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  • 1
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 12, No. 548 ( 2020-06-17)
    Abstract: Immune checkpoint therapy (ICT) can produce durable antitumor responses in metastatic urothelial carcinoma (mUCC); however, the responses are not universal. Despite multiple approvals of ICT in mUCC, we lack predictive biomarkers to guide patient selection. The identification of biomarkers may require interrogation of both the tumor mutational status and the immune microenvironment. Through multi-platform immuno-genomic analyses of baseline tumor tissues, we identified the mutation of AT-rich interactive domain-containing protein 1A ( ARID1A ) in tumor cells and expression of immune cytokine CXCL13 in the baseline tumor tissues as two predictors of clinical responses in a discovery cohort ( n = 31). Further, reverse translational studies revealed that CXCL13 −/− tumor-bearing mice were resistant to ICT, whereas ARID1A knockdown enhanced sensitivity to ICT in a murine model of bladder cancer. Next, we tested the clinical relevance of ARID1A mutation and baseline CXCL13 expression in two independent confirmatory cohorts (CheckMate275 and IMvigor210). We found that ARID1A mutation and expression of CXCL13 in the baseline tumor tissues correlated with improved overall survival (OS) in both confirmatory cohorts (CheckMate275, CXCL13 data, n = 217; ARID1A data, n = 139, and IMvigor210, CXCL13 data, n = 348; ARID1A data, n = 275). We then interrogated CXCL13 expression plus ARID1A mutation as a combination biomarker in predicting response to ICT in CheckMate275 and IMvigor210. Combination of the two biomarkers in baseline tumor tissues suggested improved OS compared to either single biomarker. Cumulatively, this study revealed that the combination of CXCL13 plus ARID1A may improve prediction capability for patients receiving ICT.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. LB-96-LB-96
    Abstract: Propelled by the advent of new technologies and an evolving regulatory landscape, the desire to personalize cancer treatments has never been greater. There is a critical need to reliably evaluate target inhibition and pharmacodynamic activity of investigational drugs in biologically relevant compartments. However, the ability to fulfill such a task in global clinical trials is complicated by varying technical expertise available at clinical sites and considerations about specimen stability for centralized laboratory analysis. We developed a novel formalin-based preservation method that enables specimen stabilization in a single step, requiring less than 20 minutes, without the need for specialized training or instrumentation. Stabilized specimens can be frozen for shipping and batched analysis at a later time point, in a specialized laboratory. Using this preservation method, we developed a flow assay enabling identification of multiple cell-types, and quantification of intracellular biomarkers in target cellular compartments, in both the peripheral blood (PB) and bone marrow (BM). We present pharmacodynamic (PD) data for a novel anticancer investigational agent intended for acute myeloid leukemia and multiple myeloma and its effect on multiple target biomarkers of the PI3K signaling pathway, including phosphorylation of the S6 ribosomal protein (S6). Our novel fixation method allowed detection of pS6 modulation in a dose dependent manner in both tumor cells and PB or BM in response to the novel investigational agent. Assay sensitivity and concordance were evaluated by comparing flow assay with western blot analysis, with each assay performed at a different site using the same batched frozen samples; exceptional preservation of phosphorylated proteins for more than 72 hours could be observed, when frozen immediately following fixation. In conclusion, our novel preservation method enables reliable quantification of signaling biomarkers in centralized laboratories at different time points post sample (PB or BM) acquisition requiring minimal processing at collection sites. Citation Format: Anil Pahuja, Abdel Saci, Shyam Sarikonda, Armin Graber, Benjamin Lee, Jelveh Lameh, Shabnam Tangri, Naveen Dakappagari. A novel blood preservation system to study oncogenic signaling pathway biomarkers by flow cytometry in leukemia/lymphoma clinical trials. [abstract] . In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-96. doi:10.1158/1538-7445.AM2014-LB-96
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 3
    In: Nature, Springer Science and Business Media LLC, Vol. 459, No. 7250 ( 2009-6), p. 1085-1090
