related AE observed in all enrolled 70 advanced HCC patients. Objective response evaluation in per-protocol population showed PR (1.6%), SD (32.8%) and PD (59.0%) and median overall survival (OS) 254day (95% CI, 172-296). DCR was achieved 34.4% (95% CI, 22.7-47.7%); Median OS for the PD-L1-positive (n=9) and negative (n=24) subgroups were 389 (95% CI, 80-522) vs. 286.5days (95%CI, 135-482), for IL-6-advantage (n=28) and disadvantage (n=16) subgroups were 328.5 (95% CI, 277-566) vs. 168 days (95% CI, 135-482), for IL-8 low (n=22) and high (n=22) subgroups were 475.5(95% CI, 309-NA) vs. 175days (95% CI, 135-295), respectively. Overall survival was significantly associated with patient genetic profiles such as neo-antigen, bacterial and viral DNA inserts.
Conclusion: Icaritin has demonstrated its favorable clinical safety and preliminary immune-modulation efficacy. Potential baseline immune biomarkers to predict the improved OS were suggested including immune cell PD-L1 expression, low level peripheral IL-8, PLR, neoantigen and infection-associated genetic variations. Both safety and immune-response efficacy are warranted for the further Phase III validation.
Citation Format: Shu-Kui Qin, Qing Li, Jianmin Xu, Jun Liang, Ying Cheng, Shu Li, Limin Zheng, Bin Ye, Kun Meng, Yan Sun. Small molecule immune-modulator icaritin: Safety, durable survival and inflammation-immune biomarkers in advanced hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT148.
Abstract LB-014: Antibody targeting soluble NKG2D ligand sMIC sensitizes metastatic prostate tumor and other MIC+ tumors to PD1/PD-L1 blockade therapy in pre-clinical models
Authors: Wu Jennifer D. , Zhang Jinyu , Larrocha Pablo , Dhar Payal 
Published: August 2019

Abstract
Targeting programmed cell death-1 (PD-1) has produced a survival benefit for patients diagnosed with many types of malignancies. However, the clinical survival benefit in metastatic prostate cancer is only marginal to-date. Currently, the understanding of why metastatic prostate cancer is resistant to PD-1 blockade therapy remains to be defined. Among the many factors that negatively impact response to PD-1 blockade treatment, tumor-derived soluble NKG2D ligands have been reported to hinder the clinical response to immune checkpoint blockade in melanoma patients. Metastatic prostate cancer cells release high levels of the circulating soluble NKG2D ligand, soluble MHC I Chain related molecule (sMIC), a molecule that is absent in classical rodent tumor model. Here, we tested the hypothesis that targeting sMIC sensitizes metastatic prostate tumors to PD-1 blockade therapy. Using a well-described double transgenic TRAMP/MIC mouse model that closely resembles the onco-immune dynamics of human metastatic prostate cancer, we demonstrate that an antibody targeting sMIC significantly enhances the response of prostate tumors to PD-1/PD-L1 blockade therapy. Mechanistically, targeting sMIC enriches NK cell and CD8 T cell infiltration into tumors, equips CD8 T cells with enhanced NKG2D and CD28 dual co-stimulation, and increases the expression of PD-L1+ on prostate tumor cells. Combination of the antibody targeting sMIC and a PD-1/PD-L1 blockade cooperatively augments intra-tumoral NK and antigen-specific CD8 T cell anti-tumor immunity. These findings were validated in syngeneic prostate tumor transplant models and other models of other cancer types. Our pre-clinical study provides proof-of-concept and uncovered novel mechanisms of a viable combination immunotherapy for metastatic prostate cancer and other MIC+ cancers.
Citation Format: Jennifer D. Wu, Jinyu Zhang, Pablo Larrocha, Payal Dhar. Antibody targeting soluble NKG2D ligand sMIC sensitizes metastatic prostate tumor and other MIC+ tumors to PD1/PD-L1 blockade therapy in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-014.
Abstract LB-017: Combining tumor mutational burden, CD8+ T-cell abundance and PD1 mRNA expression accurately predicts response to anti-PD1/PDL1 therapy across cancers
Authors: Lee Joo Sang , Ruppin Eytan 
Published: August 2019

Abstract
Introduction Anti-PD1/PDL1 therapies provide significant survival benefits in many cancers, but the efficacy of these treatments varies considerably across different cancer types. Identifying the underlying variables associated with the cancer type specific response remains an important open research challenge. Here, we systematically evaluate a multitude of variables to determine the key factors that can accurately predict the response to anti-PD1/PDL1 therapy across different cancer types.
