21 results on '"NgocDiep Le"'
Search Results
2. 396 NT-I7, a long-acting interleukin-7, promotes expansion of CD8 T cells and NK cells and immune activation in patients with newly diagnosed high-grade gliomas after chemoradiation
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Michael Rettig, Jiayi Huang, Jian Campian, Tanner Johanns, Todd Fehniger, Se Hwan Yang, Milan Chheda, Alice Zhou, Jennifer Foltz, Jingqin Luo, Omar Butt, Chai Avvaru, Ruth Katumba, Albert Kim, Gavin Dunn, Christopher Abraham, Jean Fan, Byung Ha Lee, NgocDiep Le, and George Ansstas
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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3. Data from A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors
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Cristiana Sessa, Heidi Nauwelaerts, Angela Zubel, Malte Peters, Denes Csonka, David Demanse, Kirsten Carter, Ngocdiep Le, Carolyn D. Britten, Anastasios Stathis, José Pérez-García, Eric Van Cutsem, Johan Vansteenkiste, Luis Paz-Ares, Zev A. Wainberg, Filip Janku, Josep Tabernero, and Philippe L. Bedard
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Purpose: MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated.Experimental Design: This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non–small cell lung, ovarian, or pancreatic cancer.Results: Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non–small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination.Conclusions: At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity. Clin Cancer Res; 21(4); 730–8. ©2014 AACR.
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- 2023
4. 408 Preliminary biomarker and clinical ata of a phase 2a study of NT-I7, a long-acting interleukin-7, plus pembrolizumab: cohort of subjects with checkpoint inhibitor-naïve advanced pancreatic cancer
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Dae-Won Kim, Cara Haymaker, Marya F. Chaney, Shubham Pant, Melissa Lynne Johnson, Jean Fan, Sara Ferrando-Martinez, Richard Kim, Ngocdiep Le, Aung Naing, Minal A. Barve, Hirva Mamdani, Byung Ha Lee, and Robert A. Wolff
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Pharmacology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Immunology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Interleukin ,Pembrolizumab ,medicine.disease ,Gastroenterology ,Oncology ,Refractory ,Response Evaluation Criteria in Solid Tumors ,Pancreatic cancer ,Internal medicine ,Cohort ,medicine ,Molecular Medicine ,Immunology and Allergy ,Biomarker (medicine) ,business ,Adverse effect ,RC254-282 - Abstract
BackgroundPancreatic cancer (PaC) is immune-quiescent and resistant to single-agent checkpoint inhibitor (CPI). NT-I7 (efineptakin alfa) is the first-in-class long-acting IL-7 that can increase T-cell infiltration in the tumor microenvironment (TME) and may enhance tumor responsiveness to CPI therapy. We hypothesize that the combination of NT-I7 and pembrolizumab may result in enhanced efficacy in CPI-naïve advanced PaC.MethodsThis is an open-label, phase 2a, study in subjects with relapsed/refractory (R/R) tumors, including CPI-naïve R/R PaC. Subjects received NT-I7 intramuscularly at 1200 µg/kg every 6 weeks (Q6W) plus pembro 200 mg intravenously Q3W. Antitumor activity based on Overall Response Rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Biomarker analyses of peripheral blood and tumor biopsies were performed.ResultsAs of 15-July-2021, 26 subjects were enrolled in the CPI naïve R/R PaC cohort. Median age 69 years [31–81], ECOG PS 0 (35%), 1 (65%). Twenty-one (81%) subjects had ≥ 2 prior therapies All subjects had metastatic or locally advanced disease at enrollment. The median duration of follow-up was 3.3 months. Among 10 subjects with at least 1 post-treatment tumor assessment, the RECIST1.1-based ORR and disease-control rate (DCR) were 10% and 50%, respectively. One subject with MSS and TMB of 1, achieved a confirmed partial response (cPR) with 65% tumor reduction and drastically improving CA19-9. Treatment-related adverse events (AEs) occurred in 14 (53.8%) subjects, 9 (34.6%) G1–2, 3 (11.5%) G3; 2 (7.7%) G4; no G5 AEs were reported. No subjects discontinued from treatment due to AE. NT-I7 + pembro elicited a significant increase in the peripheral absolute lymphocyte count that peaked at week 3 (>3X from baseline, p15X, pConclusionsThe chemo-free combination of NT-I7 + pembro was well tolerated and showed promising anti-tumor activity in subjects with CPI-naïve R/R PaC. Increased TSCM and CD8+ T-cell infiltration within TME may be the underlying mechanisms of action for the observed efficacy. These results support continued evaluation of NT-I7 + pembro in subjects with CPI-naïve R/R PaC.AcknowledgementsThe authors thank ICON for their partnership in conducting this trial.Trial RegistrationNCT04332653Ethics ApprovalThe trial was approved by MD Anderson IRB (#2020–0008_MOD001), Mary Crowley IRB (#20–13) and Advarra IRB (#Pro00042639)All participant gave informed consent prior to study enrollment.