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2009
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    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 4
    In: Genome Biology, Springer Science and Business Media LLC, Vol. 15, No. 9 ( 2014-9)
    Type of Medium: Online Resource
    ISSN: 1474-760X
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2014
    detail.hit.zdb_id: 2040529-7
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 6_suppl ( 2018-02-20), p. 511-511
    Abstract: 511 Background: Prior studies have correlated FGFR3 mutations (mut) and increased PPARg expression with decreased T-cell infiltration raising the possibility that these might represent mediators of PD-1/PD-L1 blockade resistance in luminal UC and targets for combination strategies. The causality of these associations remains unclear and the clinical relevance in PD-1/PD-L1 blockade treated patients has been underexplored. Methods: Archival tumor specimens from patients enrolled on CheckMate 275, a phase 2 trial of nivo in patients with platinum-resistant metastatic UC, underwent whole exome sequencing (WES) and gene expression profiling (HTG EdgeSeq). CD8 expression was determined by immunohistochemistry. Results: WES and gene expression data was available for 139 and 217 patients, respectively; the baseline characteristics and outcomes of both cohorts were similar to the full CheckMate 275 cohort. FGFR3mut were detected in 15 patients (11%) and correlated with higher FGFR3 gene expression. Neither FGFR3mut nor FGFR gene expression correlated with CD8 expression (Pearson's r -0.13; p=0.16) or with response rate (RR), progression-free survival (PFS), or overall survival (OS); RR in FGFRmut vs. FGFRwt = 20% vs 20%. PPARg gene expression was inversely correlated with CD8 (Pearson’s r -0.44; P 〈 0.001) and IFNg gene expression (Pearson’s r -0.52; P 〈 0.001). Higher PPARg gene expression was associated with inferior outcomes (Table); RR in PPARg highest vs lowest tertile = 15% vs 24%. Conclusions: FGFR3 alterations (mut/increased expression) do not preclude response to nivo and were not associated with decreased CD8. Higher PPARg expression was associated with decreased CD8, lower RR to nivo, and significantly shorter PFS and OS. These data support exploring therapeutic modulation of PPARg or downstream mediators in an effort to overcome resistance to PD-1/PD-L1 blockade. Cox proportional hazards model. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 11 ( 2019-04-10), p. 867-875
    Abstract: Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3) is approved for first-line treatment of patients with advanced melanoma in several countries. We conducted a phase IIIb/IV study (CheckMate 511) to determine if nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (NIVO3+IPI1) improves the safety profile of the combination. PATIENTS AND METHODS Patients (N = 360) age 18 years or older with previously untreated, unresectable stage III or IV melanoma were randomly assigned 1:1 to NIVO3+IPI1 or NIVO1+IPI3 once every 3 weeks for four doses. After 6 weeks, all patients received NIVO 480 mg once every 4 weeks until disease progression or unacceptable toxicity. The primary end point was a comparison of the incidence of treatment-related grade 3 to 5 adverse events (AEs) between groups. Secondary end points included descriptive analyses of objective response rate, progression-free survival, and overall survival. The study was not designed to formally demonstrate noninferiority of NIVO3+IPI1 to NIVO1+IPI3 for efficacy end points. RESULTS At a minimum follow-up of 12 months, incidence of treatment-related grade 3 to 5 AEs was 34% with NIVO3+IPI1 versus 48% with NIVO1+IPI3 ( P = .006). In descriptive analyses, objective response rate was 45.6% in the NIVO3+IPI1 group and 50.6% in the NIVO1+IPI3 group, with complete responses in 15.0% and 13.5% of patients, respectively. Median progression-free survival was 9.9 months in the NIVO3+IPI1 group and 8.9 months in the NIVO1+IPI3 group. Median overall survival was not reached in either group. CONCLUSION The CheckMate 511 study met its primary end point, demonstrating a significantly lower incidence of treatment-related grade 3-5 AEs with NIVO3+IPI1 versus NIVO1+IPI3. Descriptive analyses showed that there were no meaningful differences between the groups for any efficacy end point, although longer follow up may help to better characterize efficacy outcomes.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 7_suppl ( 2019-03-01), p. 142-142
