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Carl H June

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https://www.readbyqxmd.com/read/29765823/the-natural-growth-rate-of-residual-juvenile-angiofibroma
#1
Nicholas R Rowan, Amanda L Stapleton, Molly E Heft-Neal, Paul A Gardner, Carl H Snyderman
Objectives  Examine the postoperative growth rate of residual juvenile angiofibroma (JA) in a large series of patients relative to pediatric growth parameters and other prognostic factors. Establish an algorithm for postoperative surveillance of patients with JA. Design  Retrospective case series. Setting  Tertiary referral academic center. Participants  Pediatric patients undergoing surgical resection of JA between September 2005 and June 2015. Main Outcome Measures  Postoperative recurrence and tumor growth rates...
June 2018: Journal of Neurological Surgery. Part B, Skull Base
https://www.readbyqxmd.com/read/29713085/determinants-of-response-and-resistance-to-cd19-chimeric-antigen-receptor-car-t-cell-therapy-of-chronic-lymphocytic-leukemia
#2
Joseph A Fraietta, Simon F Lacey, Elena J Orlando, Iulian Pruteanu-Malinici, Mercy Gohil, Stefan Lundh, Alina C Boesteanu, Yan Wang, Roddy S O'Connor, Wei-Ting Hwang, Edward Pequignot, David E Ambrose, Changfeng Zhang, Nicholas Wilcox, Felipe Bedoya, Corin Dorfmeier, Fang Chen, Lifeng Tian, Harit Parakandi, Minnal Gupta, Regina M Young, F Brad Johnson, Irina Kulikovskaya, Li Liu, Jun Xu, Sadik H Kassim, Megan M Davis, Bruce L Levine, Noelle V Frey, Donald L Siegel, Alexander C Huang, E John Wherry, Hans Bitter, Jennifer L Brogdon, David L Porter, Carl H June, J Joseph Melenhorst
Tolerance to self-antigens prevents the elimination of cancer by the immune system1,2 . 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...
April 30, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29674640/the-cpt1a-inhibitor-etomoxir-induces-severe-oxidative-stress-at-commonly-used-concentrations
#3
Roddy S O'Connor, Lili Guo, Saba Ghassemi, Nathaniel W Snyder, Andrew J Worth, Liwei Weng, Yoonseok Kam, Benjamin Philipson, Sophie Trefely, Selene Nunez-Cruz, Ian A Blair, Carl H June, Michael C Milone
Etomoxir (ETO) is a widely used small-molecule inhibitor of fatty acid oxidation (FAO) through its irreversible inhibitory effects on the carnitine palmitoyl-transferase 1a (CPT1a). We used this compound to evaluate the role of fatty acid oxidation in rapidly proliferating T cells following costimulation through the CD28 receptor. We show that ETO has a moderate effect on T cell proliferation with no observable effect on memory differentiation, but a marked effect on oxidative metabolism. We show that this oxidative metabolism is primarily dependent upon glutamine rather than FAO...
April 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29669947/anti-cd19-car-t-cells-with-high-dose-melphalan-and-autologous-stem-cell-transplantation-for-refractory-multiple-myeloma
#4
Alfred L Garfall, Edward A Stadtmauer, Wei-Ting Hwang, Simon F Lacey, Jan Joseph Melenhorst, Maria Krevvata, Martin P Carroll, William H Matsui, Qiuju Wang, Madhav V Dhodapkar, Kavita Dhodapkar, Rituparna Das, Dan T Vogl, Brendan M Weiss, Adam D Cohen, Patricia A Mangan, Emily C Ayers, Selene Nunez-Cruz, Irina Kulikovskaya, Megan M Davis, Anne Lamontagne, Karen Dengel, Naseem Ds Kerr, Regina M Young, Donald L Siegel, Bruce L Levine, Michael C Milone, Marcela V Maus, Carl H June
BACKGROUND: Multiple myeloma is usually fatal due to serial relapses that become progressively refractory to therapy. CD19 is typically absent on the dominant multiple myeloma cell population but may be present on minor subsets with unique myeloma-propagating properties. To target myeloma-propagating cells, we clinically evaluated autologous T cells transduced with a chimeric antigen receptor (CAR) against CD19 (CTL019). METHODS: Subjects received CTL019 following salvage high-dose melphalan and autologous stem cell transplantation (ASCT)...
