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chimeric t cell and lymphoma

Alexandre V Hirayama, Jordan Gauthier, Kevin A Hay, Jenna M Voutsinas, Qian Wu, Ted Gooley, Daniel Li, Sindhu Cherian, Xueyan Chen, Barbara S Pender, Reed M Hawkins, Aesha Vakil, Rachel N Steinmetz, Utkarsh H Acharya, Ryan D Cassaday, Aude G Chapuis, Tejaswini M Dhawale, Paul C Hendrie, Hans-Peter Kiem, Ryan C Lynch, Jorge Ramos, Mazyar Shadman, Brian G Till, Stanley R Riddell, David G Maloney, Cameron J Turtle
Factors associated with durable remission after CD19 chimeric antigen receptor (CAR)-modified T cell immunotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) have not been identified. We report multivariable analyses of factors impacting response and progression-free survival (PFS) in aggressive NHL patients treated with cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by 2x106 CD19 CAR-T cells/kg. The best overall response rate (ORR) was 51%, with 40% of patients achieving complete remission (CR)...
February 19, 2019: Blood
Jiasheng Wang, Yongxian Hu, Shuye Yang, Guoqin Wei, Xin Zhao, Wenjun Wu, Yanlei Zhang, Yafei Zhang, Donghe Chen, Zhao Wu, Lei Xiao, Alex Hongsheng Chang, He Huang, Kui Zhao
BACKGROUND: CD19-targeting chimeric antigen receptor (CAR) T cell therapy has shown great efficacy in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), but has been associated with serious adverse effects such as cytokine release syndrome (CRS). It has been speculated that NHL baseline disease burden might affect clinical outcome and CRS, but such assumption has not been explored in detail. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG), as measured by FDG PET-CT, are quantitative indicators of baseline tumor burden...
February 12, 2019: Biology of Blood and Marrow Transplantation
Ping Zhang, Jyothy Raju, Md Ashik Ullah, Raymond Au, Antiopi Varelias, Kate H Gartlan, Stuart D Olver, Luke D Samson, Elise Sturgeon, Nienke Zomerdijk, Judy Avery, Tessa Gargett, Michael P Brown, Lachlan J Coin, Devika Ganesamoorthy, Cheryl Hutchins, Gary R Pratt, Glen A Kennedy, A James Morton, Cameron I Curley, Geoffrey R Hill, Siok-Keen Tey
Purpose: Inducible caspase 9 ( iCasp9 ) is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of iCasp9 -transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies. Patients and Methods: Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.5-1.0 × 106 /kg donor-derived iCasp9 -transduced T cells on day +25 or 26 post-transplant, with additional doses allowed for disease relapse, infection, or mixed chimerism...
February 14, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Juanjuan Zhao, Yongping Song, Delong Liu
The current treatment for pediatric acute lymphoblastic leukemia (ALL) is highly successful with high cure rate. However, the treatment of adult ALL remains a challenge, particularly for refractory and/or relapsed (R/R) ALL. The advent of new targeted agents, blinatumomab, inotuzumab ozogamycin, and chimeric antigen receptor (CAR) T cells, are changing the treatment paradigm for ALL. Tisagenlecleucel (kymriah, Novartis) is an autologous CD19-targeted CAR T cell product approved for treatment of R/R B cell ALL and lymphoma...
February 14, 2019: Journal of Hematology & Oncology
Wassim Mchayleh, Prabhjot Bedi, Rajesh Sehgal, Melhem Solh
The immune system acting via cancer immune-surveillance is considered a potential target for improving outcomes among some malignancies. The ability to harness immune cells, engineer them and educate them to target cancer cells has changed the paradigm for treating non-Hodgkin's lymphomas (NHL) and acute lymphoblastic leukemia (ALL). Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable anti-tumor activity against refractory B cell malignancies. Ongoing research aims to expand the scope of this adoptive cell therapy, understanding mechanisms of resistance and reducing toxicity...
February 7, 2019: Journal of Clinical Medicine
C Chabannon, R Bouabdallah, S Fürst, A Granata, C Saillard, N Vey, D Mokart, E Fougereau, C Lemarie, B Mfarrej, D Blaise, B Calmels
CAR-T cells are genetically modified human lymphocytes and gene therapy medicinal products. They are developed to treat cancers that express a membrane antigen targeted by the CAR. The FDA approved the two first-in-class medicinal products in 2017 and EMA in August 2018; both are autologous CAR-T cells targeting CD19 that is expressed at the surface of normal B-cells throughout their differentiation, and on B-cell lymphoid malignancies. Clinical efficacy was demonstrated for B-cell acute lymphoblastic leukemias, non-Hodgkin's lymphoma and chronic lymphocytic leukemia, although the marketing authorizations are less liberal in terms of indications...
