21 results on '"Pruteanu-Malinici I"'
Search Results
2. Tisagenlecleucel cellular kinetics, dose, and immunogenicity in relation to clinical factors in relapsed/refractory DLBCL
- Author
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Awasthi, R, Pacaud, L, Waldron, E, Tam, CS, Jager, U, Borchmann, P, Jaglowski, S, Foley, SR, van Besien, K, Wagner-Johnston, ND, Kersten, MJ, Schuster, SJ, Salles, G, Maziarz, RT, Anak, O, del Corral, C, Chu, J, Gershgorin, I, Pruteanu-Malinici, I, Chakraborty, A, Mueller, KT, Waller, EK, Awasthi, R, Pacaud, L, Waldron, E, Tam, CS, Jager, U, Borchmann, P, Jaglowski, S, Foley, SR, van Besien, K, Wagner-Johnston, ND, Kersten, MJ, Schuster, SJ, Salles, G, Maziarz, RT, Anak, O, del Corral, C, Chu, J, Gershgorin, I, Pruteanu-Malinici, I, Chakraborty, A, Mueller, KT, and Waller, EK
- Abstract
The anti-CD19 chimeric antigen receptor (CAR)-T cell therapy tisagenlecleucel was evaluated in the global, phase 2 JULIET study in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We correlated tisagenlecleucel cellular kinetics with clinical/product parameters in 111 patients treated in JULIET. Tisagenlecleucel persistence in responders and nonresponders, respectively, was demonstrated for 554 and 400 days maximum by flow cytometry and for 693 and 374 days maximum by quantitative polymerase chain reaction (qPCR). No relationships were identified between cellular kinetics (qPCR) and product characteristics, intrinsic/extrinsic factors, dose, or immunogenicity. Most patients with 3-month response had detectable transgene at time of response and continued persistence for ≥6 months. Expansion (maximal expansion of transgene/CAR-positive T-cell levels in vivo postinfusion [Cmax]) was potentially associated with response duration but this did not reach statistical significance (hazard ratio for a twofold increase in Cmax, 0.79; 95% confidence interval, 0.61-1.01). Tisagenlecleucel expansion was associated with cytokine-release syndrome (CRS) severity and tocilizumab use; no relationships were observed with neurologic events. Transgene levels were associated with B-cell levels. Dose was associated with CRS severity, but this was not statistically significant after adjusting for baseline tumor burden. In contrast to the results from B-cell precursor acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, similar exposure was observed in DLBCL in this study regardless of response and expansion was lower in DLBCL than B-ALL, likely from differences in cancer location and/or T-cell intrinsic factors. Relationships between expansion and CRS severity, and lack of relationships between dose and exposure, were similar between DLBCL and B-ALL. Tisagenlecleucel cellular kinetics in adult relapsed/refractory DLBCL improve current understa
- Published
- 2020
3. Automated annotation of gene expression image sequences via non-parametric factor analysis and conditional random fields
- Author
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Pruteanu-Malinici, I., primary, Majoros, W. H., additional, and Ohler, U., additional
- Published
- 2013
- Full Text
- View/download PDF
4. Infinite Hidden Markov Models for Unusual-Event Detection in Video
- Author
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Pruteanu-Malinici, I., primary and Carin, L., additional
- Published
- 2008
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5. Infinite Hidden Markov Models and ISA Features for Unusual-Event Detection in Video.
- Author
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Pruteanu-Malinici, I. and Carin, L.
- Published
- 2007
- Full Text
- View/download PDF
6. Correction: Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.
- Author
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Friedman AA, Amzallag A, Pruteanu-Malinici I, Baniya S, Cooper ZA, Piris A, Hargreaves L, Igras V, Frederick DT, Lawrence DP, Haber DA, Flaherty KT, Wargo JA, Ramaswamy S, Benes CH, and Fisher DE
- Abstract
[This corrects the article DOI: 10.1371/journal.pone.0140310.]., (Copyright: © 2024 Friedman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2024
- Full Text
- View/download PDF
7. Targeting the IL1β Pathway for Cancer Immunotherapy Remodels the Tumor Microenvironment and Enhances Antitumor Immune Responses.