Approach To this end we analyzed whole exome sequencing (WES) and RNA sequencing (RNAseq) of 10k patients from the Cancer Genome Atlas (TCGA) and the overall response rate (ORR) to anti-PD1/PDL1 therapy of 21 cancer types obtained from previous clinical trials. We considered more than 30 different variables of three distinct classes: those associated with (a) tumor neoantigen landscape, (b) tumor microenvironment and inflammation, and (c) the checkpoint inhibitor targets. We evaluated the performance of each of these variables and their combinations in predicting the ORR to anti-PD1/PDL1 therapy. Prediction accuracy was quantified with Spearman correlation and explained variance quantified through a standard leave-one-out cross-validation.
Results Our analysis shows CD8+ T-cell abundance is the most predictive of the response to anti-PD1/PDL1 therapy across cancer types, followed by the tumor mutational burden and the fraction of samples with high PD1 gene expression in each cancer type. Notably these top three predictors cover the three distinct classes considered, and their combination is highly predictive of the ORR to anti-PD1/PDL1 therapy (Spearman R=0.9, P&lt;1E-7), explaining more than 80% of the variance observed across different tumor types.
Conclusions and Relevance This is the first systematic evaluation of the different variables associated with PD1/PDL1 therapy response across different tumor types. Our findings show that, overall cancer types, three key variables can explain most of the observed cross-cancer response variability, but that their relative explanatory roles may vary in specific cancer types.
Citation Format: Joo Sang Lee, Eytan Ruppin. Combining tumor mutational burden, CD8+ T-cell abundance and PD1 mRNA expression accurately predicts response to anti-PD1/PDL1 therapy across cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-017.
Abstract LB-024: Inactivation of the 25-hydroxyvitamin D(3)-1(alpha)-hydroxylase gene (CYP27B1): evidence for impaired vitamin D signaling in an MMTV-PYMT mouse model of breast cancer
Authors: Jusu Sylvester , Presley John , Jean-Claude Bertrand , Stochaj Ursula , Kremer Richard 
Published: August 2019

Abstract
Purpose : The hormonally active form of vitamin D [1,25(OH)2D3], has several antitumor effects including antiproliferative, prodifferentiative and proapoptotic functions in tissues expressing and binding the vitamin D receptor. 1,25(OH)2D3 is synthesized from its precursor 25-hydroxyvitamin D [25(OH)D] via the catalytic action of the mitochondria cytochrome P450 enzyme 25(OH)D-1α-hydroxylase (CYP27B1). In the current study we investigated the role of CYP27B1 ablation on vitamin D signaling using the mouse mammary tumor virus promoter-driven polyoma middle T oncoprotein (MMTV-PyMT) mouse, an oncogene-driven model of highly aggressive spontaneous mammary tumors that closely mimics the estrogen receptor negative breast cancer in human disease.
Methods: Tumors from animals were digested and primary cells were obtained from both CYP27B1 ablated AOH93Cre+ cells and wild type MT1107 Cre- control cells. The cells were next grown in complete DMEM medium, transfected with either a GFP-tagged human VDR or RXRα and treated with 1,25(OH)2D3 (10−7 mol/L) or 25(OH)D3 (10−7 mol/L) before data acquisition.
Results: Using live and fixed cell fluorescence imaging, in situ proximity ligation assay and immunoblotting techniques, we show that the nuclear localization of both endogenous and exogenously tagged VDR and RXR were impaired in CYP27B1 ablated cells when compared to non-ablated cells. Furthermore, the intranuclear shuttling of VDR and its interaction with RXR were significantly reduced in CYP27B1 ablated cells as shown by both Florescence Recovery After Photobleaching and Fluorescence Resonance Energy Transfer techniques. Our results also show that CYP27B1 ablation disrupts VDR function by significantly impairing its nuclear localization, intranuclear transport, interaction with adaptor proteins, hVDR/hRXR, and this correlated with impaired binding to DNA and chromatin. Lastly, we demonstrate impaired induction of 53BP1, p65 and γ-H2AX DNA double-strand breaks in the CYP27B1 ablated cells compared to non-ablated cells.
Conclusion: These results suggest that ablation of CYP27B1 results in dysregulation in vitamin D signaling which may impair its anticancer functions.
Citation Format: Sylvester Jusu, John Presley, Bertrand Jean-Claude, Ursula Stochaj, Richard Kremer. Inactivation of the 25-hydroxyvitamin D(3)-1(alpha)-hydroxylase gene (CYP27B1): evidence for impaired vitamin D signaling in an MMTV-PYMT mouse model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-024.