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- 2021
5. A phase I/II study to evaluate the safety and efficacy of a novel long-acting interleukin-7, NT-I7, for patients with newly diagnosed high-grade gliomas after chemoradiotherapy: The interim result of the phase I data
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Byung Ha Lee, Jian Campian, Jingqin Luo, Jiayi Huang, Gavin P. Dunn, Tanner M. Johanns, Se Hwan Yang, Puspanjali Bhatta, Jean Fan, George Ansstas, Albert H. Kim, Christopher Abraham, Ruth Katumba, Milan G. Chheda, Sunita Ranjitka, Chai Avvaru, and Ngocdiep Le
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Oncology ,Cancer Research ,medicine.medical_specialty ,Temozolomide ,business.industry ,medicine.medical_treatment ,Interleukin ,Newly diagnosed ,Radiation therapy ,Phase i ii ,Long acting ,Interim ,Internal medicine ,medicine ,business ,Chemoradiotherapy ,medicine.drug - Abstract
2040 Background: High-grade gliomas (HGG) patients can develop prolonged lymphopenia after standard radiation therapy (RT) and temozolomide (TMZ), which has been shown to correlate with worse survival. Interleukin-7 (IL-7) level, a cytokine that stimulates T-cell homeostasis and proliferation, is disproportionally low in HGG patients with lymphopenia. NT-I7 (efineptakin alfa) is the first-in-class long-acting recombinant human IL-7 that supports proliferation and survival of CD4+ and CD8+ T-cells in humans and mice. Our previous study demonstrated that NT-I7 could correct lymphopenia and improve the survival of orthotopic murine glioma models. The current study aims to examine the safety of administering NT-17 after chemoradiotherapy to HGG patients and its effect on systemic absolute lymphocyte count (ALC). Methods: All patients with newly diagnosed HGG who have completed concurrent RT/TMZ were considered eligible, regardless of ALC. NT-I7 was initially administered intramuscularly within 1 week after completion of RT/TMZ and then every 12 weeks for up to 4 doses. Patients also received adjuvant TMZ 4 weeks after RT/TMZ. The phase I study tested 6 dose levels of NT-I7, including 60, 120, 240, 540, 720, and 960 mcg/kg, adopting an accelerated phase for the first two doses followed by the standard 3+3 design. The primary endpoint was the safety of NT-I7 in HGG. The Phase II study is a double-blinded randomized study with 10 patients per arm to evaluate the effect of NT-I7 on ALC compared to placebo controls. Blood samples at baseline and during the NT-I7 administrations will be collected for immune profiling by CyTOF, single-cell RNA-sequencing, and cytokine analysis. Results: Phase I was completed with 19 patients (2 anaplastic oligodendrogliomas and 17 glioblastomas), with a median age of 58 years (range: 25-78). Median baseline ALC was 1000 cells/mm3 before NT-I7 administration, and the median baseline dexamethasone use was 0 mg/day (range 0-12). The median number of NT-I7 doses given was 2 (range: 2-4). Treatment-related adverse events (TRAEs) were dose-dependent. The most common TRAEs were grade 1/2 injection site reactions (50%), flu-like symptoms (26%), rash (21%), and fatigue (21%). Two patients had dose-limiting toxicities at 960 mcg/kg (a grade 3 elevated alanine aminotransferase and a grade 3 muscle pain). ALC was increased in a dose-dependent manner with a range of 1.3 – 4.1 fold at week 4 after NT-I7 injection and lasted up to 12 weeks. Thus, 720 mcg/kg was identified as the recommended phase II dose (RP2D). Conclusions: NT-I7 is well tolerated for HGG patients after chemoradiotherapy and has a RP2D of 720 mcg/kg. Immune profiling and cytokine analysis are ongoing and will be updated. The Phase II randomized study to evaluate the effect of NT-I7 vs placebo on ALC and survival is ongoing. Clinical trial information: NCT03687957.
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- 2021
6. Prognostic and Immune-Related Factors for Response to Duvelisib in the Phase 2 DYNAMOTM Clinical Trial in iNHL
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Pier Luigi Zinzani, Carole B. Miller, Stephanie Lustgarten, Kam Sprott, NgocDiep Le, Jonathan A. Pachter, Ian W. Flinn, Kirit M. Ardeshna, David T. Weaver, Nina D. Wagner-Johnston, and Scott A. Tetreault
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Related factors ,Oncology ,medicine.medical_specialty ,business.industry ,Surrogate endpoint ,Immunology ,Follicular lymphoma ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Duvelisib ,Clinical trial ,chemistry.chemical_compound ,Immune system ,chemistry ,Internal medicine ,medicine ,Adverse effect ,business - Abstract
Introduction: Indolent NHL (iNHL) remains largely incurable, with the majority of patients (pts) eventually becoming refractory to standard therapies, necessitating new effective and tolerable treatments. Duvelisib is an oral dual PI3K-δ,γ inhibitor being developed for the treatment of hematologic malignancies, including CLL/SLL and follicular lymphoma (FL). In the Phase 2 DYNAMO trial of duvelisib monotherapy for relapsed/refractory iNHL(NCT01882803), the FL subgroup (n=83) had a median progression-free survival (mPFS) of 8.3 months (mo) and an overall response rate (ORR) of 43%. Although adverse events (AEs) observed with other PI3K-inhibitors also occurred with duvelisib, they infrequently led to discontinuation of treatment. An understanding of prognostic factors that can inform duvelisib responsiveness would be valuable for guiding patient selection treatment options. This study presents updated data on prognostic factors potentially associated with duvelisib efficacy and safety. Methods: To identify FL risk subgroups, clinical parameters were assessed according to the FL Prognostic Index (FLIPI). Incidences of AEs (per combined preferred term: neutropenia, diarrhea, colitis, pneumonia, pneumonitis, transaminase elevation, rash, and infections) were also evaluated for associations with clinical responses. Blood collected at baseline (Cycle1 Day1) was analyzed by a central laboratory for a 7 gene expression signature to generate the combined M7-FLIPI, and biopsies were evaluated at screening for del(6q) cytogenetics. In addition, baseline immune cell counts (subgrouped low [L] or high [H] by flow cytometry), and levels of key chemokines, cytokines, and serum factors were centrally assessed. Multivariate regression models were developed via a stepwise procedure from a selection of these parameters identified by individual univariate analysis for the efficacy endpoints of mPFS and ORR. Results: In the DYNAMO study, there were no significant differences in mPFS, ORR, or lymph node response rate (LNRR) identified for FL pts between high and low risk subgroups stratified by prognostic indexes. Efficacy responses were similar using the FLIPI (FLIPI Prognostic factors selected via univariate analyses for mPFS or ORR were advanced into multivariate models. None of these factors reached significance in a multivariate mPFS model, and only CD3H was significant in a stepwise ORR model (odds ratio H/L=2.69, 95% CI [1.20,6.06]). The FL pt subgroups having AEs were evaluated for mPFS (mo [95% CI] as follows: neutropenia, 8.3 mo [3.5,11.8], n=25; diarrhea 11.0 mo [8.3,16.4], n=40; colitis 10.0 mo [8.3,24.0], n=5; rash 8.3 mo [1.9,28.0], n=26; transaminase elevation, 11.8 mo [1.4,24.0], n=12; pneumonitis 13.0 mo [9.5,16.4], n=4; pneumonia 12.0 [4.2,28.0], n=8; and infection 9.0 [3.7,12.0], n=38. Conclusion In the Phase 2 DYNAMO study, mPFS and ORR were similar for duvelisib-treated FL pts regardless of poor prognostic indicators, including FLIPI, M7-FLIPI, and chromosome 6q deletions. Elevated levels of CXCL11 and IL2RA correlated with shorter mPFS. This analysis also shows that AEs, when managed, allow continued treatment with duvelisib and increased benefit as demonstrated by mPFS. Overall, these data suggest that duvelisib as a