tbuckley/cabot-search huggingface dataset:
CD70, a novel target of CAR T-cell therapy for gliomas
Authors: Linchun Jin, Haitao Ge, Yu Long, Changlin Yang, Yifan (Emily) Chang, Luyan Mu, Elias J Sayour, Gabriel De Leon, Qiong J Wang, James C Yang, Paul S Kubilis, Hongbo Bao, Songsong Xia, Dunyue Lu, Yingjun Kong, Li Hu, Yujiao Shang, Chencheng Jiang, Jing Nie, Shimin Li, Yunhe Gu, Jiahang Sun, Duane A Mitchell, Zhiguo Lin, Jianping Huang
Journal: Neuro-Oncology (2017)

Cancer immunotherapy represents a promising treatment approach for malignant gliomas but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified cluster of differentiation (CD)70 as a novel immunosuppressive ligand and glioma target. Normal tissues derived from 52 different organs and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression. The association between CD70 and patients' overall survival and its impact on T-cell death was also evaluated. Human and mouse CD70-specific chimeric antigen receptors (CARs) were tested respectively against human primary GBMs and murine glioma lines. The antitumor efficacies of these CARs were also examined in orthotopic xenograft and syngeneic models. CD70 was not detected in peripheral and brain normal tissues but was constitutively overexpressed by isocitrate dehydrogenase (IDH) wild-type primary LGGs and GBMs in the mesenchymal subgroup and recurrent tumors. CD70 was also associated with poor survival in these subgroups, which may link to its direct involvement in glioma chemokine productions and selective induction of CD8+ T-cell death. To explore the potential for therapeutic targeting of this newly identified immunosuppressive axis in GBM tumors, we demonstrate that both human and mouse CD70-specific CAR T cells recognize primary CD70+ GBM tumors in vitro and mediate the regression of established GBM in xenograft and syngeneic models without illicit effect. These studies identify a previously uncharacterized and ubiquitously expressed immunosuppressive ligand CD70 in GBMs that also holds potential for serving as a novel CAR target for cancer immunotherapy in gliomas.
Functional genomic screening to identify USP11 as a novel therapeutic target in breast cancer.
Authors: Darran O'Connor, Lisa Dwane, William M. Gallagher
Journal: Journal of Clinical Oncology (2016)

e12048 Background: The estrogen receptor (ER) is the principal driver of growth in breast cells and de-regulated receptor function is a key feature of ~75% of breast cancers. Here, we investigated the role of deubiquitinating enzymes (DUBs) in regulating the transcriptional activity of ER in breast cancer. Methods: To identify DUBs involved in the regulation of ER transcriptional activity, we performed an RNAi loss-of-function screen using a library of 432 shRNA vectors targeting all known human DUB genes. We found that suppression of the BRCA2-associated DUB, USP11, repressed the activity of an estrogen-response-element (ERE). The screen was subsequently validated using multiple individual hairpins and ZR-75-1 stable USP11 knockdown cell lines. Expression of ER target genes was quantified by qRT-PCR, while growth assays and Western blot analysis were used to determine changes in cell growth and survival. To determine the prognostic relevance of USP11, immunohistochemical staining of a 144 patient breast cancer tissue microarray (TMA) was performed and validated using publically available gene expression data linked to patient outcome. Results: USP11 knockdown was found to down-regulate ERα transcriptional activity as demonstrated by a pronounced decrease in estrogen-response element (ERE) luciferase reporter activity and reduced expression of endogenous ER target genes (PgR and TFF1). A global decrease in cell survival, decreased ERK and AKT phosphorylation and increased sensitivity to DNA-damaging agents was also observed following USP11 supression. TMA staining revealed a significant relationship between high USP11 expression and poor prognosis in ER+ patients, including those treated with anti-estrogen therapy. This was further validated in silico by analysis of publically available breast cancer gene expression datasets (HR 1.51, CI 1.07-2.14, p = 0.018). Conclusions: These results suggest a role for USP11 in driving cellular growth and identify USP11 as novel therapeutic target in breast cancer
Increased FoxP3 and PD-L1 in non-pCR tissue from early stage HER2 positive breast cancer patients treated with trastuzumab-pertuzumab based regimens.
Authors: Jeremy Meyer Force, Lynn Jackson Howie, Sara Abbott, Rex C. Bentley, Paul K. Marcom, Gretchen Genevieve Kimmick, Kelly E. Westbrook, Michelle Parks, Donna L. Topping, Gloria Broadwater, Kimberly L. Blackwell, Smita K Nair
Journal: Journal of Clinical Oncology (2016)

