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chimeric t cell and lymphoma

Carlos A Ramos, Rayne Rouce, Catherine S Robertson, Amy Reyna, Neeharika Narala, Gayatri Vyas, Birju Mehta, Huimin Zhang, Olga Dakhova, George Carrum, Rammurti T Kamble, Adrian P Gee, Zhuyong Mei, Meng-Fen Wu, Hao Liu, Bambi Grilley, Cliona M Rooney, Helen E Heslop, Malcolm K Brenner, Barbara Savoldo, Gianpietro Dotti
Second-generation (2G) chimeric antigen receptors (CARs) targeting CD19 are highly active against B cell malignancies, but it is unknown whether any of the costimulatory domains incorporated in the CAR have superior activity to others. Because CD28 and 4-1BB signaling activate different pathways, combining them in a single third-generation (3G) CAR may overcome the limitations of each individual costimulatory domain. We designed a clinical trial in which two autologous CD19-specific CAR-transduced T cell products (CD19...
September 13, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Sarah Löw, Catherine H Han, Tracy T Batchelor
Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL), confined to the brain, eyes, spinal cord or leptomeninges without systemic involvement. Overall prognosis, diagnosis and management of PCNSL differ from other types of NHL. Prompt diagnosis and initiation of treatment are vital to improving clinical outcomes. PCNSL is responsive to radiation therapy, however whole-brain radiotherapy (WBRT) inadequately controls the disease when used alone and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients...
2018: Therapeutic Advances in Neurological Disorders
Naoki Hosen
CAR T-cell therapy is a novel cancer immunotherapy targeting cancer-specific cell-surface antigen. CD19-CAR T cells have been demonstrated to be highly efficacious in treating B-cell leukemia/lymphoma. Currently, several researchers are developing CAR T cells for multiple myeloma. In some early-phase clinical trials, CAR T cells targeting B-cell maturation antigen have exhibited promising efficacy. Recently, we reported that CAR T cells targeting the activated integrin 7 can selectively eradicate MM cells including CD19+ clonotypic B cells; a clinical trial for further assessment regarding this study is in process...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Antonia Rotolo, Valentina S Caputo, Monika Holubova, Nicoleta Baxan, Olivier Dubois, Mohammed Suhail Chaudhry, Xiaolin Xiao, Katerina Goudevenou, David S Pitcher, Kyriaki Petevi, Carolina Kachramanoglou, Sandra Iles, Kikkeri Naresh, John Maher, Anastasios Karadimitris
Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival...
October 8, 2018: Cancer Cell
Hiroki Hosoi, Kazuo Hatanaka, Shogo Murata, Toshiki Mushino, Kodai Kuriyama, Akinori Nishikawa, Nobuyoshi Hanaoka, Shinobu Tamura, Hideki Nakakuma, Takashi Sonoki
Sezary syndrome (SS) is a leukemic form of cutaneous T-cell lymphoma and is chemo-resistant. Allogeneic hematopoietic stem cell transplantation is a promising therapy for SS; however, relapse is common. Therapeutic options after relapse have not been established. We managed an SS patient with hematological relapse within one month after transplantation. After discontinuation of immunosuppressants, she achieved complete remission and remained relapse-free. The chimeric analyses of Tcells showed that the full recipient type became complete donor chimera after immunological symptoms...
September 5, 2018: Hematology Reports
Jacob S Appelbaum, Filippo Milano
PURPOSE OF REVIEW: Cellular therapy using T cells modified to express chimeric antigen receptors (CAR-T cells) has had striking success in patients that have failed previous treatment for CD19+ B cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or acute lymphoblastic leukemia (ALL). Curative therapy for this group of diseases has previously been limited to allogeneic hematopoietic cell transplantation HCT (alloHCT). The recent results of CAR-T cell therapy raise the question of how best to integrate CAR-T cell therapy and alloHCT in the care of these patients...
October 2, 2018: Current Hematologic Malignancy Reports
Charlotte Graham, Agnieszka Jozwik, Andrea Pepper, Reuben Benjamin
Patient derived anti-CD19 chimeric antigen receptor-T (CAR-T) cells are a powerful tool in achieving a complete remission in a range of B-cell malignancies, most notably B-acute lymphoblastic leukaemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). However, there are limitations, including inability to manufacture CAR-T cells from the patient's own T cells, disease progression and death prior to return of engineered cells. T cell dysfunction is known to occur in cancer patients, and several groups have recently described differences in CAR-T cells generated from chronic lymphocytic leukaemia (CLL) patients compared with those from a healthy donor...