April 19, 2018: JCI Insight
https://www.readbyqxmd.com/read/29657904/immunotherapy-for-breast-cancer-current-and-future-strategies
#5
Austin D Williams, Kyle K Payne, Avery D Posey, Christine Hill, Jose Conejo-Garcia, Carl H June, Julia Tchou
Purpose of Review: The breast tumor microenvironment is immunosuppressive and is increasingly recognized to play a significant role in tumorigenesis. A deeper understanding of normal and aberrant interactions between malignant and immune cells has allowed researchers to harness the immune system with novel immunotherapy strategies, many of which have shown promise in breast cancer. This review discusses the application of immunotherapy to the treatment of breast cancer. Recent Findings: Both basic science and clinical trial data are rapidly developing in the use of immunotherapy for breast cancer...
December 2017: Current Surgery Reports
https://www.readbyqxmd.com/read/29643231/personalized-cancer-vaccine-effectively-mobilizes-antitumor-t-cell-immunity-in-ovarian-cancer
#6
Janos L Tanyi, Sara Bobisse, Eran Ophir, Sandra Tuyaerts, Annalisa Roberti, Raphael Genolet, Petra Baumgartner, Brian J Stevenson, Christian Iseli, Denarda Dangaj, Brian Czerniecki, Aikaterini Semilietof, Julien Racle, Alexandra Michel, Ioannis Xenarios, Cheryl Chiang, Dimitri S Monos, Drew A Torigian, Harvey L Nisenbaum, Olivier Michielin, Carl H June, Bruce L Levine, Daniel J Powell, David Gfeller, Rosemarie Mick, Urania Dafni, Vincent Zoete, Alexandre Harari, George Coukos, Lana E Kandalaft
We conducted a pilot clinical trial testing a personalized vaccine generated by autologous dendritic cells (DCs) pulsed with oxidized autologous whole-tumor cell lysate (OCDC), which was injected intranodally in platinum-treated, immunotherapy-naïve, recurrent ovarian cancer patients. OCDC was administered alone (cohort 1, n = 5), in combination with bevacizumab (cohort 2, n = 10), or bevacizumab plus low-dose intravenous cyclophosphamide (cohort 3, n = 10) until disease progression or vaccine exhaustion. A total of 392 vaccine doses were administered without serious adverse events...
April 11, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29618658/pancreatic-cancer-therapy-with-combined-mesothelin-redirected-chimeric-antigen-receptor-t-cells-and-cytokine-armed-oncolytic-adenoviruses
#7
Keisuke Watanabe, Yanping Luo, Tong Da, Sonia Guedan, Marco Ruella, John Scholler, Brian Keith, Regina M Young, Boris Engels, Suvi Sorsa, Mikko Siurala, Riikka Havunen, Siri Tähtinen, Akseli Hemminki, Carl H June
Pancreatic ductal adenocarcinoma (PDA) is characterized by its highly immunosuppressive tumor microenvironment (TME) that limits T cell infiltration and induces T cell hypofunction. Mesothelin-redirected chimeric antigen receptor T cell (meso-CAR T cell) therapy has shown some efficacy in clinical trials but antitumor efficacy remains modest. We hypothesized that combined meso-CAR T cells with an oncolytic adenovirus expressing TNF-α and IL-2 (Ad5/3-E2F-D24-TNFa-IRES-IL2, or OAd-TNFa-IL2) would improve efficacy...