January 24, 2019: La Revue de Médecine Interne
Gilles Salles, Pierre Sesques, Emmanuelle Ferrant, Violaine Safar, Hervé Ghesquieres, Emmanuel Bachy
After the promising results obtained in North American academic centers suggesting the curative potential of these treatments, the development of T cells carrying a chimeric antigen receptor (CAR-T) directed against the CD19 antigen has experienced rapid developments in recent years. Three major trials (each involving about 100 patients with relapsed or refractory aggressive B-cell lymphoma) were conducted and evaluated the efficacy of these treatments (Zuma-1, Juliet and Transcend). Tumor responses are observed in 52% to 82% of patients, with a best complete response (CR) rate of 40% to 58%...
December 2018: Bulletin du Cancer
Marie-Émilie Dourthe, Karima Yakouben, Delphine Chaillou, Emmanuelle Lesprit, Jean-Hugues Dalle, André Baruchel
CURRENT INDICATIONS IN CHILDREN AND PERSPECTIVES: 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...
December 2018: Bulletin du Cancer
Hugo Larose, G A Amos Burke, Eric J Lowe, Suzanne D Turner
Anaplastic large cell lymphoma (ALCL) is a T cell Non-Hodgkin Lymphoma that mainly presents in paediatric and young adult patients. The majority of cases express a chimeric fusion protein resulting in hyperactivation of anaplastic lymphoma kinase (ALK) as the consequence of a chromosomal translocation. Rarer cases lack expression of ALK fusion proteins and are categorised as ALCL, ALK-. An adapted regimen of an historic chemotherapy backbone is still used to this day, yielding overall survival (OS) of over 90% but with event-free survival (EFS) at an unacceptable 70%, improving little over the past 30 years...
January 25, 2019: British Journal of Haematology
Steven Feins, Weimin Kong, Erik F Williams, Michael C Milone, Joseph A Fraietta
Chimeric antigen receptor (CAR) T cell therapy represents a major advancement in personalized cancer treatment. In this strategy, a patient's own T cells are genetically engineered to express a synthetic receptor that binds a tumor antigen. CAR T cells are then expanded for clinical use and infused back into the patient's body to attack and destroy chemotherapy-resistant cancer. Dramatic clinical responses and high rates of complete remission have been observed in the setting of CAR T cell therapy of B cell malignancies...
January 25, 2019: American Journal of Hematology
Junlin Yao, Dalam Ly, Dzana Dervovic, Linan Fang, Jong Bok Lee, Hyeonjeong Kang, Yu-Hui Wang, Nhu-An Pham, Hongming Pan, Ming-Sound Tsao, Li Zhang
BACKGROUND: The advents of novel immunotherapies have revolutionized the treatment of cancer. Adoptive cellular therapies using chimeric antigen receptor T (CAR-T) cells have achieved remarkable clinical responses in B cell leukemia and lymphoma but the effect on solid tumors including lung cancer is limited. Here we present data on the therapeutic potential of allogeneic CD3+ CD4- CD8- double negative T (DNT) cells as a new cellular therapy for the treatment of lung cancer and underlying mechanisms...
January 22, 2019: Journal for Immunotherapy of Cancer
Stacie Ittershagen, Solveig Ericson, Lamis Eldjerou, Ali Shojaee, Eric Bleickardt, Manisha Patel, Tetiana Taran, Oezlem Anak, Charlene Hall, Mimi Leung, Deborah Roccoberton, Florence Salmon, Miriam Fuchs, Vadim Romanov, David Lebwohl
PURPOSE OF REVIEW: We describe the significant technological leap from bench to bedside that was achieved through a strong academic-industry collaboration between dedicated clinicians and researchers at the University of Pennsylvania, the Children's Hospital of Philadelphia, and Novartis to commercialize the chimeric antigen receptor T cell (CAR-T) therapy tisagenlecleucel (CTL019; Kymriah®; Novartis Pharma AG, Basel, Switzerland). RECENT FINDINGS: Tisagenlecleucel was the first CAR-T therapy and the first gene therapy to receive US Food and Drug Administration approval in 2017, with an initial indication for pediatric and young adult patients with relapsed or refractory (r/r) acute lymphoblastic leukemia, followed by approval in May 2018 for a second indication in adult patients with r/r diffuse large B cell lymphoma...
January 21, 2019: Current Hematologic Malignancy Reports
Renyu Zhang, Zhao Zhang, Zekun Liu, Ding Wei, Xiaodong Wu, Huijie Bian, Zhinan Chen
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. This malignancy is associated with poor prognosis and high mortality. Novel approaches for prolonging the overall survival of patients with advanced HCC are urgently needed. The antitumor activities of adoptive cell transfer therapy (ACT), such as strategies based on tumor-infiltrating lymphocytes and cytokine-induced killer cells, are more effective than those of traditional strategies. Currently, chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved numerous breakthroughs in the treatment of hematological malignancies, including relapsed or refractory lymphoblastic leukemia and refractory large B-cell lymphoma...