602 Background: Increased stromal tumor infiltrating lymphocytes (STILs) may predict for pathologic complete response (pCR) in HER2+ breast cancer patients treated with neoadjuvant trastuzumab (H). Taxanes (T) and carboplatin (C) have immune modulating effects. Antibody-dependent cytotoxicity is a major mechanism of action of H, which may be enhanced by T, C, and pertuzumab (P). Pre and posttreatment tumor microenvironment immune markers in subjects treated with neoadjuvant HER2-targeted regimens have not been thoroughly described. This study quantifies baseline and changes in STILs, CD4+, CD8+, FoxP3+, and PD-L1+ cells in thirty HER2+ patients receiving neoadjuvant H-P regimens. Methods: Thirty patients with pre and post neoadjuvant TCH (n = 4) or TCHP (n = 26) tissue available were identified. STILs were measured manually by H&E. CD4, CD8, FoxP3, and PD-L1 were stained by immunohistochemistry (IHC). Immune infiltrates were compared between the pCR and non-pCR groups using the Wilcoxon rank sums test. The Wilcoxon signed rank test was used to determine if posttreatment FoxP3+ and PD-L1 were significantly higher than pretreatment cells. Results: Fifteen (50%) patients achieved pCR (TCH n = 2, TCHP n = 13). Pretreatment STILs and CD8+ cells do not differ in the two pCR groups, p = 0.42 and p = 0.075, respectively. Also, pretreatment FoxP3+ and PD-L1+ cells do not differ in the two pCR groups, p = 0.91 and p = 0.74, respectively. However, in the non-pCR subset, posttreatment FoxP3+ and PD-L1+ cells are significantly elevated over pretreatment, p < 0.001 for both. Conclusions: TCH +/- P are effective neoadjuvant regimens with immune modulating effects. Levels of pretreatment immune markers are not different in the two pCR groups. However, increases in FoxP3+ and PD-L1+ cells in non-pCR tissues may suggest development of an immunosuppressive phenotype. Utilizing routine IHC staining on HER2+ pre and posttreatment tissue may help identify patients who might benefit from adjuvant checkpoint blockade. Further investigation with additional pre and posttreatment samples is warranted to evaluate whether immune targeted therapy may overcome treatment resistance.
Identification of clinically actionable pharmacogenetic variants during tumor genetic profiling in pediatric cancer patients.
Authors: Daniel Louis Hertz, Dan R. Robinson, Robert J Lonigro, Yi-Mi Wu, Pankaj Vats, Xuhong Cao, Andrew Nobani, Erika Mora, Arul M. Chinnaiyan, Rajen Mody
Journal: Journal of Clinical Oncology (2016)

1583 Background: Tumor genetic profiling to identify oncogenic drivers and select targeted agents is rapidly proliferating. Patient (germline) genetic information produced concurrent with tumor profiling can be used for additional purposes such as identifying clinically actionable pharmacogenetic variants. Methods: 125 pediatric patients with refractory tumors were enrolled in the Michigan Pediatric Oncology Sequencing (PEDS-MIOncoseq) study. Tumor and germline DNA underwent exome sequencing using HiSeq2500. Non-synonymous germline variants in TPMT, DPYD, CYP2C19, CYP2C9, G6PD, and CYP3A5 were extracted for discovery of clinically actionable variants based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Results: Clinically actionable variants were identified in 17 of 125 patients (14%). The majority were in TPMT, which informs 6-mercaptopurine (6-MP) dosing, or G6PD (Table 1). One DPYD variant that increases risk of severe myelotoxicity to fluoruracil (5-FU) treatment was discovered. Clinically actionable variants that are not non-synonymous (i.e. splice variants CYP3A5*3 and CYP2C19*2) were not detected due to the bioinformatic filtering process. Conclusions: Tumor genomic profiling that sequences matched germline DNA can provide additional information relevant to the patient's treatment. Sequencing and filtering processes must be optimized to ensure coverage of clinically actionable variants that are not non-synonymous. Future work will assess whether patients carrying these variants received the relevant drug, and if so, whether they experienced toxicity as predicted, and estimate the potential cost-benefit of integrating pharmacogenetic analysis into tumor genetic profiling programs. Genes Clinically Actionable Alleles Alleles Detected (n) Clinical relevance or comment TPMT *2, *3A, *3B, *3C, *4 *3A (2), *3B (5) 6-MP dosing DPYD *2, *13, rs67376798 rs67376798 (1) 5-FU toxicity CYP2C9 *2, *3 *2 (1) Warfarin and phenytoin dosing G6PD various various (8) G6PD deficiency CYP3A5 *3, *6, *7 Rare or not non-synonymous alleles CYP2C19 *2-*8, *17 Rare or not non-synonymous alleles
Abstract 180: Cd248+cd8+ T Lymphocytes Suppress Pathological Vascular Remodeling in Human Thoracic Aortic Aneurysms
Authors: Jun Li, Ting Wu, Xiaojuan Hu, Sebastian Schmull, Gabi Reichenbach, Ritai Huang, Feng Lian, Weiqiang Gao, Jun Dong, Song Xue
Journal: Circulation Research (2015)