single-agent is effective in FL patients, including pts with poor prognostic factors. Disclosures Zinzani: SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Flinn:Novartis: Research Funding; Infinity: Research Funding; Takeda: Research Funding; Gilead: Research Funding; Trillium: Research Funding; Constellation: Research Funding; Curis: Research Funding; Verastem: Research Funding; TG Therapeutics: Research Funding; Verastem: Consultancy, Research Funding; BeiGene: Research Funding; Calithera: Research Funding; Constellation: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Forty Seven: Research Funding; Merck: Research Funding; Gilead: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Verastem: Research Funding; Trillium: Research Funding; Portola: Research Funding; TG Therapeutics: Research Funding; Forma: Research Funding; Forma: Research Funding; Genentech: Research Funding; ArQule: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Agios: Research Funding; ArQule: Research Funding; Pfizer: Research Funding; Portola: Research Funding; Novartis: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Kite: Research Funding; Kite: Research Funding; Merck: Research Funding; Forty Seven: Research Funding; Pfizer: Research Funding; Agios: Research Funding; Seattle Genetics: Research Funding; Verastem: Consultancy, Research Funding; Calithera: Research Funding; Infinity: Research Funding; Janssen: Research Funding; Curis: Research Funding; Incyte: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding. Miller:CTI: Research Funding; Gilead: Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Ardeshna:Celgene: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference expenses, Research Funding. Le:Verastem Oncology: Employment. Pachter:Verastem Inc: Employment, Other: Stockholder. Sprott:Verastem Oncology: Employment. Lustgarten:Verastem Oncology: Employment. Weaver:Verastem Oncology: Employment, Other: Stockholder; Agios Pharmaceuticals: Employment; Femto Dx: Equity Ownership. Wagner-Johnston:Novartis: Research Funding; ASTEX: Research Funding; Celgene: Research Funding; JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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- 2018
7. Characterization of the Long-Term Efficacy and Safety of Duvelisib Monotherapy in Patients with Relapsed/Refractory CLL/SLL on Treatment for > 2 Years across 4 Clinical Studies
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Fritz Offner, Klaus Geissler, Matthew S. Davids, Leanne Berkhan, Stephanie Lustgarten, Jose J. Rifon Roca, Julio Delgado, NgocDiep Le, Ian W. Flinn, Zsolt Nagy, Marco Montillo, and Zoltán Gasztonyi
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Immunology ,Neutropenia ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Rectal carcinoma ,medicine ,In patient ,Adverse effect ,business.industry ,Cancer ,Cell Biology ,Hematology ,Pseudomembranous colitis ,medicine.disease ,Duvelisib ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Relapsed refractory ,business - Abstract
Background: Duvelisib (DUV) is a first-in class, oral dual inhibitor of PI3K-δ,-γ being developed for the treatment of advanced B- and T-cell malignancies. To date 304 patients (pts) with relapsed/refractory (RR) CLL/SLL have been treated with DUV monotherapy 25 mg BID in 4 studies: Study IPI-145-02 [NCT01476657], a Phase 1 study in advanced hematologic malignancies; DYNAMOTM [NCT01882803], a Phase 2 study in iNHL; DUOTM [NCT02004522], a Phase 3 study in CLL/SLL; and Study IPI-145-12 [NCT02049515], a Phase 3 crossover study from DUO. Here we present pooled efficacy and safety analyses from these 4 studies in RR CLL/SLL, examining the baseline characteristics, incidence and timing of AEs, and response in the subset of pts who received DUV monotherapy for >2 years in order to characterize the factors that contribute to long-term treatment with DUV. Methods: In this analysis we examined pts treated with DUV for >2 years (n=45) referred to as long-term (LT) pts. Efficacy and safety data from 4 studies of DUV monotherapy in pts with RR CLL/SLL treated at 25 mg BID were pooled. Response was based on investigator assessment per IWCLL/IWG criteria. Treatment-emergence (TE) was defined as those adverse events (AEs) that occurred from first dose to 30 days post last dose of DUV. All AEs were coded using MedDRA version 16.1; severity was assessed by investigators according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.03. Results: Baseline characteristics of LT pts were similar to pts who discontinued The median exposure for LT pts was 31 months, with 20 pts on DUV >3 years and 3 pts on DUV >4 years. The majority of LT pts (60%) remain on treatment as of June 2018. The median PFS in LT pts was 37 months, with an investigator-assessed ORR of 89%; best responses included 16% CR/CRi, 73% PR, and 11% SD. Among LT pts, 98% had an AE, 80% had a ≥ Gr 3 AE, 46% an SAE, and 9% an AE leading to discontinuation (after 2 years on DUV); 69% of pts had at least 1 dose modification due to an AE (69% hold, 40% reduction). Table 1 shows the incidence of AEs in LT pts by 6-month treatment intervals. Overall, ≥ Gr 3 AEs occurred less frequently over time but still occurred in 27% pts after 2 years. The rate of colitis was consistent over the 2 years of treatment (≤ 2.2% per 6-month interval). No ≥ Gr 3 AEs of diarrhea were observed within the first 6 months of treatment, while the overall rate of all grade diarrhea was consistent over time (16-27% per 6-month interval); dose modification for the management of diarrhea increased over time allowing pts to remain on therapy. Neutropenia, ALT increase, and lipase increase were more common in the first 6 months; most ≥ Gr 3 AEs of neutropenia did not require any dose modification. Compared to all pts with RR CLL/SLL treated with DUV (n=442), the incidences and types of AEs in LT pts were generally similar. Four (9%) LT pts discontinued DUV due to an AE, and included: colitis (n=2), diarrhea (n=1), Clostridium difficile colitis (n=1), and rectal adenocarcinoma (n=1). Pneumocystis jirovecii pneumonia occurred in 1 LT pt (not on prophylaxis at the time) and was the only opportunistic infection reported for this population. There have been no fatal events in the LT pts. Conclusions: 45 pts with RR CLL/SLL have been on DUV 25 mg BID for >2 years, with a median of 31 months on treatment. The investigator-assessed ORR for these long-term pts was 89% (16% CR/CRi, 78% PR) and the median PFS was 37 months. A majority (60%) of the long-term pts remain on treatment. Baseline characteristics were similar in these long-term pts compared to pts who discontinued < 2 years. Most of the commonly occurring ≥ Gr 3 AEs decreased over time, with the exception of diarrhea. The majority of ≥ Gr 3 AEs were managed through dose modification (dose interruption and or reduction). These data support DUV monotherapy as a long-term treatment option for pts with RR CLL/SLL with the potential for durable response and good tolerability over time. Disclosures Flinn: ArQule: Research Funding; Infinity: Research Funding; Verastem: Research Funding; BeiGene: Research Funding; Curis: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Agios: Research Funding; Forma: Research Funding; Portola: Research Funding; Kite: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Verastem: Consultancy, Research Funding; Incyte: Research Funding; Janssen: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Trillium: Research Funding; Novartis: Research Funding; Calithera: Research Funding; Constellation: Research Funding. Montillo:Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau. Davids:BMS: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Merck: Consultancy; Surface Oncology: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Le:Verastem Oncology: Employment. Lustgarten:Verastem Oncology: Employment.