- Author
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Diwanji R, O'Brien NA, Choi JE, Nguyen B, Laszewski T, Grauel AL, Yan Z, Xu X, Wu J, Ruddy DA, Piquet M, Pelletier MR, Savchenko A, Charette L, Rodrik-Outmezguine V, Baum J, Millholland JM, Wong CC, Martin AM, Dranoff G, Pruteanu-Malinici I, Cremasco V, Sabatos-Peyton C, and Jayaraman P
- Subjects
- Animals, Mice, Cell Line, Tumor, Docetaxel pharmacology, Immunity, Immunotherapy, Neoplasms drug therapy, Tumor Microenvironment, Interleukin-1beta antagonists & inhibitors
- Abstract
High levels of IL1β can result in chronic inflammation, which in turn can promote tumor growth and metastasis. Inhibition of IL1β could therefore be a promising therapeutic option in the treatment of cancer. Here, the effects of IL1β blockade induced by the mAbs canakinumab and gevokizumab were evaluated alone or in combination with docetaxel, anti-programmed cell death protein 1 (anti-PD-1), anti-VEGFα, and anti-TGFβ treatment in syngeneic and humanized mouse models of cancers of different origin. Canakinumab and gevokizumab did not show notable efficacy as single-agent therapies; however, IL1β blockade enhanced the effectiveness of docetaxel and anti-PD-1. Accompanying these effects, blockade of IL1β alone or in combination induced significant remodeling of the tumor microenvironment (TME), with decreased numbers of immune suppressive cells and increased tumor infiltration by dendritic cells (DC) and effector T cells. Further investigation revealed that cancer-associated fibroblasts (CAF) were the cell type most affected by treatment with canakinumab or gevokizumab in terms of change in gene expression. IL1β inhibition drove phenotypic changes in CAF populations, particularly those with the ability to influence immune cell recruitment. These results suggest that the observed remodeling of the TME following IL1β blockade may stem from changes in CAF populations. Overall, the results presented here support the potential use of IL1β inhibition in cancer treatment. Further exploration in ongoing clinical studies will help identify the best combination partners for different cancer types, cancer stages, and lines of treatment., (©2023 American Association for Cancer Research.)
- Published
- 2023
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8. Author Correction: Decade-long leukaemia remissions with persistence of CD4 + CAR T cells.
- Author
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Melenhorst JJ, Chen GM, Wang M, Porter DL, Chen C, Collins MA, Gao P, Bandyopadhyay S, Sun H, Zhao Z, Lundh S, Pruteanu-Malinici I, Nobles CL, Maji S, Frey NV, Gill SI, Loren AW, Tian L, Kulikovskaya I, Gupta M, Ambrose DE, Davis MM, Fraietta JA, Brogdon JL, Young RM, Chew A, Levine BL, Siegel DL, Alanio C, Wherry EJ, Bushman FD, Lacey SF, Tan K, and June CH
- Published
- 2022
- Full Text
- View/download PDF
9. Decade-long leukaemia remissions with persistence of CD4 + CAR T cells.
- Author
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Melenhorst JJ, Chen GM, Wang M, Porter DL, Chen C, Collins MA, Gao P, Bandyopadhyay S, Sun H, Zhao Z, Lundh S, Pruteanu-Malinici I, Nobles CL, Maji S, Frey NV, Gill SI, Loren AW, Tian L, Kulikovskaya I, Gupta M, Ambrose DE, Davis MM, Fraietta JA, Brogdon JL, Young RM, Chew A, Levine BL, Siegel DL, Alanio C, Wherry EJ, Bushman FD, Lacey SF, Tan K, and June CH
- Subjects
- Antigens, CD19 immunology, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes immunology, Cell Separation, Humans, Time Factors, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, Immunotherapy, Adoptive, Leukemia immunology, Leukemia therapy, Receptors, Chimeric Antigen immunology
- Abstract
The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers
1-7 . However, little is known about the long-term potential and clonal stability of the infused cells. Here we studied long-lasting CD19-redirected chimeric antigen receptor (CAR) T cells in two patients with chronic lymphocytic leukaemia1-4 who achieved a complete remission in 2010. CAR T cells remained detectable more than ten years after infusion, with sustained remission in both patients. Notably, a highly activated CD4+ population emerged in both patients, dominating the CAR T cell population at the later time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by a small number of clones. Single-cell profiling demonstrated that these long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics along with ongoing functional activation and proliferation. In addition, longitudinal profiling revealed a population of gamma delta CAR T cells that prominently expanded in one patient concomitant with CD8+ CAR T cells during the initial response phase. Our identification and characterization of these unexpected CAR T cell populations provide novel insight into the CAR T cell characteristics associated with anti-cancer response and long-term remission in leukaemia., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
- Full Text
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10. Author Correction: Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia.
