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https://www.readbyqxmd.com/read/29226797/axicabtagene-ciloleucel-car-t-cell-therapy-in-refractory-large-b-cell-lymphoma
#1
Sattva S Neelapu, Frederick L Locke, Nancy L Bartlett, Lazaros J Lekakis, David B Miklos, Caron A Jacobson, Ira Braunschweig, Olalekan O Oluwole, Tanya Siddiqi, Yi Lin, John M Timmerman, Patrick J Stiff, Jonathan W Friedberg, Ian W Flinn, Andre Goy, Brian T Hill, Mitchell R Smith, Abhinav Deol, Umar Farooq, Peter McSweeney, Javier Munoz, Irit Avivi, Januario E Castro, Jason R Westin, Julio C Chavez, Armin Ghobadi, Krishna V Komanduri, Ronald Levy, Eric D Jacobsen, Thomas E Witzig, Patrick Reagan, Adrian Bot, John Rossi, Lynn Navale, Yizhou Jiang, Jeff Aycock, Meg Elias, David Chang, Jeff Wiezorek, William Y Go
Background In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy. Methods In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine...
December 10, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29226781/a-milestone-for-car-t-cells
#2
Eric Tran, Dan L Longo, Walter J Urba
No abstract text is available yet for this article.
December 10, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29226764/chimeric-antigen-receptor-t-cells-in-refractory-b-cell-lymphomas
#3
Stephen J Schuster, Jakub Svoboda, Elise A Chong, Sunita D Nasta, Anthony R Mato, Özlem Anak, Jennifer L Brogdon, Iulian Pruteanu-Malinici, Vijay Bhoj, Daniel Landsburg, Mariusz Wasik, Bruce L Levine, Simon F Lacey, Jan J Melenhorst, David L Porter, Carl H June
Background Patients with diffuse large B-cell lymphoma or follicular lymphoma that is refractory to or that relapses after immunochemotherapy and transplantation have a poor prognosis. High response rates have been reported with the use of T cells modified by chimeric antigen receptor (CAR) that target CD19 in B-cell cancers, although data regarding B-cell lymphomas are limited. Methods We used autologous T cells that express a CD19-directed CAR (CTL019) to treat patients with diffuse large B-cell lymphoma or follicular lymphoma that had relapsed or was refractory to previous treatments...
December 10, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29222400/nkg2d-based-car-t-cells-and-radiotherapy-exert-synergistic-efficacy-in-glioblastoma
#4
Tobias Weiss, Michael Weller, Matthias Guckenberger, Charles L Sentman, Patrick Roth
Chimeric antigen receptor (CAR) T cell therapy is an emerging immunotherapy against several malignancies including glioblastoma, the most common and most aggressive malignant primary brain tumor in adults. The challenges in solid tumor immunotherapy comprise heterogenously expressed tumor target antigens and restricted trafficking of CAR T cells to and impaired long-term persistence at the tumor site, as well as the unaddressed integration of CAR T cell therapy into conventional anti-cancer treatments. We addressed these questions using a NKG2D-based chimeric antigen receptor construct (chNKG2D) in fully immunocompetent orthotopic glioblastoma mouse models...
December 8, 2017: Cancer Research
https://www.readbyqxmd.com/read/29213269/safety-and-immunogenicity-of-malaria-vectored-vaccines-given-with-routine-expanded-program-on-immunization-vaccines-in-gambian-infants-and-neonates-a-randomized-controlled-trial
#5
Victorine A Mensah, Sophie Roetynck, Ebrima K Kanteh, Georgina Bowyer, Amy Ndaw, Francis Oko, Carly M Bliss, Ya Jankey Jagne, Riccardo Cortese, Alfredo Nicosia, Rachel Roberts, Flavia D'Alessio, Odile Leroy, Babacar Faye, Beate Kampmann, Badara Cisse, Kalifa Bojang, Stephen Gerry, Nicola K Viebig, Alison M Lawrie, Ed Clarke, Egeruan B Imoukhuede, Katie J Ewer, Adrian V S Hill, Muhammed O Afolabi
Background: Heterologous prime-boost vaccination with chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) encoding multiple epitope string thrombospondin-related adhesion protein (ME-TRAP) has shown acceptable safety and promising immunogenicity in African adult and pediatric populations. If licensed, this vaccine could be given to infants receiving routine childhood immunizations. We therefore evaluated responses to ChAd63 MVA ME-TRAP when co-administered with routine Expanded Program on Immunization (EPI) vaccines...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29212954/inhibition-of-akt-signaling-uncouples-t-cell-differentiation-from-expansion-for-receptor-engineered-adoptive-immunotherapy
#6
Christopher A Klebanoff, Joseph G Crompton, Anthony J Leonardi, Tori N Yamamoto, Smita S Chandran, Robert L Eil, Madhusudhanan Sukumar, Suman K Vodnala, Jinhui Hu, Yun Ji, David Clever, Mary A Black, Devikala Gurusamy, Michael J Kruhlak, Ping Jin, David F Stroncek, Luca Gattinoni, Steven A Feldman, Nicholas P Restifo
Adoptive immunotherapies using T cells genetically redirected with a chimeric antigen receptor (CAR) or T cell receptor (TCR) are entering mainstream clinical practice. Despite encouraging results, some patients do not respond to current therapies. In part, this phenomenon has been associated with infusion of reduced numbers of early memory T cells. Herein, we report that AKT signaling inhibition is compatible with CAR and TCR retroviral transduction of human T cells while promoting a CD62L-expressing central memory phenotype...