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- 2018
8. Clinical and Biological Indicators of Duvelisib Efficacy in CLL from the Phase 3 DUOTM Study
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Constantine S. Tam, Kam Sprott, Jennifer R. Brown, Zsolt Nagy, Ian W. Flinn, Peter Hillmen, Ulrich Jaeger, Stephan Stilgenbauer, Bryone J. Kuss, Carol Moreno, Jonathan A. Pachter, Marco Montillo, Julio Delgado, NgocDiep Le, Stephanie Lustgarten, Paolo Ghia, Matthew S. Davids, Florence Cymbalista, and David T. Weaver
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Hematology ,business.industry ,Immunology ,Cell Biology ,Biochemistry ,Duvelisib ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Phase (matter) ,Internal medicine ,medicine ,business - Abstract
Introduction In CLL, the timing and selection of therapy is largely informed by disease stage, prognostic molecular features, tumor load, and patient (pt) performance status. Duvelisib (DUV) is a novel, oral, dual PI3K-δ,γ inhibitor in clinical development for the treatment of CLL/SLL, FL, and other hematologic malignancies. Results from the Phase 3 DUO study (NCT02004522) for relapsed/refractory CLL/SLL showed that DUV monotherapy resulted in statistically significant improvement over ofatumumab (OFA) monotherapy for median progression-free survival (mPFS; 13.3 vs 9.9 months (mo); p Methods Of the 319 pts enrolled in the DUO study, 158 were treated with DUV and 155 with OFA. Tumor burden was assessed at baseline using target lymph node diameter and absolute lymphocyte count. Baseline blood samples from Cycle1 Day1 were analyzed for cytogenetic abnormalities (17p, 11q, 6q deletions; trisomy 12); immune cell counts by flow cytometry; and serum chemokine, cytokine, and serum factor levels. Univariate analysis of these markers was conducted for PFS and ORR. The statistically significant univariate markers were tested in a stepwise multivariate regression (MVR) model using binary high [H] or low [L] thresholds based on the median. Results Tumor Burden: The mPFS (in mo) for DUV monotherapy did not appear to be impacted by baseline tumor burden: high (n=20), 16.6; medium (n=88), 12.7; and low (n=47), 15.1. Across these tumor burden levels, DUV maintained its PFS advantage over OFA. Cytogenetics: DUV-treated pts with del(11q), a marker associated with poor CLL outcomes, had a longer mPFS (in mo) and ORR compared to pts without del(11q) (mPFS: 24.8, n=25 vs 12.7, n=81; HR 0.56, 95% CI [0.30,1.06]; ORR: 80.0% vs 69.1%, odds ratio, 0.56). In contrast, mPFS was shorter in OFA-treated del(11q) pts relative to those without this deletion (5.3, n=24 vs 11.3, n=71). Median PFS was significantly extended in the del(17p) subgroup for DUV vs OFA (16.6, n=27 vs 9.2, n=27; HR 0.42, [0.21,0.85]), and, to a lesser degree, in pts without del(17p) (13.1, n=83 vs 11.1, n=74; HR 0.55 [0.37,0.83]). For the 6 DUV pts with del(11q/17p), mPFS was 17.4 mo. A shorter mPFS was observed for DUV-treated pts with trisomy 12 compared with trisomy 12-negative pts (9.1, n=16 vs 16.5, n=73). For the 10 DUV pts with trisomy 12 as well as del(11q/17p), mPFS was more similar to the trisomy 12 group, at 9.1 mo. Immune cell profiles and serum factors: Several immune cell profiles correlated with longer mPFS (in mo) for DUV, including Treg (16.4H vs 12.9L, HR 0.69 [0.43,1.12]) and monocytes (15.1L vs 12.7H, HR 0.82 [0.54,1.24]). Baseline chemokine and serum factor levels associated with longer mPFS with DUV included CCL3 (22.1L vs 12.2H, HR 0.60 [0.37,0.99]), IL2RA (16.3L vs 11.6H, HR 0.73 [0.47,1.14]), and TNFα (16.6L vs 12.2H, HR 0.78 [0.49,1.24]). Multivariate regression model: The MVR model showed that the biomarker profile of trisomy 12-negative (HR -/+, 0.15), CCL22L (HR H/L, 2.23), TNFαL (HR H/L, 3.66), TregH (HR H/L, 0.31), and monocytesL (HR H/L, 2.45), was associated with longer PFS; TNFαL and TregH were the largest associations, with estimated 73% and 69% reductions in risk of progression or death, respectively. Similarly, stepwise models yielded TNFαL (odds ratio H/L, 0.37) and CXCL11H (odds ratio H/L, 2.99) as biomarkers for improvement in ORR. Based on these analyses, pts with TNFαL tend to have better efficacy profiles for PFS and/or ORR. Conclusions: DUV monotherapy was highly efficacious in CLL/SLL pts with markers of poor response, including high tumor burden, del(17p), and del(11q) as shown by univariate analyses of tumor burden, cytogenetics, immune cell profiles, and serum factors. Multivariate analyses revealed a biomarker profile of CCL22L, TNFαL, TregH, monocytesL, and trisomy 12-negative that correlated with improved mPFS and/or ORR. Additional analyses are underway to characterize the predicted PFS for the biomarker profile. Disclosures Brown: Verastem: Consultancy, Research Funding; Janssen: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy; Sun Pharmaceutical Industries: Research Funding; TG Therapeutics: Consultancy; Sunesis: Consultancy; Gilead: Consultancy, Research Funding; Roche/Genentech: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Boehringer: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees; Loxo: Consultancy. Flinn:Novartis: Research Funding; Merck: Research Funding; Infinity: Research Funding; Forty Seven: Research Funding; Janssen: Research Funding; Trillium: Research Funding; Pharmacyclics: Research Funding; Verastem: Research Funding; Pfizer: Research Funding; Kite: Research Funding; Takeda: Research Funding; Forma: Research Funding; BeiGene: Research Funding; Curis: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Research Funding; Verastem: Consultancy, Research Funding; Portola: Research Funding; Calithera: Research Funding; ArQule: Research Funding; Celgene: Research Funding; Constellation: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Agios: Research Funding. Davids:Surface Oncology: Research Funding; Merck: Consultancy; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hillmen:F. Hoffmann-La Roche Ltd: Research Funding; Celgene: Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Montillo:Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau. Tam:Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jaeger:GSK: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Infinity: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding. Ghia:Sunesis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; AbbVie, Inc: Honoraria, Research Funding. Stilgenbauer:Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreno:Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy. Le:Verastem Oncology: Employment. Lustgarten:Verastem Oncology: Employment. Sprott:Verastem Oncology: Employment. Pachter:Verastem Inc: Employment, Other: Stockholder. Weaver:Agios Pharmaceuticals: Employment; Verastem Oncology: Employment, Other: Stockholder; Femto Dx: Equity Ownership.