- Author
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Fraietta JA, Lacey SF, Orlando EJ, Pruteanu-Malinici I, Gohil M, Lundh S, Boesteanu AC, Wang Y, O'Connor RS, Hwang WT, Pequignot E, Ambrose DE, Zhang C, Wilcox N, Bedoya F, Dorfmeier C, Chen F, Tian L, Parakandi H, Gupta M, Young RM, Johnson FB, Kulikovskaya I, Liu L, Xu J, Kassim SH, Davis MM, Levine BL, Frey NV, Siegel DL, Huang AC, Wherry EJ, Bitter H, Brogdon JL, Porter DL, June CH, and Melenhorst JJ
- Published
- 2021
- Full Text
- View/download PDF
11. High-Dimensional Immune Monitoring for Chimeric Antigen Receptor T Cell Therapies.
- Author
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Sharma S, Quinn D, Melenhorst JJ, and Pruteanu-Malinici I
- Subjects
- Animals, Humans, Receptors, Chimeric Antigen analysis, Software, T-Lymphocytes cytology, Flow Cytometry methods, Immunotherapy, Adoptive methods, Monitoring, Immunologic methods
- Abstract
Purpose of Review: High-dimensional flow cytometry experiments have become a method of choice for high-throughput integration and characterization of cell populations. Here, we present a summary of state-of-the-art R-based pipelines used for differential analyses of cytometry data, largely based on chimeric antigen receptor (CAR) T cell therapies. These pipelines are based on publicly available R libraries, put together in a systematic and functional fashion, therefore free of cost., Recent Findings: In recent years, existing tools tailored to analyze complex high-dimensional data such as single-cell RNA sequencing (scRNAseq) have been successfully ported to cytometry studies due to the similar nature of flow cytometry and scRNAseq platforms. Existing environments like Cytobank (Kotecha et al., 2010), FlowJo (FlowJo™ Software) and FCS Express (https://denovosoftware.com) already offer a variety of these ported tools, but they either come at a premium or are fairly complicated to manage by an inexperienced user. To mitigate these limitations, experienced cytometrists and bioinformaticians usually incorporate these functions into an RShiny (https://shiny.rstudio.com) application that ultimately offers a user-friendly, intuitive environment that can be used to analyze flow cytometry data. Computational tools and Shiny-based tools are the perfect answer to the ever-growing dimensionality and complexity of flow cytometry data, by offering a dynamic, yet user-friendly exploratory space, tailored to bridge the space between the lab experimental world and the computational, machine learning space.
- Published
- 2021
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12. TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts.