Abstract LB-034: Myc instructs and maintains pancreatic adenocarcinoma phenotype
Authors: Sodir Nicole M. , Kortlever Roderik M. , Barthet Valentin J.A. , Pellegrinet Luca , Campos Tania , Kupczak Steven , Soucek Laura , Arends Mark J. , Littlewood Trevor D. , Evan Gerard I. 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC) sporadically develops from pre-cancerous pancreatic intraepithelial neoplasia (PanIN). It has a very poor prognosis and lacks effective therapies. Expression of the pleiotropic transcription factor Myc is deregulated in the majority of human cancers, including PDAC. Using a rapidly and reversibly switchable genetic mouse model to toggle Myc activity, we show that Myc drives immediate transition of indolent KRasG12D-induced PanINs into aggressive pancreatic adenocarcinomas that share all the signature features of spontaneous human PDAC. Myc induces a distinct set of instructive signals, some hitherto unknown, that together orchestrate coordinated changes in the multiple, distinct stromal and inflammatory cell types that generate the characteristic PDAC stroma. We also demonstrate that continued Myc activity is required for PDAC maintenance - Myc deactivation immediately triggers meticulous disassembly of PDAC, including its attendant stroma. Thus, both the formation and deconstruction of the complex PDAC phenotype can be mediated by a single, reversible molecular switch. We have also identified a previously unknown Myc-dependent GAS6-AXL pathway that is required for stromal changes characteristic of PDAC. Using the same pre-clinical mouse PDAC model, we show that TP-0903, a specific inhibitor of AXL kinase, profoundly blocks Myc-induced influx of neutrophils into PanINs and B220+ lymphoid cells into the PanIN periphery. This significantly retards Myc-driven stellate cell activation and proliferation and impedes PDAC growth. Hence, the GAS6-AXL-mediated signaling pathway is a promising therapeutic target for pancreatic ductal adenocarcinoma. TP-0903 is currently in a Phase I/Ib clinical study in in patients with solid tumors, including PDAC.
Citation Format: Nicole M. Sodir, Roderik M. Kortlever, Valentin J.A. Barthet, Luca Pellegrinet, Tania Campos, Steven Kupczak, Laura Soucek, Mark J. Arends, Trevor D. Littlewood, Gerard I. Evan. Myc instructs and maintains pancreatic adenocarcinoma phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-034.
Abstract LB-036: Tetraspanin 5 expressing macrophages promote mammary tumor growth
Authors: Moamin Mohammed Ridha , Monk Peter , Cox Angela , Ottewell Penelope , Saint-Pol Julien , Rubinstein Eric , Muthana Munitta 
Published: August 2019

Abstract
Rationale: Tetraspanins (TSPANs) have emerged as key players in regulating tumor cell migration, invasion, and metastasis. Whilst we know TSPANs are expressed by macrophages very little is known regarding their role in Tumor Associated Macrophages (TAMs). We have shown that all 33 TSPAN members are differentially expressed by macrophages; however, following exposure to tumor-derived factors we see a significant increase in TSPAN5. We hypothesize that TSPAN5 plays a role in supporting the pro-tumor activities of TAMs and targeting tetraspanins in cancer may be a novel therapeutic approach.
Objectives: To determine TSPAN5 expression by macrophages in vitro and in situ in human breast cancer tissue and investigate the role of TSPAN5 in regulating the pro-tumor phenotype of TAMs.
Methodology: Expression of TSPAN5 was confirmed at the gene and protein level by qPCR, flow cytometry, western blotting, immunocytochemistry and by immunohistochemistry in formalin fixed breast cancer tissue. Accell siRNA knockdown was performed to determine the role of TSPAN5 in macrophage phenotype and function. NextSeq500 was performed to identify how TSPAN5 influences gene expression in BMDMs prepared from C57Bl/6 wild-type (WT) and TSPAN5 knockout (KO) mice. The role of TSPAN5 in a mammary carcinoma model in C57BL/6 WT and TSPAN5KO mice was also determined.
Findings: TSPAN5 was up-regulated by tumor-conditioned macrophages both in vitro and in vivo. This expression was also evident in TAMs located in patient derived breast cancer tissue (n=30). Interestingly, 64% of TAMs expressed TSPAN5 and these cells were the main source of TSPAN5 in human breast tumors (77%). Knockdown of TSPAN5 promoted a pro-inflammatory macrophage phenotype and NextSeq500 (n=3) revealed significant changes in genes involved in cell adhesion (Fn1, Cdh11, Lamb1, Cyr61, Postn and Wisp2) and immune regulation (PTGS2, GPX8 and Crip2) in BMDMs from TSPAN5KO mice compared to WT mice. Genetic and antibody ablation of TSPAN5 in C57BL/6 significantly reduced primary EO771 tumors and enhanced the survival of tumor bearing mice. Interestingly, clodronate depletion of macrophages in TSPAN5KO mice promoted mammary tumor growth.
Conclusion: Our study demonstrates for the first-time expression of TSPAN5 by TAMs in breast cancers and the pro-tumor properties of TSPAN5 in primary and metastatic mammary tumor growth.
Citation Format: Mohammed Ridha Moamin, Peter Monk, Angela Cox, Penelope Ottewell, Julien Saint-Pol, Eric Rubinstein, Munitta Muthana. Tetraspanin 5 expressing macrophages promote mammary tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-036.