- Published
- 2018
9. Inability of memory T cells to induce graft-versus-host disease is a result of an abortive alloresponse
- Author
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Jessica Son, John F. Whitesides, Divino Deoliveira, Benny J. Chen, NgocDiep Le, Xiuyu Cui, and Nelson J. Chao
- Subjects
CD4-Positive T-Lymphocytes ,Male ,Isoantigens ,Immunology ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,In Vitro Techniques ,Biology ,Biochemistry ,Mice ,Interleukin 21 ,Immune system ,Animals, Congenic ,T-Lymphocyte Subsets ,medicine ,Animals ,Cytotoxic T cell ,Mice, Inbred BALB C ,Mice, Inbred C3H ,Transplantation ,ELISPOT ,CD28 ,Cell Biology ,Hematology ,T lymphocyte ,medicine.disease ,Mice, Inbred C57BL ,surgical procedures, operative ,Graft-versus-host disease ,Hemocyanins ,Female ,Lymphocyte Culture Test, Mixed ,Stem cell ,Immunologic Memory ,Stem Cell Transplantation - Abstract
Several groups, including our own, have independently demonstrated that effector memory T cells from non–alloantigen-primed donors do not cause graft-versus-host disease (GVHD). In the current study, we further investigated whether this approach could be extended to all memory T cells, and we studied the underlying mechanisms. Neither total memory T cells nor purified central memory T cells were able to induce GVHD. Memory T cells were at least 3-log less potent than bulk T cells in mediating GVHD. As expected, memory T cells failed to elicit cytotoxicity and proliferated poorly against alloantigens in standard 5-day mixed-lymphocyte cultures. However, the proliferative responses of memory T cells were more comparable with those of bulk and naive T cells when the culture time was shortened. Moreover, the frequencies of IL-2–secreting cells measured by 42-hour enzyme-linked immunosorbent spot (ELISPOT) assay were similar among naive, memory, and bulk T cells. These data indicated that memory T cells are able to respond to alloantigens initially but fail to develop to full potential. The abortive immune response, which was mediated by non–alloantigen-specific memory T cells in response to alloantigens, may explain why memory T cells from unprimed and non–alloantigen-primed donors could not induce GVHD.
- Published
- 2006
10. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas
- Author
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Max E. Scheulen, Chung-Pin Li, Ngocdiep Le, Joon Oh Park, Yuan Liu, Klaudia Steplewski, Saifuddin M. Kasubhai, Do-Youn Oh, Jeffrey R. Infante, Bradley G. Somer, and Suman Redhu
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Antimetabolites, Antineoplastic ,Pyridones ,Placebo-controlled study ,Medizin ,Phases of clinical research ,Administration, Oral ,Pyrimidinones ,Adenocarcinoma ,medicine.disease_cause ,Placebo ,Gastroenterology ,Deoxycytidine ,Double-Blind Method ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Protein Kinase Inhibitors ,Aged ,Trametinib ,Aged, 80 and over ,business.industry ,MEK inhibitor ,Cancer ,Middle Aged ,medicine.disease ,Survival Analysis ,Gemcitabine ,Surgery ,Pancreatic Neoplasms ,Oncology ,Female ,KRAS ,business ,medicine.drug - Abstract
Background Trametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed. Methods Adults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000 mg/m2 (weekly × 7 for 8 weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2 mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups. Results Baseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67–1.44; P = .453); median OS was 8.4 months with gemcitabine plus trametinib and 6.7 months with gemcitabine plus placebo. Median PFS (16 versus 15 weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1 weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients (n = 103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia. Conclusions The addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA.
- Published
- 2013
11. Disabled Is a Putative Adaptor Protein That Functions during Signaling by the Sevenless Receptor Tyrosine Kinase
- Author
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Michael A. Simon and Ngocdiep Le
- Subjects
Proline ,viruses ,Nerve Tissue Proteins ,Receptor tyrosine kinase ,Cell Line ,src Homology Domains ,Animals ,Drosophila Proteins ,Phosphorylation ,Tyrosine ,Eye Proteins ,Cell Growth and Development ,Molecular Biology ,Membrane Glycoproteins ,biology ,Activator (genetics) ,virus diseases ,Receptor Protein-Tyrosine Kinases ,Signal transducing adaptor protein ,Cell Biology ,respiratory system ,Molecular biology ,Cell biology ,biology.protein ,Insect Proteins ,Drosophila ,GRB2 ,Signal transduction ,Phosphotyrosine-binding domain ,Signal Transduction - Abstract
DRK, the Drosophila homolog of the SH2-SH3 domain adaptor protein Grb2, is required during signaling by the sevenless receptor tyrosine kinase (SEV). One role of DRK is to provide a link between activated SEV and the Ras1 activator SOS. We have investigated the possibility that DRK performs other functions by identifying additional DRK-binding proteins. We show that the phosphotyrosine-binding (PTB) domain-containing protein Disabled (DAB) binds to the DRK SH3 domains. DAB is expressed in the ommatidial clusters, and loss of DAB function disrupts ommatidial development. Moreover, reduction of DAB function attenuates signaling by a constitutively activated SEV. Our biochemical analysis suggests that DAB binds SEV directly via its PTB domain, becomes tyrosine phosphorylated upon SEV activation, and then serves as an adaptor protein for SH2 domain-containing proteins. Taken together, these results indicate that DAB is a novel component of the SEV signaling pathway.
