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https://www.readbyqxmd.com/read/29481659/cytokine-release-syndrome-grade-is-a-predictive-marker-for-infections-in-relapsed-or-refractory-b-cell-all-patients-treated-with-car-t-cells
#1
Jae H Park, F Andres Romero, Ying Taur, Michel Sadelain, Renier J Brentjens, Tobias M Hohl, Susan K Seo
Background: Chimeric antigen receptor (CAR)-modified T cells that target the CD19 antigen present a novel promising therapy for the treatment of relapsed B-cell acute lymphoblastic leukemia (ALL). Although cytokine release syndrome (CRS) and neurotoxicity have emerged as predominant non-infectious complications of CD19 CAR T cell therapy, infections associated with this treatment modality have not been well documented. Methods: We analyzed infectious complications that followed CD19 CAR T cell therapy in 53 adult patients with relapsed ALL enrolled in a phase I clinical trial at Memorial Sloan Kettering Cancer Center (NCT01044069)...
February 22, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29458735/gene-therapy-and-genome-editing
#2
REVIEW
Farid Boulad, Jorge Mansilla-Soto, Annalisa Cabriolu, Isabelle Rivière, Michel Sadelain
The β-thalassemias are inherited blood disorders that result from insufficient production of the β-chain of hemoglobin. More than 200 different mutations have been identified. β-Thalassemia major requires life-long transfusions. The only cure for severe β-thalassemia is to provide patients with hematopoietic stem cells. Globin gene therapy promises a curative autologous stem cell transplantation without the immunologic complications of allogeneic transplantation. The future directions of gene therapy include enhancement of lentiviral vector-based approaches, fine tuning of the conditioning regimen, and the design of safer vectors...
April 2018: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/29425516/reprint-of-building-a-safer-and-faster-car-seatbelts-airbags-and-crispr
#3
REVIEW
Miguel-Angel Perales, Partow Kebriaei, Leslie S Kean, Michel Sadelain
Therapeutic T cell engineering has recently garnered widespread interest because of the success of CD19 chimeric antigen receptor (CAR) therapy. CARs are synthetic receptors for antigen that redirect the specificity and reprogram the function of the T cells in which they are genetically introduced. CARs targeting CD19, a cell surface molecule found in most leukemias and lymphomas, have yielded high remission rates in patients with chemorefractory, relapsed disease, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma...
March 2018: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29419425/safety-and-efficacy-of-plerixafor-dose-escalation-for-the-mobilization-of-cd34-hematopoietic-progenitor-cells-in-patients-with-sickle-cell-disease-interim-results
#4
Farid Boulad, Tsiporah Shore, Koen van Besien, Caterina Minniti, Mihaela Barbu-Stevanovic, Sylvie Wiener Fedus, Fabiana Perna, June Greenberg, Danielle Guarneri, Vijay Nandi, Audrey Mauguen, Karina Yazdanbakhsh, Michel Sadelain, Patricia A Shi
Gene therapy for sickle cell disease is limited by the yield of hematopoietic progenitor cell harvest for transduction or gene editing. We therefore performed a Phase I dose-escalation study of the hematopoietic progenitor cell mobilizing agent plerixafor to evaluate the efficacy and safety of standard dosing on peripheral blood CD34+ cell mobilization. Of 15 patients enrolled to date, only one was chronically transfused and 10 were on hydroxyurea. Of 8 patients achieving a CD34+ cell concentration >30 cells/μl, 6 were on hydroxyurea...
February 1, 2018: Haematologica
https://www.readbyqxmd.com/read/29385376/long-term-follow-up-of-cd19-car-therapy-in-acute-lymphoblastic-leukemia
#5
Jae H Park, Isabelle Rivière, Mithat Gonen, Xiuyan Wang, Brigitte Sénéchal, Kevin J Curran, Craig Sauter, Yongzeng Wang, Bianca Santomasso, Elena Mead, Mikhail Roshal, Peter Maslak, Marco Davila, Renier J Brentjens, Michel Sadelain
BACKGROUND: CD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients. METHODS: We conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics...
February 1, 2018: New England Journal of Medicine
https://www.readbyqxmd.com/read/29358181/posttransplant-chimeric-antigen-receptor-therapy
#6
REVIEW
Melody Smith, Johannes Zakrzewski, Scott James, Michel Sadelain
Therapeutic T-cell engineering is emerging as a powerful approach to treat refractory hematological malignancies. Its most successful embodiment to date is based on the use of second-generation chimeric antigen receptors (CARs) targeting CD19, a cell surface molecule found in most B-cell leukemias and lymphomas. Remarkable complete remissions have been obtained with autologous T cells expressing CD19 CARs in patients with relapsed, chemo-refractory B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma...