    Abstract: 142 Background: Immune checkpoint inhibitor monotherapy has shown limited clinical benefit in patients (pts) with prostate cancer, likely due to an immunologically “cold” tumor microenvironment. We report preplanned interim efficacy/safety for NIVO + IPI in pts with mCRPC from CheckMate 650. Methods: Asymptomatic/minimally symptomatic pts who progressed after 2nd-generation hormone therapy and have not received chemotherapy for mCRPC (cohort 1) and pts who progressed after taxane-based chemotherapy (cohort 2) were included. Treatment was NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses, then NIVO 480 mg every 4 weeks. Coprimary endpoints: objective response rate (ORR) and radiographic PFS per PCWG2. Safety is a secondary endpoint. Exploratory endpoints include correlation of biomarkers with efficacy. Results: 78 pts had a minimum follow-up of 6 months; among pts with baseline measurable disease, ORR was 26% and 10% in cohorts 1 and 2 (Table). In both cohorts, ORR was higher in pts with PD-L1 ≥1%, DNA damage repair (DDR), homologous recombination deficiency (HRD), or above-median tumor mutational burden (TMB). Of all PSA responding pts (Table), 4 had PSA 〈 0.2 ng/mL. Grade 3–4 treatment-related adverse events occurred in 39% and 51% of pts in cohorts 1 and 2; one grade 5 event occurred in each cohort. Conclusions: In a malignancy where immune checkpoint inhibitor monotherapy has previously shown limited success, NIVO + IPI demonstrated activity in pretreated pts with mCRPC, particularly in a biomarker-enriched population, with a safety profile consistent with this dosing schedule. Further study is warranted. Clinical trial information: NCT02985957. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. CT037-CT037
    Abstract: Background: Increased tumor mutational burden (TMB) and inflammation are associated with improved clinical outcomes to immuno-oncology (I-O) therapy in many tumor types. Genomic correlates of response to nivolumab (N) vs dacarbazine (D) (CheckMate [CM] 066; NCT01721772) and N+ipilimumab (I) combination therapy or N vs I (CM 067; NCT01844505) were evaluated for association of TMB and an inflammatory gene signature with clinical outcomes. Methods: In pretreatment tumor samples from eligible patients (pts), TMB was analyzed by whole-exome sequencing using median number of total missense mutations to define high vs low TMB (TMB-H/TMB-L). Associations of TMB with progression-free survival (PFS) and overall survival (OS) were evaluated per protocol-defined exploratory analyses using 4-year follow-up data for both trials. PFS and OS associations with an inflammatory signature were assessed by RNAseq in CM 067 samples only and grouped into tertiles for analysis. HR and 95% CI were calculated using Cox modeling and P values were calculated using the Wald test. Results: In CM 066, TMB was evaluable in 122 of 411 pts. PFS and OS were significantly longer in pts treated with N, but not with D, for TMB-H vs TMB-L tumors. The benefit of PFS and OS for N vs D was greater in pts with TMB-H than TMB-L (Table). In CM 067, 583 of 937 pts were evaluable for TMB and 299 were evaluable using an inflammatory signature. PFS and OS were longer in each treatment (tx) arm in pts with TMB-H vs TMB-L (Table). Across tx arms, a numerical benefit was observed for PFS and OS in pts with high vs low inflammatory signature (Table). TMB-H and a high inflammatory signature score were independently associated with clinical outcomes to I-O. Conclusions: High TMB or high inflammatory signature was associated with benefit to I-O. TMB status did not differentiate between N+I and N, and higher inflammatory status increased the likelihood of benefit for N+I and N, suggesting further evaluation of these biomarkers to characterize the response to I-O regimens in melanoma. Association of TMB (CM 066) or TMB and inflammatory signature (CM 067) with PFS and OSCategorical comparisonClinical measureHR (95% CI; P value)CM 066NDPatients with evaluable TMB, n (high, low)53 (23, 30)69 (38, 31)TMB-H vs TMB-LPFSOS0.33 (0.16-0.69; 0.0031)0.43 (0.2-0.91; 0.027)0.67 (0.39-1.10; 0.13)0.66 (0.39-1.10; 0.13)N vs D in TMB-HPFSOS0.28 (0.14-0.59; 0.00083)0.35 (0.17-0.73; 0.0046)N vs D in TMB-LPFSOS0.57 (0.33-0.99; 0.047)0.55 (0.31-0.98; 0.044)Categorical comparisonClinical measureHR (95% CI; P value)CM 067N+INIPatients with evaluable TMB, n (high, low)197 (94, 103)192 (95, 97)194 (101, 93)TMB-H vs TMB-LPFSOS0.56 (0.39-0.81; 0.002)0.53 (0.34-0.81; 0.0032)0.45 (0.31-0.65; 0.00002)0.48 (0.31-0.72; 0.00046)0.64 (0.47-0.87; 0.005)0.59 (0.42-0.83; 0.0022)N+I vs N in TMB-HPFSOS0.95 (0.63-1.40; 0.81)0.97 (0.60-1.60; 0.88)-N+I vs N in TMB-LPFSOS0.77 (0.56-1.10; 0.12)0.87 (0.61-1.30; 0.46)-Patients with evaluable inflammatory signature, n (low, med, high)93 (33, 32, 28)106 (39, 31, 36)100 (28, 36, 36)Inflammatory signature, high vs lowPFSOS0.38 (0.18-0.80; 0.01)0.53 (0.24-1.18; 0.12)0.60 (0.34-1.00; 0.069)0.35 (0.18-0.69; 0.0025)0.48 (0.27-0.85; 0.012)0.52 (0.27-1.00; 0.049) Citation Format: F. Stephen Hodi, Jedd D. Wolchok, Dirk Schadendorf, James Larkin, Max Qian, Abdel Saci, Tina C. Young, Sujaya Srinivasan, Han Chang, Megan Wind-Rotolo, Jasmine I. Rizzo, Donald G. Jackson, Paolo A. Ascierto. Genomic analyses and immunotherapy in advanced melanoma [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 CT037.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 9
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3221-3221
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3221-3221
    Abstract: Background: Immunomodulatory cancer drugs such as anti-programmed death 1 (PD-1) and anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibodies have shown significant clinical benefits across multiple indications. However, not all patients benefit from checkpoint blockade (CB) treatment strategies, highlighting the need for predictive biomarkers of response. Features of the T-cell receptor (TCR) repertoire have been reported to correlate with CB treatment and response (1). Here, we performed a comprehensive, retrospective analysis of TCR repertoires from different tissues (blood and tumor) at different time points (baseline and on treatment). To the best of our knowledge, our study, comprising a total of 558 samples across 3 tumor types (non-small cell lung cancer [NSCLC], renal cell carcinoma [RCC] , and melanoma), is the largest analysis of TCR-sequencing data in CB clinical trials to date. Methods: We performed TCR sequencing on formalin-fixed paraffin-embedded tissue samples or peripheral blood samples using immunoSEQ Assays (Adaptive Biotechnologies Corp.) to profile the immune repertoire of patients from 3 clinical trials of nivolumab (anti-PD-1) or nivolumab + ipilimumab (anti-CTLA4) (NCT02041533, NCT01358721, NCT01621490). Repertoire clonality and clonal expansion statistics were computed, compared, and tested for their association with clinical activity. Results: We characterized the TCR repertoire from peripheral blood at baseline for 263 patients (209 NSCLC, 54 RCC) with matched on-treatment profiles for 49 patients (49 RCC). In addition, we profiled tumor TCR repertoires at baseline and on treatment for 127 patients (54 RCC, 73 melanoma) at time points predefined in each study’s protocol. Our analyses show that clonal expansion was accompanied by a comparable contraction of other clones and thus was not directionally enriched upon CB treatment. Moreover, comparison of baseline and on-treatment repertoire clonality did not reveal a significant shift following CB treatment. Results were consistent in blood and tumor tissue and across response groups. Baseline peripheral blood TCR clonality was not associated with best overall response or progression-free survival. Conclusions: Our results highlight that TCR repertoires are highly dynamic and that the currently established metrics are difficult to interpret or implement clinically as pharmacodynamic or response biomarkers. The variability in TCR clonality modulation upon CB treatment underscores the challenge of selecting the adequate on-treatment time point. Thus, our comprehensive analysis highlights the need for a better understanding of the TCR repertoire dynamics and development of methods to identify and functionally annotate tumor-specific TCRs. Reference: 1. Riaz N et al. Cell 2017;171:934-49 Citation Format: Simon Papillon-Cavanagh, Alice M. Walsh, Zhenhao Qi, Megan Wind-Rotolo, Abdel Saci, Parul Doshi, Radu Dobrin, Joseph Szustakowski. T-cell receptor sequencing for pharmacodynamic and response biomarkers of checkpoint blockade [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 3221.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
    Online Resource
    Online Resource
    Journal of Sport Science Technology and Physical Activities ; 2021
    In:  المجلة العلمية العلوم والتكنولوجية للنشاطات البدنية والرياضية
    In: المجلة العلمية العلوم والتكنولوجية للنشاطات البدنية والرياضية, Journal of Sport Science Technology and Physical Activities
    Type of Medium: Online Resource
    Language: Unknown
    Publisher: Journal of Sport Science Technology and Physical Activities
    Publication Date: 2021
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