April 5, 2018: JCI Insight
https://www.readbyqxmd.com/read/29588319/improving-car-t-cell-therapy-of-solid-tumors-with-oncolytic-virus-driven-production-of-a-bispecific-t-cell-engager
#8
Anna Wing, Carlos Alberto Fajardo, Avery D Posey, Carolyn Shaw, Tong Da, Regina Young, Ramon Alemany, Carl H June, Sonia Guedan
T cells expressing chimeric antigen receptors (CARTs) have shown significant promise in clinical trials to treat hematologic malignancies, but their efficacy in solid tumors has been limited. Oncolytic viruses have the potential to act in synergy with immunotherapies due to their immunogenic oncolytic properties and the opportunity of incorporating therapeutic transgenes in their genomes. Here, we hypothesized that an oncolytic adenovirus armed with an EGFR-targeting, bispecific T-cell engager (OAd-BiTE) would improve the outcome of CART-cell therapy in solid tumors...
March 27, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29567707/car-t-cell-immunotherapy-for-human-cancer
#9
REVIEW
Carl H June, Roddy S O'Connor, Omkar U Kawalekar, Saba Ghassemi, Michael C Milone
Adoptive T cell transfer (ACT) is a new area of transfusion medicine involving the infusion of lymphocytes to mediate antitumor, antiviral, or anti-inflammatory effects. The field has rapidly advanced from a promising form of immuno-oncology in preclinical models to the recent commercial approvals of chimeric antigen receptor (CAR) T cells to treat leukemia and lymphoma. This Review describes opportunities and challenges for entering mainstream oncology that presently face the CAR T field, with a focus on the challenges that have emerged over the past several years...
March 23, 2018: Science
https://www.readbyqxmd.com/read/29567081/activity-of-mesothelin-specific-chimeric-antigen-receptor-t-cells-against-pancreatic-carcinoma-metastases-in-a-phase-1-trial
#10
Gregory L Beatty, Mark H O'Hara, Simon F Lacey, Drew A Torigian, Farzana Nazimuddin, Fang Chen, Irina M Kulikovskaya, Michael C Soulen, Maureen McGarvey, Anne Marie Nelson, Whitney L Gladney, Bruce L Levine, J Joseph Melenhorst, Gabriela Plesa, Carl H June
Pancreatic ductal adenocarcinoma (PDAC) is resistant to T-cell mediated immunotherapy. We engineered T cells to transiently express an mRNA encoding a chimeric antigen receptor (CAR) specific for mesothelin-a protein that is over-expressed by PDAC cells. We performed a phase 1 study to evaluate the safety and efficacy of adoptive cell therapy with autologous mesothelin-specific CAR T cells (CARTmeso cells) in 6 patients with chemotherapy-refractory metastatic PDAC. Patients were given intravenous CARTmeso cells 3 times weekly for 3 weeks...
March 19, 2018: Gastroenterology
https://www.readbyqxmd.com/read/29547084/endoscopic-endonasal-surgery-for-epidermoid-and-dermoid-cysts-a-10-year-experience
#11
Francisco Vaz-Guimaraes, Maria Koutourousiou, John R de Almeida, Elizabeth C Tyler-Kabara, Juan C Fernandez-Miranda, Eric W Wang, Carl H Snyderman, Paul A Gardner
OBJECTIVE Epidermoid and dermoid cysts may be found along the cranial base and are commonly resected via open transcranial approaches. The use of endoscopic endonasal approaches for resection of these tumors has been rarely reported. METHODS The authors retrospectively reviewed the medical records of 21 patients who underwent endoscopic endonasal surgery for epidermoid and dermoid cyst resection at the University of Pittsburgh Medical Center between January 2005 and June 2014. Surgical outcomes and variables that might affect the extent of resection and complications were analyzed...