- Published
- 1998
12. Novel mechanism of Rapamycin in GVHD: increase in interstitial regulatory T cells
- Author
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Benny J. Chen, Jeanne M. Palmer, Divino Deoliveira, Nelson J. Chao, and NgocDiep Le
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,Graft vs Host Disease ,T-Lymphocytes, Regulatory ,Interstitial cell ,Article ,Mice ,Internal medicine ,medicine ,Splenocyte ,Animals ,Skin ,Sirolimus ,Transplantation ,Mice, Inbred BALB C ,Hematology ,business.industry ,Forkhead Transcription Factors ,T lymphocyte ,medicine.disease ,Intestines ,Graft-versus-host disease ,Immunosuppressive drug ,Liver ,Immunology ,Cancer research ,Female ,Stem cell ,business ,medicine.drug - Abstract
Rapamycin (RAPA) is an immunosuppressive drug that prevents and treats graft versus host disease (GVHD) after allogeneic hematopoeitic cell transplant (HCT). One possible mechanism for its efficacy is induction of tolerance, through increased number or enhanced survival of regulatory T cells. In our experiments, B10.D2 bone marrow and splenocytes were injected into lethally irradiated BALB/cJ recipients. The mice received intraperitoneal injections of either RAPA or vehicle control on days 1–28. There was a significant survival advantage in RAPA treated mice. Evaluation of the skin biopsies demonstrated a dense cellular infiltrate in RAPA treated mice. Further characterization of these cells revealed a higher percentage of regulatory T cells characterized by FoxP3 positive cells in high dose RAPA treated mice as compared to controls on day 30. This effect appears to be dose dependant. When peripheral blood analysis for FoxP3 positive cells was done, there was no significant difference observed in the RAPA treated mice as compared to control mice. These data demonstrates a novel mechanism of rapamycin in GVHD, accumulation of regulatory T cells in the GvHD target tissue: the skin.
- Published
- 2009
13. Regulating regulatory T cells
- Author
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Nelson J. Chao and NgocDiep Le
- Subjects
Population ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,Thymus Gland ,Biology ,T-Lymphocytes, Regulatory ,Immune system ,Antigen ,T-Lymphocyte Subsets ,Immunopathology ,medicine ,Animals ,Homeostasis ,Humans ,education ,Transplantation ,education.field_of_study ,Graft vs Tumor Effect ,Hematology ,T lymphocyte ,medicine.disease ,Disease Models, Animal ,Graft-versus-host disease ,Self Tolerance ,Immunology ,Stem cell ,Biomarkers - Abstract
Regulatory T cells (Tregs) are a specialized subpopulation of T cells that act to suppress activation of other immune cells and thereby maintain immune system homeostasis, self-tolerance as well as control excessive response to foreign antigens. The mere concept of Tregs was the subject of significant controversy among immunologists for many years owing to the paucity of reliable markers for defining these cells and the ambiguity of the nature and molecular basis of suppressive phenomena. However, recent advances in the molecular characterization of this cell population have firmly established their existence and their vital role in the vertebrate immune system. Of interest, accumulating evidence from both humans and experimental animal models has implicated the involvement of Tregs in the development of graft-versus-host disease (GVHD). The demonstration that Tregs could separate GVHD from graft-versus-tumor (GVT) activity suggests that their immunosuppressive potential could be manipulated to reduce GVHD without detrimental consequence on GVT effect. Although a variety of T lymphocytes with suppressive capabilities have been reported, the two best-characterized subsets are the naturally arising, intrathymic-generated Tregs (natural Tregs) and the peripherally generated, inducible Tregs (inducible Tregs). This review summarizes our current knowledge of the generation, function and regulation of these two populations of Tregs during an immune response. Their role in the development of GVHD and their therapeutic potential for the prevention and treatment of GVHD will also be described.
- Published
- 2006
14. Selective elimination of alloreactivity from immunotherapeutic T cells by photodynamic cell purging and memory T-cell sorting
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Benny J. Chen, NgocDiep Le, and Nelson J. Chao
- Subjects
Cancer Research ,T-Lymphocytes ,Immunology ,Cell ,Graft vs Host Disease ,Graft vs Leukemia Effect ,Cell Separation ,Biology ,Lymphocyte Depletion ,Immune system ,Homologous chromosome ,medicine ,Immunology and Allergy ,Humans ,Transplantation, Homologous ,Genetics (clinical) ,Transplantation ,Graft vs Tumor Effect ,Cell Biology ,Recovery of Function ,surgical procedures, operative ,medicine.anatomical_structure ,Oncology ,Photochemotherapy ,Stem cell ,Memory T cell ,DISEASE RELAPSE ,Immunologic Memory ,Stem Cell Transplantation - Abstract
Allogeneic stem cell transplantation (alloSCT), especially in the mismatched setting, carries a high risk of life-threatening GvHD because of activation of donor T cells by Ag present on host cells. Removal of mature donor T cells can prevent GvHD but leads to delayed immune reconstitution, and an increased incidence of opportunistic infections and disease relapse. These findings demonstrate the vital role of donor T cells in providing graft-versus-tumor (GvT) and anti-pathogen effects as well as facilitating immune reconstitution. It has been well documented that GvHD can be separated from GvT effects, making it possible potentially to eliminate GvHD while preserving the immunotherapeutic benefits of donor T cells. Over the past decade, major attempts have been made to reduce GvHD incidence without loss of GvT effect, especially in the haplo-identical setting. Novel techniques to deplete host-reactive donor T cells selectively have been explored. This review focuses on the use of the photodynamic cell purging (PDP) process and of sorting memory T cells for the selective elimination of alloreactivity. Minimizing the threat of GvHD while maximizing the beneficial GvT effect would broaden the scope and effectiveness of alloSCT.