- Author
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Grauel AL, Nguyen B, Ruddy D, Laszewski T, Schwartz S, Chang J, Chen J, Piquet M, Pelletier M, Yan Z, Kirkpatrick ND, Wu J, deWeck A, Riester M, Hims M, Geyer FC, Wagner J, MacIsaac K, Deeds J, Diwanji R, Jayaraman P, Yu Y, Simmons Q, Weng S, Raza A, Minie B, Dostalek M, Chikkegowda P, Ruda V, Iartchouk O, Chen N, Thierry R, Zhou J, Pruteanu-Malinici I, Fabre C, Engelman JA, Dranoff G, and Cremasco V
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cancer-Associated Fibroblasts drug effects, Carcinoma immunology, Carcinoma pathology, Cell Line, Tumor transplantation, Cell Plasticity drug effects, Cell Plasticity immunology, Disease Models, Animal, Drug Synergism, Female, Humans, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Mice, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Stromal Cells drug effects, Stromal Cells immunology, Transforming Growth Factor beta metabolism, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cancer-Associated Fibroblasts immunology, Carcinoma drug therapy, Interferon-beta immunology, Transforming Growth Factor beta antagonists & inhibitors
- Abstract
Despite the increasing interest in targeting stromal elements of the tumor microenvironment, we still face tremendous challenges in developing adequate therapeutics to modify the tumor stromal landscape. A major obstacle to this is our poor understanding of the phenotypic and functional heterogeneity of stromal cells in tumors. Herein, we perform an unbiased interrogation of tumor mesenchymal cells, delineating the co-existence of distinct subsets of cancer-associated fibroblasts (CAFs) in the microenvironment of murine carcinomas, each endowed with unique phenotypic features and functions. Furthermore, our study shows that neutralization of TGFβ in vivo leads to remodeling of CAF dynamics, greatly reducing the frequency and activity of the myofibroblast subset, while promoting the formation of a fibroblast population characterized by strong response to interferon and heightened immunomodulatory properties. These changes correlate with the development of productive anti-tumor immunity and greater efficacy of PD1 immunotherapy. Along with providing the scientific rationale for the evaluation of TGFβ and PD1 co-blockade in the clinical setting, this study also supports the concept of plasticity of the stromal cell landscape in tumors, laying the foundation for future investigations aimed at defining pathways and molecules to program CAF composition for cancer therapy.
- Published
- 2020
- Full Text
- View/download PDF
13. Tisagenlecleucel cellular kinetics, dose, and immunogenicity in relation to clinical factors in relapsed/refractory DLBCL.
- Author
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Awasthi R, Pacaud L, Waldron E, Tam CS, Jäger U, Borchmann P, Jaglowski S, Foley SR, van Besien K, Wagner-Johnston ND, Kersten MJ, Schuster SJ, Salles G, Maziarz RT, Anak Ö, Del Corral C, Chu J, Gershgorin I, Pruteanu-Malinici I, Chakraborty A, Mueller KT, and Waller EK
- Subjects
- Adult, Antigens, CD19, Humans, Kinetics, Lymphoma, Large B-Cell, Diffuse drug therapy, Receptors, Antigen, T-Cell genetics
- Abstract
The anti-CD19 chimeric antigen receptor (CAR)-T cell therapy tisagenlecleucel was evaluated in the global, phase 2 JULIET study in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We correlated tisagenlecleucel cellular kinetics with clinical/product parameters in 111 patients treated in JULIET. Tisagenlecleucel persistence in responders and nonresponders, respectively, was demonstrated for 554 and 400 days maximum by flow cytometry and for 693 and 374 days maximum by quantitative polymerase chain reaction (qPCR). No relationships were identified between cellular kinetics (qPCR) and product characteristics, intrinsic/extrinsic factors, dose, or immunogenicity. Most patients with 3-month response had detectable transgene at time of response and continued persistence for ≥6 months. Expansion (maximal expansion of transgene/CAR-positive T-cell levels in vivo postinfusion [Cmax]) was potentially associated with response duration but this did not reach statistical significance (hazard ratio for a twofold increase in Cmax, 0.79; 95% confidence interval, 0.61-1.01). Tisagenlecleucel expansion was associated with cytokine-release syndrome (CRS) severity and tocilizumab use; no relationships were observed with neurologic events. Transgene levels were associated with B-cell levels. Dose was associated with CRS severity, but this was not statistically significant after adjusting for baseline tumor burden. In contrast to the results from B-cell precursor acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, similar exposure was observed in DLBCL in this study regardless of response and expansion was lower in DLBCL than B-ALL, likely from differences in cancer location and/or T-cell intrinsic factors. Relationships between expansion and CRS severity, and lack of relationships between dose and exposure, were similar between DLBCL and B-ALL. Tisagenlecleucel cellular kinetics in adult relapsed/refractory DLBCL improve current understanding of in vivo expansion and its relationships with safety/efficacy endpoints. This trial was registered at www.clinicaltrials.gov as #NCT02445248., (© 2020 by The American Society of Hematology.)