Aortic aneurysms are characterized by vascular inflammation, neovascularization, and extracellular matrix destruction of the aortic wall. Although experimental studies indicate a potential role of CD248 in microvessel remodeling the functions of CD248 in human vascular pathologies remain unexplored. Here we aimed to study how CD248 interferes with pathological vascular remodeling of human aortic aneurysms. Immunofluorescent staining showed that CD248 expression was mainly localized in the CD8+ T cells infiltrating in the adventitia and media of aortic walls of patients with ascending thoracic aortic aneurysms (TAA). qPCR and immunofluorescent staining analyses revealed increased aortic CD248 expression and infiltrating CD248+CD8+ T cells in aortic aneurysms than in nonaneurysmal aortas. Flow cytometry analysis of human peripheral blood further identified a fraction of circulating CD248+ cells which was confined in the CD8+ T-cell compartment. The increased infiltrating of CD248+CD8+ T cells was coincident with reduced circulating CD248+CD8+ T cells in patients with ascending TAA when compared with patients with coronary artery diseases (CAD) and healthy donors. The CD248+CD8+ T cells were characterized by upregulated IL-10 and downregulated IL-1β/INF-γ expression when compared with CD248-CD8+ T cells. Moreover, when co-cultured with human aortic endothelial cells, the CD248+CD8+ T cells not only downregulated endothelial expression of ICAM1/VCAM1 and MMP2/3 but also suppressed endothelial migration. Thus, this study shows that CD248 reduces pathological vascular remodeling via anti-inflammatory CD248+CD8+ T cells, revealing a CD248-mediated cellular mechanism against human aortic aneurysms.
A Phase 2, multicenter, single-arm, global study of MEDI4736 monotherapy in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): HAWK (NCT02207530).
Authors: Dan Paul Zandberg, Anthony Jarkowski, Ugochi A Emeribe, Trishna Goswami, Giovanni Melillo
Journal: Journal of Clinical Oncology (2015)

TPS6086 Background: Patients (pts) with R/M SCCHN have a poor prognosis, with current systemic therapy options after failure of first-line platinum-based chemotherapy yielding objective response rates (ORRs) of approximately 10% and an overall survival (OS) of 6 months. In SCCHN, tumors create a highly immunosuppressive environment and evade immune detection by exploiting inhibitory immune checkpoints such as the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis. Upregulation of PD-L1 by SCCHN tumor cells is associated with inhibition of antitumor T-cell responses. Thus, therapeutic intervention with immune-modulating agents targeting this pathway holds promise. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80 with high affinity and selectivity. Evidence of clinical activity for MEDI4736 in R/M SCCHN has been seen in a Phase 1 study (NCT01693562), with initial data indicating that PD-L1 expression is associated with a higher ORR. A comprehensive clinical development program of MEDI4736 in SCCHN is underway. Here we describe the HAWK study (NCT02207530), a trial with registrational potential, assessing MEDI4736 monotherapy in pts with PD-L1+ R/M SCCHN. Methods: In this Phase 2, open-label, single-arm, multicenter study, 112 PD-L1+ pts will be enrolled from North American and European sites to investigate the efficacy and safety of MEDI4736 (10 mg/kg IV every 2 weeks for up to 12 months). Eligible pts, who are immunotherapy naïve and have tumor progression or recurrence during or after treatment with 1 platinum-containing regimen for R/M disease, will receive MEDI4736 monotherapy. The primary outcome measure is ORR (RECIST v1.1), based on independent central review. Secondary outcome measures will further assess disease control rate, duration of response, progression-free survival, and OS (using RECIST v1.1 and immune-related RECIST criteria); safety (CTCAE v4.03) and tolerability; and health-related quality of life. Exploratory outcomes include PK, immunogenicity, and potential biomarkers of response to MEDI4736. Recruitment is ongoing. Clinical trial information: NCT02207530.
Identification of single nucleotide polymorphism of PI3k-AKT-TOR pathway as a risk factor of central nervous system metastasis in metastatic breast cancer.
Authors: Jacques Bonneterre, Nicolas Bertrand, Emmanuelle Tresch-Bruneel, Aurelie Dumont, Matthias Preusser, Michael Weller, Francoise Revillion, Emilie Le Rhun
Journal: Journal of Clinical Oncology (2017)