March 16, 2018: Journal of Neurosurgery
https://www.readbyqxmd.com/read/29509936/car-t-cell-therapy-for-glioblastoma-recent-clinical-advances-and-future-challenges
#12
Stephen J Bagley, Arati S Desai, Gerald P Linette, Carl H June, Donald M O'Rourke
In patients with certain hematologic malignancies, the use of autologous T cells genetically modified to express chimeric antigen receptors (CARs) has led to unprecedented clinical responses. Although progress in solid tumors has been elusive, recent clinical studies have demonstrated the feasibility and safety of CAR T cell therapy for glioblastoma. In addition, despite formidable barriers to T cell localization and effector function in glioblastoma, signs of efficacy have been observed in select patients...
March 2, 2018: Neuro-oncology
https://www.readbyqxmd.com/read/29467322/gut-microbiota-modulates-adoptive-cell-therapy-via-cd8%C3%AE-dendritic-cells-and-il-12
#13
Mireia Uribe-Herranz, Kyle Bittinger, Stavros Rafail, Sonia Guedan, Stefano Pierini, Ceylan Tanes, Alex Ganetsky, Mark A Morgan, Saar Gill, Janos L Tanyi, Frederic D Bushman, Carl H June, Andrea Facciabene
Adoptive T cell therapy (ACT) is a promising new modality for malignancies. Here, we report that adoptive T cell efficacy in tumor-bearing mice is significantly affected by differences in the native composition of the gut microbiome or treatment with antibiotics, or by heterologous fecal transfer. Depletion of bacteria with vancomycin decreased the rate of tumor growth in mice from The Jackson Laboratory receiving ACT, whereas treatment with neomycin and metronidazole had no effect, indicating the role of specific bacteria in host response...
February 22, 2018: JCI Insight
https://www.readbyqxmd.com/read/29385370/tisagenlecleucel-in-children-and-young-adults-with-b-cell-lymphoblastic-leukemia
#14
MULTICENTER STUDY
Shannon L Maude, Theodore W Laetsch, Jochen Buechner, Susana Rives, Michael Boyer, Henrique Bittencourt, Peter Bader, Michael R Verneris, Heather E Stefanski, Gary D Myers, Muna Qayed, Barbara De Moerloose, Hidefumi Hiramatsu, Krysta Schlis, Kara L Davis, Paul L Martin, Eneida R Nemecek, Gregory A Yanik, Christina Peters, Andre Baruchel, Nicolas Boissel, Francoise Mechinaud, Adriana Balduzzi, Joerg Krueger, Carl H June, Bruce L Levine, Patricia Wood, Tetiana Taran, Mimi Leung, Karen T Mueller, Yiyun Zhang, Kapildeb Sen, David Lebwohl, Michael A Pulsipher, Stephan A Grupp
BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL...
February 1, 2018: New England Journal of Medicine
https://www.readbyqxmd.com/read/29370379/glycan-directed-car-t-cells
#15
Catharina Steentoft, Denis Migliorini, Tiffany R King, Ulla Mandel, Carl H June, Avery D Posey
Cancer immunotherapy is rapidly advancing in the treatment of a variety of hematopoietic cancers, including pediatric acute lymphoblastic leukemia and diffuse large B cell lymphoma, with chimeric antigen receptor (CAR)-T cells. CARs are genetically encoded artificial T cell receptors that combine the antigen specificity of an antibody with the machinery of T cell activation. However, implementation of CAR technology in the treatment of solid tumors has been progressing much slower. Solid tumors are characterized by a number of challenges that need to be overcome, including cellular heterogeneity, immunosuppressive tumor microenvironment (TME), and, in particular, few known cancer-specific targets...