- Published
- 2020
- Full Text
- View/download PDF
14. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma.
- Author
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Cohen AD, Garfall AL, Stadtmauer EA, Melenhorst JJ, Lacey SF, Lancaster E, Vogl DT, Weiss BM, Dengel K, Nelson A, Plesa G, Chen F, Davis MM, Hwang WT, Young RM, Brogdon JL, Isaacs R, Pruteanu-Malinici I, Siegel DL, Levine BL, June CH, and Milone MC
- Subjects
- Adult, Aged, Autografts, B-Cell Maturation Antigen immunology, Cyclophosphamide adverse effects, Disease-Free Survival, Female, Humans, Male, Middle Aged, Multiple Myeloma genetics, Multiple Myeloma immunology, Multiple Myeloma mortality, Neoplasm Proteins genetics, Neoplasm Proteins immunology, Survival Rate, T-Lymphocytes immunology, T-Lymphocytes pathology, T-Lymphocytes transplantation, Transduction, Genetic, Cyclophosphamide administration & dosage, Immunotherapy, Adoptive, Lymphocyte Depletion, Multiple Myeloma therapy, Receptors, Chimeric Antigen genetics, Receptors, Chimeric Antigen immunology
- Abstract
Background: Chimeric antigen receptor (CAR) T cells are a promising therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM)., Methods: We conducted a phase I study of autologous T cells lentivirally-transduced with a fully-human, BCMA-specific CAR containing CD3ζ and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts: 1) 1-5 x 108 CART-BCMA cells alone; 2) Cyclophosphamide (Cy) 1.5 g/m2 + 1-5 x 107 CART-BCMA cells; and 3) Cy 1.5 g/m2 + 1-5 x 108 CART-BCMA cells. No pre-specified BCMA expression level was required., Results: CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3-4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe CRS and encephalopathy. Responses (based on treated subjects) were seen in 4/9 (44%) in cohort 1, 1/5 (20%) in cohort 2, and 7/11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4:CD8 T cell ratio and frequency of CD45RO-CD27+CD8+ T cells in the pre-manufacturing leukapheresis product., Conclusion: CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily-pretreated MM patients., Trial Registration: NCT02546167., Funding: University of Pennsylvania-Novartis Alliance and NIH.
- Published
- 2019
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- View/download PDF
15. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia.
- Author
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Fraietta JA, Lacey SF, Orlando EJ, Pruteanu-Malinici I, Gohil M, Lundh S, Boesteanu AC, Wang Y, O'Connor RS, Hwang WT, Pequignot E, Ambrose DE, Zhang C, Wilcox N, Bedoya F, Dorfmeier C, Chen F, Tian L, Parakandi H, Gupta M, Young RM, Johnson FB, Kulikovskaya I, Liu L, Xu J, Kassim SH, Davis MM, Levine BL, Frey NV, Siegel DL, Huang AC, Wherry EJ, Bitter H, Brogdon JL, Porter DL, June CH, and Melenhorst JJ
- Subjects
- Animals, Female, Interleukin-6 metabolism, Male, Mice, STAT3 Transcription Factor metabolism, Transcription, Genetic, Treatment Outcome, Antigens, CD19 metabolism, Immunotherapy, Adoptive, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Receptors, Chimeric Antigen metabolism
- Abstract
Tolerance to self-antigens prevents the elimination of cancer by the immune system
1,2 . We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cells from complete-responding patients with CLL were enriched in memory-related genes, including IL-6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27+ CD45RO- CD8+ T cells before CAR T cell generation, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cells from patients produced STAT3-related cytokines, and serum IL-6 correlated with CAR T cell expansion. IL-6/STAT3 blockade diminished CAR T cell proliferation. Furthermore, a mechanistically relevant population of CD27+ PD-1- CD8+ CAR T cells expressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cell biology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies.- Published
- 2018
- Full Text
- View/download PDF
16. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas.