2007 Background: Although new therapeutic options are available, an early diagnosis of central nervous system (CNS) metastasis may be needed to improve the prognosis. The PI3k-Akt-mTor pathway has been shown to be relevant in the development of CNS metastasis. Our aim was to identify risk-associated single nucleotide polymorphisms (SNP) of the PI3K Akt-mTOR pathway in the development of CNS metastasis in patients with metastatic breast cancer. Methods: We performed a secondary analysis in a subpopulation of patients from the GENEOM study (NCT00959556). In this previous study, blood samples were collected from 914 breast cancer patients treated by chemotherapy in the neoadjuvant, adjuvant or metastatic setting for genomic analysis. We identified CNS metastatic patients (both leptomeningeal and parenchymal) and non-CNS metastatic patients (no neurological symptoms or normal brain MRI before death or during 5-years metastatic period). Based on the literature, 88 SNPs of the PI3K-Akt-mTOR pathway were analyzed, including AKT1 (17 SNPs), AKT2 (4), FGFR1 (2), mTOR (7), PDK1 (4), PI3KR1 (11), PI3KCA (20), PTEN (17), RPS6KB1 (6). Results: Of the 342 patients with metastases in the GENEOM cohort, 100 patients with CNS metastasis (parenchymal lesions only, n = 51; leptomeningeal lesions only, n = 18; both, n = 31) and 107 patients without CNS metastasis were included. Negative hormonal status (p = 0.002) and presence of vascular emboli on breast cancer samples (p = 0.006) were associated with CNS metastasis. In univariate analysis, genotypes CC of AKT1 rs3803304, AA of AKT2 rs3730050, CC of AKT2 rs8100018, TT of PDK1 rs1168690, GG of PDK1 rs11904366 and GG of PI3KR1 rs251408 were associated with CNS metastasis at the p &lt; 0.05 threshold. Only genotype TT of PI3KR1-rs706716 was statistically associated with CNS metastasis after Bonferroni correction (p = 0.0003, &lt; 0.00085). Conclusions: PI3KR1-rs706716 is associated with CNS metastasis in metastatic breast cancer patients, in addition to negative hormonal status and presence of vascular emboli and could be combined in a composite score to predict the risk of and to detect early CNS metastasis in this population.
Population pharmacokinetics of durvalumab and fixed dosing regimens in patients with advanced solid tumors.
Authors: Paul Baverel, Vincent Dubois, Chaoyu Jin, Xuyang Song, Xiaoping Jin, Pralay Mukhopadhyay, Ashok Kumar Gupta, Phillip A. Dennis, Yong Ben, Lorin Roskos, Rajesh Narwal
Journal: Journal of Clinical Oncology (2017)