- Published
- 2005
15. COMBI-d: A randomized, double-blinded, Phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma
- Author
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Jean-Jacques Grob, Ngocdiep Le, Michael Millward, Thomas Jouary, E. Levchenko, Daniil L. Stroyakovsky, Vanna Chiarion-Sileni, Keith T. Flaherty, Mario Mandalà, Jhangir G. Irani, James Larkin, Douglas J Demarini, Michelle Casey, Claus Garbe, Filippo de Braud, Kiran Patel, Axel Hauschild, Georgina V. Long, Helen Gogas, and Céleste Lebbé
- Subjects
Oncology ,Trametinib ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,MEK inhibitor ,medicine.medical_treatment ,Dabrafenib ,Placebo ,Surgery ,First line therapy ,Internal medicine ,Cutaneous melanoma ,medicine ,In patient ,business ,neoplasms ,medicine.drug - Abstract
9011^ Background: As monotherapies, the BRAF inhibitor dabrafenib (D) and the MEK inhibitor trametinib (T) demonstrated superior progression-free survival (PFS) v chemotherapy in pts with BRAFV600 ...
- Published
- 2014
16. Phase I dose-escalation of the oral MEK1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral AKT inhibitor GSK2141795 (GSK795)
- Author
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Donna S. Cox, T. Gonzalez, Theresa Mays, Amita Patnaik, David S. Hong, R. Kurzrock, Deborah A. Smith, Glenda Chambers, Apostolia-Maria Tsimberidou, L. Rosenstein, J. L. Gauvin, Anthony W. Tolcher, Lon Smith, Douglas J Demarini, Kyri Papadopoulos, Siquing Fu, Shannon R. Morris, Ngocdiep Le, Aung Naing, and Gerald Steven Falchook
- Subjects
Cancer Research ,Oncology ,business.industry ,Allosteric regulation ,Dose escalation ,Medicine ,Oral Akt Inhibitor GSK2141795 ,Pharmacology ,business ,Protein kinase B ,PI3K/AKT/mTOR pathway - Abstract
3085 Background: The RAS/RAF/MEK and PI3K/AKT pathways are activated in many human cancers. GSK212 is a potent and selective allosteric inhibitor of MEK1/2 and GSK795 is a potent ATP-competitive in...
- Published
- 2011
17. A phase Ib study of the MEK inhibitor GSK1120212 combined with gemcitabine in patients with solid tumors: Interim results
- Author
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J. R. Infante, Johanna C. Bendell, Kevin M. Bellew, Ngocdiep Le, Anthony W. Tolcher, Yanmei Xu, H. A. Burris, Donna S. Cox, Amita Patnaik, and Kyri Papadopoulos
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,Pharmacology ,medicine.disease ,Gastroenterology ,Gemcitabine ,Regimen ,Oncology ,Tolerability ,Pharmacokinetics ,Internal medicine ,Medicine ,business ,Adverse effect ,Febrile neutropenia ,Pneumonitis ,medicine.drug - Abstract
278 Background: GSK1120212 (212) is a reversible, allosteric inhibitor of MEK1/MEK2. The objectives of this open-label, single-arm study are to evaluate the safety, pharmacokinetics (PK), and anti-tumor activity of 212 + gemcitabine (gem), and to determine the recommended phase II regimen (RP2R) in patients (pts) with advanced solid tumors. Methods: 212 (1-2.5mg) is given continuously, orally, once daily. Gem (1,000mg/m2) is infused on days 1, 8, and 15 every 28 days. Doses are escalated to the maximum tolerated dose (MTD) and followed by an expansion cohort to confirm the RP2R tolerability. Results: 28 pts received ≥ 1 dose of 212 + gem, including 8 pancreatic, 6 breast, and 4 non-small cell lung (NSCLC) cancer pts. The MTD and RP2R is 2mg 212 + 1,000mg/m2 gem. Dose-limiting toxicities (DLTs) are G3/G4 febrile neutropenia (n=2), G3 AST elevation (n=2), and G2 uveitis (n=1). 16 serious adverse events (SAEs) were reported; 5 were considered to be related to study drugs (1 pneumonitis, 3 febrile neutropenia, 1 dyspnea). All DLTs and SAEs have resolved. The most common AEs at the RP2R (n=18) were rash (78%), fatigue (67%), thrombocytopenia (61%), neutropenia (50%), decreased appetite (50%), nausea (44%), diarrhea and constipation (39%); all ≤ G2 except thrombocytopenia (17% ≥ G3) and neutropenia (33% ≥ G3). Co-administration did not affect the PK profiles of 212 or gem. 25 pts had measurable disease at baseline. 1 pancreatic cancer pt with previous radiotherapy and 2 cycles of gem achieved a partial response and stayed on study for 6 months. 3 additional pancreatic cancer pts reported stable disease; 2 of which were on the study for 3.5-5 months and the third pt continues in the study. 1 triple-negative breast cancer pt, refractory to chemotherapy, and 1 parotid cancer pt experienced a complete response of their target lesions. Conclusions: 212 + gem is tolerable with an acceptable safety profile in this pt population, with evidence of clinical activity in pancreatic cancer. A randomized phase II study in previously untreated patients with metastatic pancreatic cancer is underway to investigate the clinical activity of this combination. [Table: see text]
- Published
- 2011
18. Rapamycin Induces Tolerance by Increasing Regulatory T Cells in Chronic Graft Versus Host Disease Model
- Author
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Benny J. Chen, Nelson J. Chao, Jeanne Palmer, and NgocDiep Le
- Subjects
Graft-versus-host disease ,business.industry ,Immunology ,medicine ,Immunology and Allergy ,medicine.disease ,business - Published
- 2007
19. Prevention of Graft-Versus-Host Disease by Selective Depletion of Alloreactive T Cells
- Author
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NgocDiep Le and Nelson J. Chao
- Subjects
medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biology ,medicine.disease ,Biochemistry ,Granzyme B ,Transplantation ,Interleukin 21 ,Graft-versus-host disease ,Antigen ,medicine ,Cytotoxic T cell ,IL-2 receptor - Abstract