- Author
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Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, Brogdon JL, Pruteanu-Malinici I, Bhoj V, Landsburg D, Wasik M, Levine BL, Lacey SF, Melenhorst JJ, Porter DL, and June CH
- Subjects
- Adult, Aged, Antigens, CD19, B-Lymphocytes immunology, Biomarkers analysis, Disease-Free Survival, Female, Humans, Lymphoma, Follicular mortality, Lymphoma, Large B-Cell, Diffuse mortality, Male, Middle Aged, Remission Induction, Survival Analysis, T-Lymphocytes immunology, Immunotherapy, Adoptive, Lymphoma, Follicular therapy, Lymphoma, Large B-Cell, Diffuse therapy, Receptors, Antigen, T-Cell therapeutic use
- Abstract
Background: Patients with diffuse large B-cell lymphoma or follicular lymphoma that is refractory to or that relapses after immunochemotherapy and transplantation have a poor prognosis. High response rates have been reported with the use of T cells modified by chimeric antigen receptor (CAR) that target CD19 in B-cell cancers, although data regarding B-cell lymphomas are limited., Methods: We used autologous T cells that express a CD19-directed CAR (CTL019) to treat patients with diffuse large B-cell lymphoma or follicular lymphoma that had relapsed or was refractory to previous treatments. Patients were monitored for response to treatment, toxic effects, the expansion and persistence of CTL019 cells in vivo, and immune recovery., Results: A total of 28 adult patients with lymphoma received CTL019 cells, and 18 of 28 had a response (64%; 95% confidence interval [CI], 44 to 81). Complete remission occurred in 6 of 14 patients with diffuse large B-cell lymphoma (43%; 95% CI, 18 to 71) and 10 of 14 patients with follicular lymphoma (71%; 95% CI, 42 to 92). CTL019 cells proliferated in vivo and were detectable in the blood and bone marrow of patients who had a response and patients who did not have a response. Sustained remissions were achieved, and at a median follow-up of 28.6 months, 86% of patients with diffuse large B-cell lymphoma who had a response (95% CI, 33 to 98) and 89% of patients with follicular lymphoma who had a response (95% CI, 43 to 98) had maintained the response. Severe cytokine-release syndrome occurred in 5 patients (18%). Serious encephalopathy occurred in 3 patients (11%); 2 cases were self-limiting and 1 case was fatal. All patients in complete remission by 6 months remained in remission at 7.7 to 37.9 months (median, 29.3 months) after induction, with a sustained reappearance of B cells in 8 of 16 patients and with improvement in levels of IgG in 4 of 10 patients and of IgM in 6 of 10 patients at 6 months or later and in levels of IgA in 3 of 10 patients at 18 months or later., Conclusions: CTL019 cells can be effective in the treatment of relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. High rates of durable remission were observed, with recovery of B cells and immunoglobulins in some patients. Transient encephalopathy developed in approximately one in three patients and severe cytokine-release syndrome developed in one in five patients. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02030834 .).
- Published
- 2017
- Full Text
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17. Detection of dysregulated protein-association networks by high-throughput proteomics predicts cancer vulnerabilities.
- Author
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Lapek JD Jr, Greninger P, Morris R, Amzallag A, Pruteanu-Malinici I, Benes CH, and Haas W
- Subjects
- Breast Neoplasms metabolism, Cell Line, Tumor, Female, Humans, High-Throughput Screening Assays methods, Neoplasms metabolism, Protein Interaction Maps, Proteomics methods
- Abstract
The formation of protein complexes and the co-regulation of the cellular concentrations of proteins are essential mechanisms for cellular signaling and for maintaining homeostasis. Here we use isobaric-labeling multiplexed proteomics to analyze protein co-regulation and show that this allows the identification of protein-protein associations with high accuracy. We apply this 'interactome mapping by high-throughput quantitative proteome analysis' (IMAHP) method to a panel of 41 breast cancer cell lines and show that deviations of the observed protein co-regulations in specific cell lines from the consensus network affects cellular fitness. Furthermore, these aberrant interactions serve as biomarkers that predict the drug sensitivity of cell lines in screens across 195 drugs. We expect that IMAHP can be broadly used to gain insight into how changing landscapes of protein-protein associations affect the phenotype of biological systems.