October 1, 2018: Cells
Coralie Hoareau-Aveilla, Cathy Quelen, Annabelle Congras, Nina Caillet, Delphine Labourdette, Christine Dozier, Pierre Brousset, Laurence Lamant, Fabienne Meggetto
Anaplastic large-cell lymphoma, a T cell neoplasm, is primarily a pediatric disease. 75% of pediatric anaplastic large-cell lymphoma cases harbor the chromosomal translocation t(2;5)(p23;q35) leading to the ectopic expression of NPM-ALK, a chimeric tyrosine kinase. NPM-ALK consists of an N-terminal nucleophosmin (NPM) domain fused to an anaplastic lymphoma kinase (ALK) cytoplasmic domain. Pediatric NPM-ALK(+) anaplastic large-cell lymphoma is often a disseminated disease and young patients are prone to chemoresistance or relapse shortly after chemotherapeutic treatment...
September 27, 2018: Haematologica
Hasan Mollanoori, Hojat Shahraki, Yazdan Rahmati, Shahram Teimourian
Clustered regularly interspaced short palindromic repeats/CRISPR associated nuclease9 (CRISPR/Cas9) technology, an acquired immune system in bacteria and archaea, has provided a new tool for accurately genome editing. Using only a single nuclease protein in complex with 2 short RNA as a site-specific endonuclease made it a simple and flexible genome editing tool to target nearly any genomic locus. Due to recent developments in therapeutic engineered T cell and effective responses of CD19-directed chimeric antigen receptor T cells (CART19) in patients with B-cell leukemia and lymphoma, adoptive T cell immunotherapy, particularly CAR-T cell therapy became a rapidly growing field in cancer therapy and recently Kymriah and Yescarta (CD19-directed CAR-T cells) were approved by FDA...
September 24, 2018: Human Immunology
Jun Zhang, L Jeffrey Medeiros, Ken H Young
Remarkable progress has been made in the field of cancer immunotherapy in the past few years. Immunotherapy has become a standard treatment option for patients with various cancers, including melanoma, lymphoma, and carcinomas of the lungs, kidneys, bladder, and head and neck. Promising immunotherapy approaches, such as chimeric antigen receptor (CAR) T cell therapy and therapeutic blockade of immune checkpoints, in particular cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 pathway (PD-1/PD-L1), have boosted the development of new therapeutic regimens for patients with cancer...
2018: Frontiers in Oncology
Haziq F Siddiqi, Karl W Staser, Vinod E Nambudiri
Chimeric antigen receptor (CAR) and chimeric autoantibody receptor T cell therapy hold great promise in the treatment of cancer and autoimmune disease, respectively. This powerful technique involves genetically engineering T lymphocytes to enable selective destruction of disease-causing cells. In the current approach, a patient's T cells are genetically engineered to express an antigen-specific antibody fragment fused to activating cytoplasmic T cell signaling domains. Following ex vivo activation and genetic modification of a patient's own T cells, the individually-tailored CAR T cells are then infused into the patient for the selective destruction of cells bearing the targeted antigen...
September 19, 2018: Journal of Investigative Dermatology
Marie Émilie Dourthe, Karima Yakouben, Delphine Chaillou, Emmanuelle Lesprit, Jean-Hugues Dalle, André Baruchel
Acute lymphoblastic leukemia (ALL) is the first cause of cancer in children. Five-year overall survival is greater than 90% but leukemia remains a major cause of death from cancer in children. A new class of immunotherapy based on a chimeric antigen receptor "CAR" targeting the CD19 on the B leukemic cells and that is transduced in an autologous or allogenic T lymphocyte will allow to transform the prognosis of refractory or relapsed B-ALL. Overall response rates range from 60 to 90% in phase I-II studies in patients with second relapse or more or with refractory disease...
September 17, 2018: Bulletin du Cancer
Teresa Poggio, Justus Duyster, Anna L Illert
T cell non-Hodgkin lymphoma (T-NHL) is a rare and heterogeneous group of neoplasms of the lymphoid system. With the exception of a few relatively indolent entities, T-NHL is typically aggressive, treatment resistant, and associated with poor prognosis. Relatively few options with proven clinical benefit are available for patients with relapsed or refractory disease. Immunotherapy has emerged as a promising treatment for the management of patients with hematological malignancies. The identification of tumor antigens has provided a large number of potential targets...
September 18, 2018: Cancers
Paolo Strati, Shabnum Patel, Loretta Nastoupil, Michelle A Fanale, Catherine M Bollard, Adam Y Lin, Leo I Gordon
Immune-based treatment strategies, such as checkpoint inhibition and chimeric antigen receptor (CAR) T cells, have started a new frontier for treatment in non-Hodgkin lymphoma (NHL). Checkpoint inhibition has been most successful in Hodgkin lymphoma, where higher expression of PD-L1 is correlated with better overall response rate. Combinations of checkpoint inhibition with various chemotherapy or biologics are in clinical trials, with initially promising results and manageable safety profiles. CAR T-cell therapies that target CD19 are a promising and attractive therapy for B-cell NHLs, with a product approved by the US Food and Drug Administration in 2017...
