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chimeric t cell and lymphoma

Jennifer N Brudno, James N Kochenderfer
Chimeric antigen receptor (CAR) T-cell therapy is an effective new treatment for hematologic malignancies. Two CAR T-cell products are now approved for clinical use by the U.S. FDA: tisagenlecleucel for pediatric acute lymphoblastic leukemia (ALL) and adult diffuse large B-cell lymphoma subtypes (DLBCL), and axicabtagene ciloleucel for DLBCL. CAR T-cell therapies are being developed for multiple myeloma, and clear evidence of clinical activity has been generated. A barrier to widespread use of CAR T-cell therapy is toxicity, primarily cytokine release syndrome (CRS) and neurologic toxicity...
November 14, 2018: Blood Reviews
Sonia Guedan, Marco Ruella, Carl H June
Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimeric antigen receptor (CAR) T cells were recently approved by the US Food and Drug Administration and are poised to enter the practice of medicine for leukemia and lymphoma, demonstrating that engineered immune cells can serve as a powerful new class of cancer therapeutics. The emergence of synthetic biology approaches for cellular engineering provides a broadly expanded set of tools for programming immune cells for enhanced function...
December 10, 2018: Annual Review of Immunology
Bu-Nam Jeon, Hye-Ran Kim, Yun Shin Chung, Bo-Ra Na, Hyunkyung Park, Chorong Hong, Yasmin Fatima, Hyeonju Oh, Chang-Hyun Kim, Chang-Duk Jun
Correct temporal and spatial control of actin dynamics is essential for the cytotoxic T cell effector function against tumor cells. However, little is known whether actin engineering in tumor-targeted T cells can enhance their antitumor responses, thereby potentiating the adoptive T cell therapy. Here, we report that TAGLN2, a 22-KDa actin-stabilizing protein which is physically associated with lymphocyte function-associated antigen-1 (LFA-1), potentiates the OTI TCR CD8+ T cells to kill the intercellular adhesion molecule-1 (ICAM-1)-positive/OVA-presenting E0771 cells, but not ICAM-1-negative OVA-B16F10 cells, suggesting an 'inside-out' activation of LFA-1, which causes more efficient immunological synapse formation between T cells and tumor cells...
2018: Oncoimmunology
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No abstract text is available yet for this article.
December 6, 2018: Blood
Christopher R Flowers, John P Leonard, Loretta J Nastoupil
Follicular lymphoma (FL) remains a lymphoma subtype that is remarkably sensitive to immunotherapy-based treatment strategies. Anti-CD20 antibody therapy administered as a single agent and in combination as a first-line treatment and at relapse continues to be the most broadly used therapy for this disease. Autologous and allogeneic stem cell transplantation provide meaningful durable remissions for patients with FL. However, identifying the most suitable patients and the optimal timing for these approaches has become increasingly challenging with the advent of novel therapies...
November 30, 2018: Hematology—the Education Program of the American Society of Hematology
Jonathon B Cohen
Most patients with aggressive non-Hodgkin lymphoma will be cured with initial chemoimmunotherapy; however, most patients with relapsed disease will not be cured and will die as a result of their disease. In these cases, continued treatment with conventional chemotherapy is typically not of benefit and can contribute to significant toxicities and decreased quality of life for patients. Fortunately, a number of therapies are currently available or under investigation for this group of patients, ranging from oral tyrosine kinase inhibitors targeting multiple pathways within the malignant cells to adoptive cellular therapies that harness the patient's immune system to fight disease...
November 30, 2018: Hematology—the Education Program of the American Society of Hematology
Stephen J Schuster, Michael R Bishop, Constantine S Tam, Edmund K Waller, Peter Borchmann, Joseph P McGuirk, Ulrich Jäger, Samantha Jaglowski, Charalambos Andreadis, Jason R Westin, Isabelle Fleury, Veronika Bachanova, S Ronan Foley, P Joy Ho, Stephan Mielke, John M Magenau, Harald Holte, Serafino Pantano, Lida B Pacaud, Rakesh Awasthi, Jufen Chu, Özlem Anak, Gilles Salles, Richard T Maziarz
BACKGROUND: Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study. METHODS: We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation...
December 1, 2018: New England Journal of Medicine
Navneet S Majhail, Rajshekhar Chakraborty, Gunjan L Shah, Betty K Hamilton, Michael Scordo, Surbhi Sidana
Patient-reported outcomes (PROs) are an important tool to assess the impact of a new therapy on symptom burden and health-related quality of life (HRQoL). Chimeric Antigen Receptor-T (CAR-T) cell therapies have been approved for use in relapsed or refractory leukemia and lymphoma based on promising efficacy in clinical trials. However, there is a lack of data on patient-reported toxicity and impact on HRQoL. This review provides an overview of the incorporation of PROs in CAR-T cell therapy and the specific challenges in this context...