January 18, 2019: Frontiers of Medicine
Yuta Ito, Shinichi Makita, Kensei Tobinai
Peripheral T-cell lymphoma (PTCL) is a relatively rare, heterogeneous group of mature T-cell neoplasms generally associated with poor prognosis, partly because of refractoriness against conventional cytotoxic chemotherapies. To improve the outcome of patients with PTCL, the clinical development of several novel agents is currently under investigation. Areas covered: Since the first approval of pralatrexate (dihydrofolate reductase inhibitor) by the US Food and Drug Administration, belinostat, romidepsin (histone deacetylase inhibitors), and brentuximab vedotin (anti-CD30 antibody-drug conjugate) have been approved in the US, and many other countries...
March 2019: Expert Opinion on Biological Therapy
Haiyuan Yu, Jun Pan, Zhicheng Guo, Chunhua Yang, Lijun Mao
In recent years, the, chimeric antigen receptor T (CAR-T) cell therapy as an adoptive immunotherapy has received great attention and made great breakthroughs. CAR-T cells show great specificity, targeting, and less major histocompatibility complex restriction in tumor immunotherapy, significantly different from traditional T cells. In spite of the progress of CART-T technology in the treatment of lymphoma, leukemia, and other blood system tumor, there are still many difficulties in the treatment of solid tumors by CAR-T technology...
2019: OncoTargets and Therapy
Apostolia Papalexandri, Maria Karypidou, Evangelia Stalika, Konstantina Kotta, Tasoula Touloumenidou, Panagiota Zerva, Angeliki Paleta, Despina Mallouri, Ioannis Batsis, Ioanna Sakellari, Ioannis Kotsianidis, Achilles Anagnostopoulos, Anastasia Hadzidimitriou, Dimitris Margaritis, Kostas Stamatopoulos
Rituximab is known to affect T cell immune responses. We and others have reported expansions of T large granular lymphocytes (T-LGLs) in lymphoma patients after Rituximab. We report here the immunogenetic profiling of the T cell receptor (TR) gene repertoire in 14 patients who received Rituximab post allo-HCT and explore clinicobiological correlations. All experienced antigenic triggers, CMV, EBV re-activation and chronic GvHD and had been treated with Rituximab. Skewing of TRBV genes was observed: 3 TRBV genes accounted for half of the repertoire...
January 17, 2019: Leukemia & Lymphoma
Adam Levin, Nirav N Shah
Chimeric antigen receptor modified T (CAR-T) cell therapy against the CD19 antigen has revolutionized the therapeutic landscape for patients with relapsed, refractory B cell non-Hodgkin lymphoma (NHL). Currently there are two FDA approved products (axicabtagene ciloleucel and tisagenlecleucel) for B cell NHL, with several other constructs under clinical investigation. This review will focus on the clinical outcomes, toxicity profile, and differences among candidate CD19 CAR-T cell products for major subtypes of B cell NHL including diffuse large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma...
January 16, 2019: American Journal of Hematology
Jessica Michie, Paul A Beavis, Andrew J Freeman, Stephin J Vervoort, Kelly M Ramsbottom, Vignesh Narasimhan, Emily J Lelliott, Najoua Lalaoui, Robert G Ramsay, Ricky W Johnstone, John Silke, Phillip K Darcy, Ilia Voskoboinik, Conor J Kearney, Jane Oliaro
Chimeric antigen receptor (CAR) T-cell therapy has proven successful in the treatment of hematological malignancies, notably acute lymphoblastic leukemia and B-cell lymphoma. However, the efficacy of CAR T cells against solid tumors is poor, likely due to tumor-associated immunosuppression. Here, we demonstrated that antagonizing the "inhibitor of apoptosis proteins" with the clinical smac-mimetic, birinapant, significantly enhanced the antitumor activity of CAR T cells in a tumor necrosis factor (TNF)-dependent manner...
February 2019: Cancer Immunology Research
Rajat K Das, Lauren Vernau, Stephan A Grupp, David M Barrett
Translational data on chimeric antigen receptor (CAR) T cell trials indicates the presence of naive T cells in the pre-manufacture product is important to clinical response and persistence. In anticipation of developing CAR trials for other tumors, we investigated the T cell distribution from children with solid tumors and lymphomas at diagnosis and after every cycle of chemotherapy. We found that patients with T cells enriched for naive and stem central memory cells expanded well in vitro, but the majority of tumor types showed chemotherapy related depletion of early lineage cells with a corresponding decline in successful ex vivo stimulation response...
January 10, 2019: Cancer Discovery
Francesco Ceppi, Raffaele Renella, Manuel Diezi, Marc Ansari, Michel A Duchosal, Caroline Arber, Lana Kandalaft, George Coukos, Maja Beck-Popovic
Fighting leukemia using the immune system (antibodies, lymphocytes) is an old idea, which has already been fulfilled in allogeneic bone marrow transplantation. Indeed, the effectiveness of the transplant depends on the action of the donor lymphocytes. To limit the adverse effects on bystander organs (graft-versus-host disease), autologous T cells can be engineered to express synthetic chimeric antigen receptors (CARs) with artificially redirected antigen specificity. Autologous T cells engineered to express a CAR targeting CD19 have shown unprecedented efficacy in clinical trials for relapsed/refractory B-cell leukemias and lymphomas...
January 9, 2019: Revue Médicale Suisse
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