May 23, 2018: American Society of Clinical Oncology Educational Book
Anett Pfeiffer, Frederic B Thalheimer, Sylvia Hartmann, Annika M Frank, Ruben R Bender, Simon Danisch, Caroline Costa, Winfried S Wels, Ute Modlich, Renata Stripecke, Els Verhoeyen, Christian J Buchholz
Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B-cell malignancies. Notwithstanding, CAR T-cell manufacturing requires complex procedures impeding the broad supply chain. Here, we provide evidence that human CD19-CAR T cells can be generated directly in vivo using the lentiviral vector CD8-LV specifically targeting human CD8+ cells. Administration into mice xenografted with Raji lymphoma cells and human peripheral blood mononuclear cells led to CAR expression solely in CD8+ T cells and efficacious elimination of CD19+ B cells...
September 17, 2018: EMBO Molecular Medicine
Narmeen N Fathi, Dara K Mohammad, André Görgens, Samir El Andaloussi, Rula Zain, Beston F Nore, C I Edvard Smith
Many cancer types carry mutations in protein tyrosine kinase (PTK) and such alterations frequently drive tumor progression. One category is gene translocation of PTKs yielding chimeric proteins with transforming capacity. In this study, we characterized the role of ITK-FER [Interleukin-2-inducible T-cell Kinase (ITK) gene fused with Feline Encephalitis Virus-Related kinase (FER) gene] and ITK-SYK [Interleukin-2-inducible T-cell Kinase (ITK) gene fused with the Spleen Tyrosine Kinase (SYK)] in Peripheral T Cell Lymphoma (PTCL) signaling...
October 12, 2018: Biochemical and Biophysical Research Communications
Ranjit Nair, Sattva S Neelapu
Relapsed or refractory aggressive B-cell lymphoma has an extremely poor prognosis and efforts to develop novel therapies for these patients have failed for almost four decades until the advent of chimeric antigen receptor (CAR) T-cell therapy. Within the last one year, two anti-CD19 CAR T-cell therapy products, axicabtagene ciloleucel and tisagenlecleucel, were approved by the United States Food and Drug Administration for the treatment of relapsed or refractory large B-cell lymphoma after at least two lines of systemic therapy based on multicenter single-arm phase two clinical trials...
September 2018: Best Practice & Research. Clinical Haematology
Yanfen Liu, Xinfeng Chen, Dao Wang, Hong Li, Jianmin Huang, Zhen Zhang, Yingjin Qiao, Hongling Zhang, Ying Zeng, Chao Tang, Shuangning Yang, Xiaochun Wan, Youhai H Chen, Yi Zhang
Cytokine release syndrome (CRS) remains to be a major adverse effect of chimeric antigen receptor T (CAR-T) cell therapy in B-cell acute lymphoblastic leukemia (B-ALL) and lymphoma. It was urgent to explore novel strategy for managing severe CRS. We conducted a clinical trial to assess the safety and efficacy of CD19-targeting CAR-T-cells in the treatment of relapsed and chemotherapy-refractory B-ALL and lymphoma. A 10-year-old boy with B-ALL who never achieved minimal residual disease (MRD) negative status after 5 courses of chemotherapy was enrolled into our study and received a total of 3...
November 2018: Journal of Immunotherapy
Benjamin Heyman, Yiping Yang
The development of immunotherapies for lymphoma has undergone a revolutionary evolution over the past decades. Since the advent of rituximab as the first successful immunotherapy for B-cell non-Hodgkin lymphoma over two decades ago, a plethora of new immunotherapeutic approaches to treat lymphoma has ensued. Four of the most exciting classes of immunotherapies include: chimeric antigen receptor T-cells, bispecific antibodies, immune checkpoint inhibitors, and vaccines. However, with addition of these novel therapies the appropriate timing of treatment, optimal patient population, duration of therapy, toxicity, and cost must be considered...
August 2018: Cancer Biology & Medicine
Ana P Teixeira, Martin Fussenegger
Synthetic biology aims to repurpose cells to sense a wide range of input signals and respond by conditionally expressing user-defined output genes. In this review, we highlight the latest developments in synthetic-biology-inspired in vitro and in vivo diagnostics and therapeutics employing engineered mammalian cells. Recent work has led to the creation of modular synthetic receptors with adaptable ligand-binding domains whose recognition specificity can be easily tailored to target various diseases. Engineered cells can now sense a great variety of soluble and surface-bound antigens with unprecedented selectivity and sensitivity, and implanted designer cells equipped with appropriate response modules can successfully treat diabetes, cancer and autoimmune diseases in animal models...
September 5, 2018: Current Opinion in Biotechnology
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