March 8, 2018: Blood
https://www.readbyqxmd.com/read/29343642/mechanogenetics-for-the-remote-and-noninvasive-control-of-cancer-immunotherapy
#7
Yijia Pan, Sangpil Yoon, Jie Sun, Ziliang Huang, Changyang Lee, Molly Allen, Yiqian Wu, Ya-Ju Chang, Michel Sadelain, K Kirk Shung, Shu Chien, Yingxiao Wang
While cell-based immunotherapy, especially chimeric antigen receptor (CAR)-expressing T cells, is becoming a paradigm-shifting therapeutic approach for cancer treatment, there is a lack of general methods to remotely and noninvasively regulate genetics in live mammalian cells and animals for cancer immunotherapy within confined local tissue space. To address this limitation, we have identified a mechanically sensitive Piezo1 ion channel (mechanosensor) that is activatable by ultrasound stimulation and integrated it with engineered genetic circuits (genetic transducer) in live HEK293T cells to convert the ultrasound-activated Piezo1 into transcriptional activities...
January 17, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29326244/gene-therapy-comes-of-age
#8
REVIEW
Cynthia E Dunbar, Katherine A High, J Keith Joung, Donald B Kohn, Keiya Ozawa, Michel Sadelain
After almost 30 years of promise tempered by setbacks, gene therapies are rapidly becoming a critical component of the therapeutic armamentarium for a variety of inherited and acquired human diseases. Gene therapies for inherited immune disorders, hemophilia, eye and neurodegenerative disorders, and lymphoid cancers recently progressed to approved drug status in the United States and Europe, or are anticipated to receive approval in the near future. In this Review, we discuss milestones in the development of gene therapies, focusing on direct in vivo administration of viral vectors and adoptive transfer of genetically engineered T cells or hematopoietic stem cells...
January 12, 2018: Science
https://www.readbyqxmd.com/read/29245005/cd19-car-t-cells
#9
Michel Sadelain
CARs are synthetic receptors that reprogram immune cells for therapeutic purposes. They comprise three canonical domains for antigen recognition, T cell activation, and costimulation. The CAR cDNA is genetically integrated in the T cell genome. Autologous CAR T cells are generated from the patient's peripheral blood T cells and expand in the recipient to eliminate the targeted tumor. To view this Bench to Bedside, open or download the PDF.
December 14, 2017: Cell
https://www.readbyqxmd.com/read/29100432/cancer-antigen-profiling-for-malignant-pleural-mesothelioma-immunotherapy-expression-and-coexpression-of-mesothelin-cancer-antigen-125-and-wilms-tumor-1
#10
Takashi Eguchi, Kyuichi Kadota, Marissa Mayor, Marjorie G Zauderer, Andreas Rimner, Valerie W Rusch, William D Travis, Michel Sadelain, Prasad S Adusumilli
Background: To develop cancer antigen-targeted immunotherapeutic strategies for malignant pleural mesothelioma (MPM), we investigated the individual and coexpressions of the cancer-associated antigens mesothelin (MSLN), cancer antigen 125 (CA125), and Wilms tumor 1 (WT1) in both epithelioid and non-epithelioid MPM. Methods: All available hematoxylin and eosin-stained slides from patients who were diagnosed with MPM (1989-2010) were reviewed. We constructed tissue microarrays from 283 patients (epithelioid = 234; non-epithelioid = 49)...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29043880/concurrent-therapy-of-chronic-lymphocytic-leukemia-and-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-utilizing-cd19-targeted-car-t-cells
#11
Mark B Geyer, Shwetha H Manjunath, Andrew G Evans, Jae H Park, Marco L Davila, Corey S Cutler, Xiuyan Wang, Yongzeng Wang, Brigitte Senechal, Isabelle Rivière, Michel Sadelain, Jane L Liesveld, Renier J Brentjens
No abstract text is available yet for this article.
October 18, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29032264/building-a-safer-and-faster-car-seatbelts-airbags-and-crispr
#12
REVIEW
Miguel-Angel Perales, Partow Kebriaei, Leslie S Kean, Michel Sadelain
Therapeutic T cell engineering has recently garnered widespread interest because of the success of CD19 chimeric antigen receptor (CAR) therapy. CARs are synthetic receptors for antigen that redirect the specificity and reprogram the function of the T cells in which they are genetically introduced. CARs targeting CD19, a cell surface molecule found in most leukemias and lymphomas, have yielded high remission rates in patients with chemorefractory, relapsed disease, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma...
January 2018: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29017060/integrating-proteomics-and-transcriptomics-for-systematic-combinatorial-chimeric-antigen-receptor-therapy-of-aml
#13
Fabiana Perna, Samuel H Berman, Rajesh K Soni, Jorge Mansilla-Soto, Justin Eyquem, Mohamad Hamieh, Ronald C Hendrickson, Cameron W Brennan, Michel Sadelain
Chimeric antigen receptor (CAR) therapy targeting CD19 has yielded remarkable outcomes in patients with acute lymphoblastic leukemia. To identify potential CAR targets in acute myeloid leukemia (AML), we probed the AML surfaceome for overexpressed molecules with tolerable systemic expression. We integrated large transcriptomics and proteomics datasets from malignant and normal tissues, and developed an algorithm to identify potential targets expressed in leukemia stem cells, but not in normal CD34+CD38- hematopoietic cells, T cells, or vital tissues...