November 27, 2018: Biology of Blood and Marrow Transplantation
Yiyang Xu, Zhiyuan Yang, Lucas H Horan, Pengbo Zhang, Lianxing Liu, Bryan Zimdahl, Shon Green, Jingwei Lu, Javier F Morales, David M Barrett, Stephan A Grupp, Vivien W Chan, Hong Liu, Cheng Liu
The clinical use of genetically modified T-cell therapies has led to unprecedented response rates in leukemia and lymphoma patients treated with anti-CD19 chimeric antigen receptor (CAR)-T. Despite this clinical success, FDA-approved T-cell therapies are currently limited to B-cell malignancies, and challenges remain with managing cytokine-related toxicities. We have designed a novel antibody-T-cell receptor (AbTCR) platform where we combined the Fab domain of an antibody with the γ and δ chains of the TCR as the effector domain...
2018: Cell Discovery
Yan Leyfman
Background: Chimeric antigen receptors (CARs) represent a novel facet of modern day synthetic biology that exemplifies personalized medicine at work through their ability to harness and redirect a patient's immune system to fight cancer. Body: By combining the target-specificity of antibodies to the effector capabilities of T cells, CARs have yielded high remission rates for many late staged and relapsed/refractory (r/r) hematological malignancies, including acute lymphoblastic leukemias (ALL) and Non-Hodgkin's lymphomas...
2018: Cancer Cell International
Alexey V Stepanov, Oleg V Markov, Ivan V Chernikov, Daniil V Gladkikh, Hongkai Zhang, Teresa Jones, Alexandra V Sen'kova, Elena L Chernolovskaya, Marina A Zenkova, Roman S Kalinin, Maria P Rubtsova, Alexander N Meleshko, Dmitry D Genkin, Alexey A Belogurov, Jia Xie, Alexander G Gabibov, Richard A Lerner
We report the development of a novel platform to enhance the efficacy and safety of follicular lymphoma (FL) treatment. Since lymphoma is a clonal malignancy of a diversity system, every tumor has a different antibody on its cell surface. Combinatorial autocrine-based selection is used to rapidly identify specific ligands for these B cell receptors on the surface of FL tumor cells. The selected ligands are used in a chimeric antigen receptor T cell (CAR-T) format for redirection of human cytotoxic T lymphocytes...
November 2018: Science Advances
Felicitas Rataj, Severin J Jacobi, Stefan Stoiber, Florian Asang, Justyna Ogonek, Nicholas Tokarew, Bruno L Cadilha, Erwin van Puijenbroek, Constanze Heise, Peter Duewell, Stefan Endres, Christian Klein, Sebastian Kobold
BACKGROUND: CD16-chimeric antigen receptors (CAR) T cells recognise the Fc-portion of therapeutic antibodies, which can enable the selective targeting of different antigens. Limited evidence exists as to which CD16-CAR design and antibody partner might be most effective. We have hypothesised that the use of high-affinity CD16 variants, with increased Fc-terminus antibody affinity, combined with Fc-engineered antibodies, would provide superior CD16-CAR T cell efficacy. METHODS: CD16-CAR T (wild-type or variants) cells were co-cultured with Panc-1 pancreatic cancer, Raji lymphoma or A375 melanoma cells in the presence or absence of anti-CD20, anti-MCSP, wild-type or the glycoengineered antibody variants...
November 15, 2018: British Journal of Cancer
Pashna N Munshi, Chaitra Ujjani
Recent advances in diffuse large B-cell lymphomas have included both identification of high-risk subtypes characterized by multiply relapsed and/or refractory disease as well as novel treatment in the form of cellular therapy. Chimeric antigen receptor (CAR)-T cell therapy is a recently developed approach to address the poor outcomes in this patient population. The CAR-T cell construct has evolved although several iterations as it transitioned from the lab to the clinic. Three major studies have evaluated the efficacy of CD19-directed CAR-T cell therapy in aggressive B-cell non-Hodgkin lymphoma; each demonstrating durable complete remissions in heavily pretreated patients...
November 14, 2018: Hematological Oncology
Sonia Guedan, Ramon Alemany
Adoptive transfer of chimeric antigen receptor (CAR)-modified T cells has resulted in unprecedented rates of long-lasting complete responses in patients with leukemia and lymphoma. However, despite the impressive results in patients with hematologic malignancies, CAR-T cells have showed limited effect against solid cancers. New approaches will need to simultaneously overcome the multiple challenges that CAR-T cells encounter in solid tumors, including the immunosuppressive tumor microenvironment and heterogeneity of antigen expression...