- Published
- 2017
- Full Text
- View/download PDF
18. Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.
- Author
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Friedman AA, Amzallag A, Pruteanu-Malinici I, Baniya S, Cooper ZA, Piris A, Hargreaves L, Igras V, Frederick DT, Lawrence DP, Haber DA, Flaherty KT, Wargo JA, Ramaswamy S, Benes CH, and Fisher DE
- Subjects
- ATP Binding Cassette Transporter, Subfamily B metabolism, Animals, Antineoplastic Agents pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cell Death drug effects, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Drug Synergism, High-Throughput Screening Assays, Humans, Indoles pharmacology, Indoles therapeutic use, Melanoma pathology, Mice, Proto-Oncogene Proteins B-raf metabolism, Quinazolines pharmacology, Quinazolines therapeutic use, Receptors, Platelet-Derived Growth Factor metabolism, Receptors, Vascular Endothelial Growth Factor metabolism, Sulfonamides pharmacology, Sulfonamides therapeutic use, Xenograft Model Antitumor Assays, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Melanoma drug therapy, Molecular Targeted Therapy, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Receptors, Platelet-Derived Growth Factor antagonists & inhibitors, Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors
- Abstract
A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines. We find that even the most synergistic drug pairs are effective only in a discrete number of cell lines, underlying a strong context dependency for synergy, with strong, widespread synergies often corresponding to non-specific or off-target drug effects such as multidrug resistance protein 1 (MDR1) transporter inhibition. We identified drugs sensitizing cell lines that are BRAFV600E mutant but intrinsically resistant to BRAF inhibitor PLX4720, including the vascular endothelial growth factor receptor/kinase insert domain receptor (VEGFR/KDR) and platelet derived growth factor receptor (PDGFR) family inhibitor cediranib. The combination of cediranib and PLX4720 induced apoptosis in vitro and tumor regression in animal models. This synergistic interaction is likely due to engagement of multiple receptor tyrosine kinases (RTKs), demonstrating the potential of drug- rather than gene-specific combination discovery approaches. Patients with elevated biopsy KDR expression showed decreased progression free survival in trials of mitogen-activated protein kinase (MAPK) kinase pathway inhibitors. Thus, high-throughput unbiased screening of targeted drug combinations, with appropriate library selection and mechanistic follow-up, can yield clinically-actionable drug combinations.
- Published
- 2015
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- View/download PDF
19. Small molecules facilitate rapid and synchronous iPSC generation.
- Author
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Bar-Nur O, Brumbaugh J, Verheul C, Apostolou E, Pruteanu-Malinici I, Walsh RM, Ramaswamy S, and Hochedlinger K
- Subjects
- Animals, Antioxidants pharmacology, Apoptosis, Cell Cycle Checkpoints, Cell Differentiation genetics, Cell Proliferation, Cells, Cultured, Glycogen Synthase Kinase 3 antagonists & inhibitors, Glycogen Synthase Kinase 3 beta, Green Fluorescent Proteins genetics, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors biosynthesis, Kruppel-Like Transcription Factors genetics, Mice, Octamer Transcription Factor-3 biosynthesis, Octamer Transcription Factor-3 genetics, Proto-Oncogene Proteins c-myc biosynthesis, Proto-Oncogene Proteins c-myc genetics, SOXB1 Transcription Factors biosynthesis, SOXB1 Transcription Factors genetics, Ascorbic Acid pharmacology, Cellular Reprogramming genetics, Embryonic Stem Cells cytology, Induced Pluripotent Stem Cells cytology, Pyridines pharmacology, Pyrimidines pharmacology
- Abstract
The reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) upon overexpression of OCT4, KLF4, SOX2 and c-MYC (OKSM) provides a powerful system to interrogate basic mechanisms of cell fate change. However, iPSC formation with standard methods is typically protracted and inefficient, resulting in heterogeneous cell populations. We show that exposure of OKSM-expressing cells to both ascorbic acid and a GSK3-β inhibitor (AGi) facilitates more synchronous and rapid iPSC formation from several mouse cell types. AGi treatment restored the ability of refractory cell populations to yield iPSC colonies, and it attenuated the activation of developmental regulators commonly observed during the reprogramming process. Moreover, AGi supplementation gave rise to chimera-competent iPSCs after as little as 48 h of OKSM expression. Our results offer a simple modification to the reprogramming protocol, facilitating iPSC induction at unparalleled efficiencies and enabling dissection of the underlying mechanisms in more homogeneous cell populations.