October 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28541315/therapeutic-t-cell-engineering
#14
REVIEW
Michel Sadelain, Isabelle Rivière, Stanley Riddell
Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimaeric antigen receptors (CARs) are a class of synthetic receptors that reprogram lymphocyte specificity and function. CARs targeting CD19 have demonstrated remarkable potency in B cell malignancies. Engineered T cells are applicable in principle to many cancers, pending further progress to identify suitable target antigens, overcome immunosuppressive tumour microenvironments, reduce toxicities, and prevent antigen escape...
May 24, 2017: Nature
https://www.readbyqxmd.com/read/28456379/chimeric-antigen-receptors-a-cell-and-gene-therapy-perspective
#15
REVIEW
Isabelle Rivière, Michel Sadelain
Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T lymphocytes to target chosen antigens. The targeting of CD19, a cell surface molecule expressed in the vast majority of leukemias and lymphomas, has been successfully translated in the clinic, earning CAR therapy a special distinction in the selection of "cancer immunotherapy" by Science as the breakthrough of the year in 2013. CD19 CAR therapy is predicated on advances in genetic engineering, T cell biology, tumor immunology, synthetic biology, target identification, cell manufacturing sciences, and regulatory compliance-the central tenets of CAR therapy...
May 3, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28225754/targeting-a-car-to-the-trac-locus-with-crispr-cas9-enhances-tumour-rejection
#16
Justin Eyquem, Jorge Mansilla-Soto, Theodoros Giavridis, Sjoukje J C van der Stegen, Mohamad Hamieh, Kristen M Cunanan, Ashlesha Odak, Mithat Gönen, Michel Sadelain
Chimeric antigen receptors (CARs) are synthetic receptors that redirect and reprogram T cells to mediate tumour rejection. The most successful CARs used to date are those targeting CD19 (ref. 2), which offer the prospect of complete remission in patients with chemorefractory or relapsed B-cell malignancies. CARs are typically transduced into the T cells of a patient using γ-retroviral vectors or other randomly integrating vectors, which may result in clonal expansion, oncogenic transformation, variegated transgene expression and transcriptional silencing...
March 2, 2017: Nature
https://www.readbyqxmd.com/read/28067900/donor-cd19-car-t-cells-exert-potent-graft-versus-lymphoma-activity-with-diminished-graft-versus-host-activity
#17
Arnab Ghosh, Melody Smith, Scott E James, Marco L Davila, Enrico Velardi, Kimon V Argyropoulos, Gertrude Gunset, Fabiana Perna, Fabiana M Kreines, Emily R Levy, Sophie Lieberman, Hillary V Jay, Andrea Z Tuckett, Johannes L Zakrzewski, Lisa Tan, Lauren F Young, Kate Takvorian, Jarrod A Dudakov, Robert R Jenq, Alan M Hanash, Ana Carolina F Motta, George F Murphy, Chen Liu, Andrea Schietinger, Michel Sadelain, Marcel R M van den Brink
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies...
February 2017: Nature Medicine
https://www.readbyqxmd.com/read/27898090/lips-a3s-a-human-genomic-site-for-robust-expression-of-inserted-transgenes
#18
Andriana G Kotini, Michel Sadelain, Eirini P Papapetrou
Transgenesis of human pluripotent stem cells (hPSCs) can enable and empower a variety of studies in stem cell research, including lineage tracing and functional genetics studies. While in recent years much progress has been made in the development of tools for gene targeting, little attention has been given to the identification of sites in the human genome where transgenes can be inserted and reliably expressed. In order to find human genomic sites capable of supporting long-term and high-level transgene expression in hPSCs, we performed a lentiviral screen in human induced pluripotent stem cells (iPSCs)...
November 29, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27760047/targeted-antibody-mediated-depletion-of-murine-cd19-car-t-cells-permanently-reverses-b-cell-aplasia
#19
Paulina J Paszkiewicz, Simon P Fräßle, Shivani Srivastava, Daniel Sommermeyer, Michael Hudecek, Ingo Drexler, Michel Sadelain, Lingfeng Liu, Michael C Jensen, Stanley R Riddell, Dirk H Busch
The adoptive transfer of T cells that have been genetically modified to express a CD19-specific chimeric antigen receptor (CAR) is effective for treating human B cell malignancies. However, the persistence of functional CD19 CAR T cells causes sustained depletion of endogenous CD19+ B cells and hypogammaglobulinemia. Thus, there is a need for a mechanism to ablate transferred T cells after tumor eradication is complete to allow recovery of normal B cells. Previously, we developed a truncated version of the epidermal growth factor receptor (EGFRt) that is coexpressed with the CAR on the T cell surface...
November 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27675589/radiation-sensitizes-tumor-cells-to-car-t-cell-immunotherapy
#20
C J DeSelm, M Hamieh, M Sadelain
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
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