OBJECTIVE: Mismatched allogeneic hematopoietic cell transplantation (alloHCT) carries a high risk of life-threatening graft-versus-host disease (GVHD) due to activation of donor T cells by antigens present on host cells. Removal of donor mature T cells can prevent GVHD but leads to an increased incidence of opportunistic infections and disease relapse. This study aims to selectively deplete host-reactive donor T cells responsible for GVHD while preserving T cells with anti-tumor and anti-viral effects. METHODS: We utilized a photosensitizer, 4,5-dibromorhodamine-methyl ester (TH9402, Celmed Biosciences Inc., Saint-Laurent, Canada), in an ex vivo photodynamic purging (PDP) process to specifically eradicate host-reactive T cells. Donor T cells with anti-host specificity were identified in a unidirectional mixed lymphocyte culture (MLC) where they were activated and became proliferating. TH9402 is taken up by all cells and extruded out of the cell by P-glycoprotein (Pgp) in non-activated cells. However, due to inactivation of Pgp in activated T cells, TH9402 is retained in the mitochondria. Upon exposure to 514 nm light in the Theralux™ device (Celmed), it becomes extremely cytotoxic resulting in cell death. In this study, after treatment with various concentrations of TH9402, the cells were exposed to light for the elimination of alloreactive T cells. The efficiency of allodepletion was assessed by Granzyme B (GrB) assay. T-cell proliferation assays were used to demonstrate the preservation of anti-tumor and anti-viral effects. Finally, the skin explant assay, an in vitro model of GVHD, was utilized to examine the efficacy of the PDP treatment in the removal of alloreactive T cells responsible for GVHD. The parameters of the PDP treatment were optimized for use in subsequent clinical studies. RESULTS: After 72-hour MLC, optimal proliferative response was obtained at a responder: stimulator ratio of 1:1. Activated T cells expressed high level of activation markers such as CD25 and CD69. After the PDP treatment with 20μM of TH9402, alloreactive T cells were consistently depleted by more than 2 logs (Figure 1). Moreover, the PDP treatment did not significantly affect anti-tumor and anti-viral effects as evidenced by responses to third-party stimulators (Figure 2A), cytomegalovirus (CMV) (Figure 2B) and Candida antigens. Most importantly, co-culture of recipient’s skin with PDP-treated cells showed a reduction of graft-versus-host reaction (GVHR) in a TH9402-dose dependent manner. The PDP treatment with 20μM of TH9402 completely abolished GVHR in a skin explant assay. CONCLUSIONS: The PDP treatment can effectively remove donor T cells responsible for GVHD while preserve T cells with anti-tumor and anti-viral effects. These preclinical results provide a basis for initiating a clinical trial to assess the feasibility and efficacy of infusing PDP-treated donor T cells to alloHCT recipient in order to augment anti-tumor and anti-pathogen effects without causing GVHD. Figure 1 PDP treatment reduceds the frequency of alloreactive T cells in a TH9402 does dependent manner. Figure 1. PDP treatment reduceds the frequency of alloreactive T cells in a TH9402 does dependent manner. Figure 2 PDP treatment preserves responses to third-party stimulator and viral antigens. Figure 2. PDP treatment preserves responses to third-party stimulator and viral antigens.
- Published
- 2006
20. Concomitant Induction of CMVpp65-Specific CD4+ and CD8+ T Cells Using Dendritic Cells Transfected with mRNA Encoding an Invariant Chain-pp65 Fusion Protein
- Author
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Johannes Vieweg, Nelson J. Chao, NgocDiep Le, and Jens Dannull
- Subjects
Cellular immunity ,MHC class II ,biology ,medicine.medical_treatment ,ELISPOT ,T cell ,Immunology ,virus diseases ,Cell Biology ,Hematology ,Immunotherapy ,Biochemistry ,CTL ,medicine.anatomical_structure ,Immune system ,medicine ,biology.protein ,Cytotoxic T cell - Abstract
Human cytomegalovirus (CMV) disease is increasingly recognized as a major cause of morbidity and mortality in post-stem cell transplant (SCT) recipients due to a lack of cellular immunity. Thus, novel therapies that offer the restoration of cellular immunity in SCT patients are highly desirable for clinical use. Cytotoxic T lymphocyte (CTL) responses against CMV represent a major effector arm of the immune system to control viremia. However, it is well established that the efficient induction and persistence of CTL responses in vivo requires the concomitant induction of antigen-specific CD4+ T helper cells. In this study, we sought to determine whether human dendritic cells (DC) transfected with mRNA encoding an invariant chain-CMVpp65 fusion protein (Ii-pp65) were capable of inducing concomitant CMV-specific CTL and CD4+ responses, thereby constituting a useful strategy for immunotherapy of CMV disease. We show that transfection of DC with Ii-pp65 mRNA leads to enhanced stimulation of CMV-specific CTL in vitro (Figure 1). Furthermore, DC expressing Ii-pp65 are potent inducers of primary CMV-specific CD4+ T cell responses as evidenced by ELISPOT analyses of primed CD4+CD45RA+ T cells (Figure 2). Lastly, efficient routing of Ii-pp65 into the MHC class II presentation pathway is demonstrated by confocal microscopy (data not shown). Based on these preclinical findings, we propose a clinical trial to administer DC, transfected with mRNA encoding a chimeric Ii-pp65, to post-SCT patients. Our primary goal will be to prevent CMV infection and reactivation by inducing strong immune reactivities against CMV. Figure Figure
- Published
- 2005
21. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas.
- Author
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Infante, Jeffrey R., Somer, Bradley G., Joon Oh Park, Chung-Pin Li, Scheulen, Max E., Kasubhai, Saifuddin M., Do-Youn Oh, Yuan Liu, Redhu, Suman, Steplewski, Klaudia, and Ngocdiep Le
- Subjects
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PROTEIN kinase inhibitors , *ANTINEOPLASTIC agents , *COMBINATION drug therapy , *CONFIDENCE intervals , *GENETIC mutation , *HEALTH outcome assessment , *PANCREATIC tumors , *PLACEBOS , *SAFETY , *SURVIVAL , *WORLD health , *RANDOMIZED controlled trials , *TREATMENT effectiveness , *BLIND experiment , *ISLET cell tumor , *THERAPEUTICS - Abstract
Background Trametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed. Methods Adults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000mg/m² (weekly x 7 for 8weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups. Results Baseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67-1.44; P=.453); median OS was 8.4months with gemcitabine plus trametinib and 6.7months with gemcitabine plus placebo. Median PFS (16 versus 15weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients (n=103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia. Conclusions The addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
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