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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
Leonid Cherkassky, Aurore Morello, Jonathan Villena-Vargas, Yang Feng, Dimiter S Dimitrov, David R Jones, Michel Sadelain, Prasad S Adusumilli
Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication...
August 1, 2016: Journal of Clinical Investigation
Michel Sadelain
The advent of second generation chimeric antigen receptors and the CD19 paradigm have ushered a new therapeutic modality in oncology. In contrast to earlier forms of adoptive cell therapy, which were based on the isolation and expansion of naturally occurring T cells, CAR therapy is based on the design and manufacture of engineered T cells with optimized properties. A new armamentarium, comprising not only CARs but also chimeric costimulatory receptors, chimeric cytokine receptors, inhibitory receptors and synthetic Notch receptors, expressed in naïve, central memory or stem cell-like memory T cells, is being developed for clinical use in a wide range of cancers...
August 2016: Current Opinion in Immunology
Marco L Davila, Michel Sadelain
Chimeric antigen receptor (CAR)-modified T cells have generated broad interest in oncology following a series of dramatic clinical successes in patients with chemorefractory B cell malignancies. CAR therapy now appears to be on the cusp of regulatory approval as a cell-based immunotherapy. We review here the T cell biology and cell engineering research that led to the development of second generation CARs, the selection of CD19 as a CAR target, and the preclinical studies in animal models that laid the foundation for clinical trials targeting CD19+ malignancies...
July 2016: International Journal of Hematology
Michel Sadelain
Both T cells bearing chimeric antigen receptors and tumor-specific antibodies can successfully target some malignancies, but antigen escape can lead to relapse. Two articles in this issue of Cancer Immunology Research explore what effective countermeasures may prevent it. Cancer Immunol Res; 4(6); 473-473. ©2016 AACRSee articles by Zah et al., p. 498, and Rufener et al., p. 509.
June 2016: Cancer Immunology Research
Aisha N Hasan, Annamalai Selvakumar, Elena Shabrova, Xiao-Rong Liu, Faiz Afridi, Glenn Heller, Isabelle Riviere, Michel Sadelain, Bo Dupont, Richard J O'Reilly
The lack of persistence of infused T-cells is a principal limitation of adoptive immunotherapy in man. IL-15 can sustain memory T-cell expansion when presented in complex with IL-15Rα (15Rα/15). We developed a novel in vitro system for generation of stable 15Rα/15 complexes. Immunologically quantifiable amounts of IL-15 were obtained when both IL-15Rα and IL-15 genes were co-transduced in NIH 3T3 fibroblast based artificial antigen presenting cells expressing human HLA A:0201, β2 microglobulin, CD80 and CD54 (A2-AAPC) and a murine pro-B cell line (Baf-3) (A2-AAPC (15Rα/15) and Baf-3(15Rα/15) )...
May 26, 2016: Clinical and Experimental Immunology
Jorge Mansilla-Soto, Isabelle Riviere, Farid Boulad, Michel Sadelain
The beta-thalassemias are inherited anemias caused by mutations that severely reduce or abolish expression of the beta-globin gene. Like sickle cell disease, a related beta-globin gene disorder, they are ideal candidates for performing a genetic correction in patient hematopoietic stem cells (HSCs). The most advanced approach utilizes complex lentiviral vectors encoding the human β-globin gene, as first reported by May et al. in 2000. Considerable progress toward the clinical implementation of this approach has been made in the past five years, based on effective CD34+ cell mobilization and improved lentiviral vector manufacturing...
April 2016: Human Gene Therapy
Maria Themeli, Michel Sadelain
T cells expressing chimeric antigen receptors (CARs) are a formidable platform for the study and application of synthetic biology approaches to study customized and flexible control of cellular functions. Recent reports in the journal Cell provide a new twist on combinatorial antigen targeting, profiting from the singular cleavage and signaling of the Notch receptor to conditionally express CARs.
April 2016: Trends in Molecular Medicine
Michel Sadelain
No abstract text is available yet for this article.
March 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
Andriana G Kotini, Elisa de Stanchina, Maria Themeli, Michel Sadelain, Eirini P Papapetrou
Human pluripotent stem cells (hPSCs) hold great promise for cell therapy. However, a major concern is the risk of tumor formation by residual undifferentiated cells contaminating the hPSC-derived cell product. Suicide genes could safeguard against such adverse events by enabling elimination of cells gone astray, but the efficacy of this approach has not yet been thoroughly tested. Here, we engineered a lentivirally encoded herpes simplex virus thymidine kinase (HSVtk) with expression restricted to undifferentiated hPSCs through regulation by the let7 family of miRNAs...
2016: Molecular Therapy. Nucleic Acids
Aurore Morello, Michel Sadelain, Prasad S Adusumilli
UNLABELLED: Chimeric antigen receptors (CAR) are synthetic receptors that target T cells to cell-surface antigens and augment T-cell function and persistence. Mesothelin is a cell-surface antigen implicated in tumor invasion, which is highly expressed in mesothelioma and lung, pancreas, breast, ovarian, and other cancers. Its low-level expression in mesothelia, however, commands thoughtful therapeutic interventions. Encouragingly, recent clinical trials evaluating active immunization or immunoconjugates in patients with pancreatic adenocarcinoma or mesothelioma have shown responses without toxicity...