- Published
- 2014
- Full Text
- View/download PDF
20. A microfluidic device and computational platform for high-throughput live imaging of gene expression.
- Author
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Busch W, Moore BT, Martsberger B, Mace DL, Twigg RW, Jung J, Pruteanu-Malinici I, Kennedy SJ, Fricke GK, Clark RL, Ohler U, and Benfey PN
- Subjects
- Arabidopsis, Microfluidic Analytical Techniques, Microscopy, Confocal methods, Gene Expression Regulation, Plant physiology, Plant Roots metabolism
- Abstract
To fully describe gene expression dynamics requires the ability to quantitatively capture expression in individual cells over time. Automated systems for acquiring and analyzing real-time images are needed to obtain unbiased data across many samples and conditions. We developed a microfluidics device, the RootArray, in which 64 Arabidopsis thaliana seedlings can be grown and their roots imaged by confocal microscopy over several days without manual intervention. To achieve high throughput, we decoupled acquisition from analysis. In the acquisition phase, we obtain images at low resolution and segment to identify regions of interest. Coordinates are communicated to the microscope to record the regions of interest at high resolution. In the analysis phase, we reconstruct three-dimensional objects from stitched high-resolution images and extract quantitative measurements from a virtual medial section of the root. We tracked hundreds of roots to capture detailed expression patterns of 12 transgenic reporter lines under different conditions.
- Published
- 2012
- Full Text
- View/download PDF
21. Automatic annotation of spatial expression patterns via sparse Bayesian factor models.
- Author
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Pruteanu-Malinici I, Mace DL, and Ohler U
- Subjects
- Algorithms, Animals, Area Under Curve, Artificial Intelligence, Cluster Analysis, Drosophila melanogaster genetics, Drosophila melanogaster metabolism, Gene Expression Regulation, Developmental, Humans, Models, Biological, Oligonucleotide Array Sequence Analysis, Bayes Theorem, Computational Biology methods, Gene Expression Profiling methods, Image Processing, Computer-Assisted methods, Pattern Recognition, Automated methods
- Abstract
Advances in reporters for gene expression have made it possible to document and quantify expression patterns in 2D-4D. In contrast to microarrays, which provide data for many genes but averaged and/or at low resolution, images reveal the high spatial dynamics of gene expression. Developing computational methods to compare, annotate, and model gene expression based on images is imperative, considering that available data are rapidly increasing. We have developed a sparse Bayesian factor analysis model in which the observed expression diversity of among a large set of high-dimensional images is modeled by a small number of hidden common factors. We apply this approach on embryonic expression patterns from a Drosophila RNA in situ image database, and show that the automatically inferred factors provide for a meaningful decomposition and represent common co-regulation or biological functions. The low-dimensional set of factor mixing weights is further used as features by a classifier to annotate expression patterns with functional categories. On human-curated annotations, our sparse approach reaches similar or better classification of expression patterns at different developmental stages, when compared to other automatic image annotation methods using thousands of hard-to-interpret features. Our study therefore outlines a general framework for large microscopy data sets, in which both the generative model itself, as well as its application for analysis tasks such as automated annotation, can provide insight into biological questions.
- Published
- 2011
- Full Text
- View/download PDF
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