January 23, 2018: Glycobiology
https://www.readbyqxmd.com/read/29321369/enhancing-car-t-cell-persistence-through-icos-and-4-1bb-costimulation
#16
Sonia Guedan, Avery D Posey, Carolyn Shaw, Anna Wing, Tong Da, Prachi R Patel, Shannon E McGettigan, Victoria Casado-Medrano, Omkar U Kawalekar, Mireia Uribe-Herranz, Decheng Song, J Joseph Melenhorst, Simon F Lacey, John Scholler, Brian Keith, Regina M Young, Carl H June
Successful tumor eradication by chimeric antigen receptor-expressing (CAR-expressing) T lymphocytes depends on CAR T cell persistence and effector function. We hypothesized that CD4+ and CD8+ T cells may exhibit distinct persistence and effector phenotypes, depending on the identity of specific intracellular signaling domains (ICDs) used to generate the CAR. First, we demonstrate that the ICOS ICD dramatically enhanced the in vivo persistence of CAR-expressing CD4+ T cells that, in turn, increased the persistence of CD8+ T cells expressing either CD28- or 4-1BB-based CARs...
January 11, 2018: JCI Insight
https://www.readbyqxmd.com/read/29226764/chimeric-antigen-receptor-t-cells-in-refractory-b-cell-lymphomas
#17
Stephen J Schuster, Jakub Svoboda, Elise A Chong, Sunita D Nasta, Anthony R Mato, Özlem Anak, Jennifer L Brogdon, Iulian Pruteanu-Malinici, Vijay Bhoj, Daniel Landsburg, Mariusz Wasik, Bruce L Levine, Simon F Lacey, Jan J Melenhorst, David L Porter, Carl H June
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...
December 28, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29213079/human-cd26-high-t-cells-elicit-tumor-immunity-against-multiple-malignancies-via-enhanced-migration-and-persistence
#18
Stefanie R Bailey, Michelle H Nelson, Kinga Majchrzak, Jacob S Bowers, Megan M Wyatt, Aubrey S Smith, Lillian R Neal, Keisuke Shirai, Carmine Carpenito, Carl H June, Michael J Zilliox, Chrystal M Paulos
CD8+ T lymphocytes mediate potent immune responses against tumor, but the role of human CD4+ T cell subsets in cancer immunotherapy remains ill-defined. Herein, we exhibit that CD26 identifies three T helper subsets with distinct immunological properties in both healthy individuals and cancer patients. Although CD26neg T cells possess a regulatory phenotype, CD26int T cells are mainly naive and CD26high T cells appear terminally differentiated and exhausted. Paradoxically, CD26high T cells persist in and regress multiple solid tumors following adoptive cell transfer...
December 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/29203150/retroviral-and-lentiviral-safety-analysis-of-gene-modified-t-cell-products-and-infused-hiv-and-oncology-patients
#19
Katherine T Marcucci, Julie K Jadlowsky, Wei-Ting Hwang, Megan Suhoski-Davis, Vanessa E Gonzalez, Irina Kulikovskaya, Minnal Gupta, Simon F Lacey, Gabriela Plesa, Anne Chew, J Joseph Melenhorst, Bruce L Levine, Carl H June
Replication-competent retrovirus/lentivirus (RCR/L) and insertional oncogenesis are potential safety risks with integrating viruses in gene-modified cell therapies. As such, the Food and Drug Administration guidances outline RCR/L-monitoring methods throughout the entire gene therapy treatment cycle. We present data for 17 vector lots, 375 manufactured T cell products, and 308 patients post-infusion across both HIV and oncology indications, showing no evidence of RCR/L. Given our data, a Poisson probability model estimates that a single patient, or a group of patients, would need to be followed for at least 52...
January 3, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29158268/car-t-cell-therapies-in-glioblastoma-a-first-look
#20
Denis Migliorini, Pierre-Yves Dietrich, Roger Stupp, Gerald P Linette, Avery D Posey, Carl H June
Glioblastoma is an aggressive malignancy with a poor prognosis. The current standard of care for newly diagnosed glioblastoma patients includes surgery to the extent, temozolomide combined with radiotherapy, and alternating electric fields therapy. After recurrence, there is no standard therapy and survival is less than 9 months. Recurrent glioblastoma offers a unique opportunity to investigate new treatment approaches in a malignancy known for remarkable genetic heterogeneity, an immunosuppressive microenvironment, and a partially permissive anatomic blood-brain barrier...
February 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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