February 2016: Cancer Discovery
Zeguo Zhao, Maud Condomines, Sjoukje J C van der Stegen, Fabiana Perna, Christopher C Kloss, Gertrude Gunset, Jason Plotkin, Michel Sadelain
T cell engineering is a powerful means to rapidly generate anti-tumor T cells. The costimulatory properties of second-generation chimeric antigen receptors (CARs) determine the overall potency of adoptively transferred T cells. Using an in vivo "stress test" to challenge CD19-targeted T cells, we studied the functionality and persistence imparted by seven different CAR structures providing CD28 and/or 4-1BB costimulation. One configuration, which uses two signaling domains (CD28 and CD3ζ) and the 4-1BB ligand, provided the highest therapeutic efficacy, showing balanced tumoricidal function and increased T cell persistence accompanied by an elevated CD8/CD4 ratio and decreased exhaustion...
October 12, 2015: Cancer Cell
Michel Sadelain
Twenty-five years after its inception, the genetic engineering of T cells is now a therapeutic modality pursued at an increasing number of medical centers. This immunotherapeutic strategy is predicated on gene transfer technology to instruct T lymphocytes to recognize and reject tumor cells. Chimeric antigen receptors (CARs) are synthetic receptors that mediate antigen recognition, T cell activation, and - in the case of second-generation CARs - costimulation to augment T cell functionality and persistence...
September 2015: Journal of Clinical Investigation
Theodore Friedmann, Erica C Jonlin, Nancy M P King, Bruce E Torbett, Nelson A Wivel, Yasufumi Kaneda, Michel Sadelain
No abstract text is available yet for this article.
August 2015: Molecular Therapy: the Journal of the American Society of Gene Therapy
Sjoukje J C van der Stegen, Mohamad Hamieh, Michel Sadelain
Second-generation chimeric antigen receptors (CARs) retarget and reprogramme T cells to augment their antitumour efficacy. The combined activating and co-stimulatory domains incorporated in these CARs critically determine the function, differentiation, metabolism and persistence of engineered T cells. CD19-targeted CARs that incorporate CD28 or 4-1BB signalling domains are the best known to date. Both have shown remarkable complete remission rates in patients with refractory B cell malignancies. Recent data indicate that CD28-based CARs direct a brisk proliferative response and boost effector functions, whereas 4-1BB-based CARs induce a more progressive T cell accumulation that may compensate for less immediate potency...
July 2015: Nature Reviews. Drug Discovery
Maud Condomines, Jon Arnason, Reuben Benjamin, Gertrude Gunset, Jason Plotkin, Michel Sadelain
Adoptive T cell therapy represents a promising treatment for cancer. Human T cells engineered to express a chimeric antigen receptor (CAR) recognize and kill tumor cells in a MHC-unrestricted manner and persist in vivo when the CAR includes a CD28 costimulatory domain. However, the intensity of the CAR-mediated CD28 activation signal and its regulation by the CTLA-4 checkpoint are unknown. We investigated whether T cells expressing an anti-CD19, CD3 zeta and CD28-based CAR (19-28z) displayed the same proliferation and anti-tumor abilities than T cells expressing a CD3 zeta-based CAR (19z1) costimulated through the CD80/CD28, ligand/receptor pathway...
2015: PloS One
Garyfalia Karponi, Nikoletta Psatha, Carsten Werner Lederer, Jennifer Eileen Adair, Fani Zervou, Nikolaos Zogas, Marina Kleanthous, Constantinos Tsatalas, Achilles Anagnostopoulos, Michel Sadelain, Isabelle Rivière, George Stamatoyannopoulos, Evangelia Yannaki
Globin gene therapy requires abundant numbers of highly engraftable, autologous hematopoietic stem cells expressing curative levels of β-globin on differentiation. In this study, CD34+ cells from 31 thalassemic patients mobilized with hydroxyurea+granulocyte colony-stimulating factor (G-CSF), G-CSF, Plerixafor, or Plerixafor+G-CSF were transduced with the TNS9.3.55 β-globin lentivector and compared for transducibility and globin expression in vitro, as well as engraftment potential in a xenogeneic model after partial myeloablation...
July 30, 2015: Blood
Michel Sadelain, Renier Brentjens, Isabelle Rivière, Jae Park
Chimeric antigen receptor (CAR) therapy is an emerging immunotherapy that shows great promise for cancer, in particular acute lymphoblastic leukemia (ALL). CARs are recombinant receptors for antigen, which, in a single molecule, redirect the specificity and function of T lymphocytes. Following their genetic transfer to patient T cells, the latter acquire the ability to recognize leukemia cells and destroy them. Several years ago, we identified CD19 as an attractive target for CAR therapy for most B cell malignancies, including ALL...
2015: American Society of Clinical Oncology Educational Book
Jacqueline Corrigan-Curay, Marina O'Reilly, Donald B Kohn, Paula M Cannon, Gang Bao, Frederic D Bushman, Dana Carroll, Toni Cathomen, J Keith Joung, David Roth, Michel Sadelain, Andrew M Scharenberg, Christof von Kalle, Feng Zhang, Robert Jambou, Eugene Rosenthal, Morad Hassani, Aparna Singh, Matthew H Porteus
No abstract text is available yet for this article.
May 2015: Molecular Therapy: the Journal of the American Society of Gene Therapy
Jacques F A P Miller, Michel Sadelain
Recent advances in cancer immunotherapy have directly built on 50 years of fundamental and technological advances that made checkpoint blockade and T cell engineering possible. In this review, we intend to show that research, not specifically designed to bring relief or cure to any particular disease, can, when creatively exploited, lead to spectacular results in the management of cancer. The discovery of thymus immune function, T cells, and immune surveillance bore the seeds for today's targeted immune interventions and chimeric antigen receptors...
April 13, 2015: Cancer Cell
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