2566 Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The objectives of this analysis were to develop a population pharmacokinetics (PK) model of durvalumab, to quantitate the effect of patient/disease characteristics on PK, and to compare weight (WT)-based versus fixed dosing regimens. Methods: Data were pooled from two studies: Study 1108 (Phase 1/2; various tumor types) and ATLANTIC (Phase 2; NSCLC). A total of 1324 patients provided data following 0.1 to 20 mg/kg IV durvalumab. The population PK was performed using a non-linear mixed effects modeling approach in NONMEM software. The impact of demographics, clinical indices, and biomarkers on PK was explored. Results: Durvalumab PK was best described using a 2-compartment model with both linear and non-linear clearances. The mean (between-patient variability) linear clearance (CL) and central volume of distribution (V 1 ) were 226 mL/day (~29%) and 3.51 L (~21%), respectively. Although population PK analysis identified a few statistically significant covariates (WT, sex, CrCL, post-baseline ADA, ECOG performance status, LDH, sPDL1 levels, tumor type, and albumin), none were found to be clinically relevant (effect on PK parameters &lt; 30%), indicating no need for dose adjustment. Simulations indicated similar overall PK exposures following WT-based (10 mg/kg Q2W) and fixed dosing regimens (1500 mg Q4W or 750 mg Q2W); with all regimens expected to maintain target trough exposure of ~50 µg/mL in ≥95% patients. In a post-hoc analysis, durvalumab clearance was found to decrease slightly over time, with a mean maximal reduction from baseline value of 15.5%. The decrease in CL was associated with tumor shrinkage, decreased LDH, increased albumin and decreased neutrophil to lymphocyte ratio. The small decrease in CL was not considered relevant to PK exposure or dosing. Conclusions: A population PK model of durvalumab was developed and validated. No dose adjustments were needed based on any patient or disease characteristics. The analysis demonstrated the feasibility of switching to a fixed dose regimen. Clinical trial information: NCT02087423 and NCT01693562.
Novel Bruton's Tyrosine Kinase Inhibitor Bgb-3111 Demonstrates Potent Activity in Mantle Cell Lymphoma
Authors: Carrie J Li, Yang Liu, Taylor Bell, Jack Wang, Hui Guo, Makhdum Ahmed, Hui Zhang, Laura T Lam, Krystle Nomie, Lai Wang, Liang Zhang, Michael Wang
Journal: Blood (2016)
Does race play a role in genetic screening for hereditary cancer syndromes?
Authors: Sudeshna Chatterjee, Melissa K Frey, Zhen Ni Zhou, Ann Carlson, Thomas A. Caputo, Kevin Holcomb, Eloise Chapman-Davis
Journal: Journal of Clinical Oncology (2017)

1578 Background: Molecular analysis of cancer predisposition genes may influence cancer screening, prevention strategies and options for targeted therapy. We sought to identify ethnic differences in patterns of genetic testing. Methods: Results of all patients with known ancestry who underwent genetic testing at the hereditary breast and ovarian cancer center at a single institution between 7/1/2013-12/31/2016 were reviewed. Race was stratified as Black, White, Asian, and Hispanic. Ashkenazi Jews were excluded from the White subgroup because of their higher rates of testing for deleterious founder mutations. White patients were utilized as the reference population for all statistical analysis. Results: 894 patients were included: 139 Black, 613 White, 33 Hispanic and 108 Asian. Black patients were more likely to undergo genetic testing for a personal history of cancer rather than family history risk assessment compared to White patients (p = 0.002). There was no difference in genetic testing rates based on personal or family history of cancer between Asians or Hispanics and Whites (p = 0.398 ;p = 0.366). Black patients were more likely than White patients to undergo testing with targeted-gene rather than multigene panels (p = 0.026). The use of targeted and multigene panels were not different among Asians or Hispanics ( p = 1.0). Blacks, Asians and Hispanics had a lower rate of known deleterious mutations but a higher rate of variants of unknown significance (VUS) than Whites (15.1% p = 0.048; 22.2% p = .001; 33.3%p = .002 respectively). BRCA1/2 mutations accounted for 100% of identified mutations across all the non-White populations. Among Blacks, BRCA1/2 accounted for 38.1% of VUS compared to 27.9% in Whites ( p = .2114). VUS in the ATM gene accounted for 28.6% in Blacks compared to 8.2% in Whites (p = 0.028). Conclusions: Black patients were less likely to undergo testing based on family history, suggesting a missed opportunity for cancer prevention. They were more likely to undergo targeted testing and100% of identified mutations were in BRCA1/2 genes. Non-white patients had higher rates of VUS, emphasizing the need for improved VUS reclassification in non-White populations.
Post-Thrombotic Syndrome and Functional Disability in Patients with Upper Extremity Deep Vein Thrombosis: A Prospective Cohort Study
Authors: Alejandro Lazo-Langner, Susan R Kahn, Philip S Wells, David Anderson, Marc Rodger, Marc Carrier, Annmarie A. Bosco, Judy Kovacs, Roweena Corpuz, Michael J. Kovacs
Journal: Blood (2016)
Children who miss appointments may be at risk from lack of follow-up
Authors: Ingrid Torjesen
Journal: BMJ (2017)

Hospitals often fail to tell GPs when children miss appointments, and most practices have no protocol for dealing with such children when they become aware of them, a study has found.1

Poor communication between primary and secondary care has important implications for child protection, as doctors may miss the opportunity to identify children at risk, said researchers from the University of Bristol.

To learn more about the characteristics of children who do not attend, the …