2018: Frontiers in Immunology
Susanne E Aydin, Alexandra F Freeman, Waleed Al-Herz, Hamoud A Al-Mousa, Rand K Arnaout, Roland C Aydin, Vincent Barlogis, Bernd H Belohradsky, Carmem Bonfim, Robbert G Bredius, Julia I Chu, Oana C Ciocarlie, Figen Doğu, Hubert B Gaspar, Raif S Geha, Andrew R Gennery, Fabian Hauck, Abbas Hawwari, Dennis D Hickstein, Manfred Hoenig, Aydan Ikinciogullari, Christoph Klein, Ashish Kumar, Marianne R S Ifversen, Susanne Matthes, Ayse Metin, Benedicte Neven, Sung-Yun Pai, Suhag H Parikh, Capucine Picard, Ellen D Renner, Özden Sanal, Ansgar S Schulz, Friedhelm Schuster, Nirali N Shah, Evan B Shereck, Mary A Slatter, Helen C Su, Joris van Montfrans, Wilhelm Woessmann, John B Ziegler, Michael H Albert
BACKGROUND: Biallelic variations in the DOCK8 gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8 deficient patients...
November 1, 2018: Journal of Allergy and Clinical Immunology in Practice
Hui Pan, Jing Huang, Jun-Nan Li, Li Yang, Jian-Yu Wang, Xin Wang, Lin Liu, Ze-Song Yang, Li Wang
RATIONALE: Hepatosplenic T-cell lymphoma (HSTCL) is a rare but aggressive type of peripheral T-cell lymphoma (PTCL). There is an urgent need for effective treatment due to the poor prognosis of HSTCL. Here, for the 1st time we describe the rare successful case of HSTCL who relapsed after a previous allogeneic stem-cell transplantation (allo-SCT), achieved remission with the second allo-SCT from the same donor. PATIENT CONCERNS: A 24-year-old male, presented with a 2-week history of fever, drenching night sweats and nonquantified weight loss...
November 2018: Medicine (Baltimore)
Yingxi Xu, Saisai Li, Ying Wang, Jia Liu, Xinhe Mao, Haiyan Xing, Zheng Tian, Kejing Tang, Xiaolong Liao, Qing Rao, Dongsheng Xiong, Min Wang, Jianxiang Wang
CD20 is an effective immunotherapy target for CD20+ B-cell malignant cells. Monoclonal antibody, especially Rituximab, has been a conventional strategy in the treatment of B-cell malignancies such as non-Hodgkin's lymphoma (NHL). However, treatment with monoclonal antibodies has not been enough to overcome the refractory/relapsed problems. Chimeric antigen receptor engineered T (CAR-T) cells have revealed excellent therapeutic effect on lymphocytic leukemia in recent years. In this study, a CD20 specific CAR was constructed and the cytotoxic efficacy of CD20 CAR-T cells on B-cell malignant cells was evaluated by CD107a degranulation, pro-inflammation cytokine production and true lytic ability in vitro and in vivo...
November 1, 2018: Human Gene Therapy
A Quaiser, U Köhl
Cell and gene therapy as part of immuno-oncology has reached an important milestone in medicine. After decades of experience stem cell transplantation is well established with worldwide >1 million transplantations to date. Due to the improved success of the last years using chimeric antigen receptor (CAR) T cells for CD19 positive leukemia and lymphomas, the interest in cellular therapies is continuously increasing. The current review also gives a short overview about donor lymphocytes, antigen-specific T cells, regulatory T cells, natural killer (NK) cells, mesenchymal stromal cells and induced pluripotent stem (iPS) cells in immuno-oncology...
December 2018: Der Internist
Robert Havard, Deborah M Stephens
PURPOSE OF REVIEW: This article will review the use of anti-CD19 CAR-T therapy used in relapsed/refractory diffuse large B cell lymphoma. RECENT FINDINGS: The clinical outcomes, safety analysis, and other relevant considerations will be discussed with an emphasis on the most recently published data regarding the ZUMA-1, JULIET, and TRANSCEND NHL-001 trials. Anti-CD19 CAR-T therapy is an exciting new therapy now approved and available to patients with relapsed/refractory diffuse large B cell lymphoma...
October 25, 2018: Current Hematologic Malignancy Reports
Eyad Z Gharaibeh, Mohammad Telfah, Benjamin C Powers, Michael E Salacz
Ifosfamide is an alkylating chemotherapeutic agent used in the treatment of many malignancies. Ifosfamide-induced encephalopathy is one potential side effect that represents a major drawback to ifosfamide therapy and often necessitates discontinuation of chemotherapy. Previous reports demonstrate moderate effectiveness of prophylactic methylene blue at thwarting ifosfamide-induced encephalopathy. This is a report of a 64-year-old female with relapsed double-hit diffuse large B-cell lymphoma who developed severe altered mental status and neurological symptoms after receiving a second dose of ifosfamide as part of her salvage standard dose R-IE (rituximab, ifosfamide, etoposide), in preparation for chimeric antigen receptor T-cell therapy...
October 22, 2018: Journal of Oncology Pharmacy Practice
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