December 7, 2017: JCI Insight
https://www.readbyqxmd.com/read/29209570/car-t-cell-immunotherapy-of-met-expressing-malignant-mesothelioma
#7
Thivyan Thayaparan, Roseanna M Petrovic, Daniela Y Achkova, Tomasz Zabinski, David M Davies, Astero Klampatsa, Ana C Parente-Pereira, Lynsey M Whilding, Sjoukje Jc van der Stegen, Natalie Woodman, Michael Sheaff, Jennifer R Cochran, James F Spicer, John Maher
Mesothelioma is an incurable cancer for which effective therapies are required. Aberrant MET expression is prevalent in mesothelioma, although targeting using small molecule-based therapeutics has proven disappointing. Chimeric antigen receptors (CARs) couple the HLA-independent binding of a cell surface target to the delivery of a tailored T-cell activating signal. Here, we evaluated the anti-tumor activity of MET re-targeted CAR T-cells against mesothelioma. Using immunohistochemistry, MET was detected in 67% of malignant pleural mesotheliomas, most frequently of epithelioid or biphasic subtype...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29209061/car-t-cells-the-narrow-path-between-hope-and-bankruptcy
#8
EDITORIAL
C Chabannon, J Kuball, E Mcgrath, P Bader, C Dufour, A Lankester, G W Basak, S Montoto, A Nagler, J A Snowden, J Styczynski, R F Duarte, N Kröger, M Mohty
No abstract text is available yet for this article.
December 2017: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/29208775/cns-endothelial-cell-activation-emerges-as-a-driver-of-car-t-cell-associated-neurotoxicity
#9
COMMENT
Crystal L Mackall, David B Miklos
<b/> Central nervous system (CNS) toxicity associated with chimeric antigen receptor-based therapeutics has emerged as a significant cause of morbidity and mortality, and insights into the pathophysiology of this syndrome have been lacking. A new study provides evidence that cytokine-induced CNS endothelial cell activation leading to disruption of the blood-brain barrier plays an early and critical role in this phenomenon. These insights provide new opportunities for targeted therapeutic interventions to modulate endothelial cell activation...
December 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29207878/cd20-cd19-bispecific-car-t-cells-for-the-treatment-of-b-cell-malignancies
#10
Alexandra Martyniszyn, Ann-Christin Krahl, Maya C André, Andreas A Hombach, Hinrich Abken
The treatment of leukemia/lymphoma by chimeric antigen receptor (CAR) redirected T cells with specificity for CD19 induced complete remissions in the majority of patients with a realistic hope for cure. However, recent follow-up data revealed a substantial risk of relapse through leukemic cells which lack the CAR targeted antigen. In this situation a bispecific CAR with binding domains for CD19 and CD20 is aimed at recognizing also leukemic cells with only one cognate antigen. The anti-CD20-CD19 bispecific CAR induced a full T cell response upon engagement of CD19 or CD20 on target cells showing a true "OR" gate recognition in redirecting T cell activation...
December 5, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/29207115/current-status-and-future-prospects-of-the-strategy-of-combining-car%C3%A2-t-with-pd%C3%A2-1-blockade-for-antitumor-therapy-review
#11
Jinjing Xu, Qing Zhang, Kang Tian, Haiyu Wang, Hong Yin, Junnian Zheng
The immune system serves an important role in controlling and eradicating malignant cells. Immunotherapy for treating tumors has received much attention in recent years due to its marked effect. There are two approaches which currently lead this field: Chimeric antigen receptor‑modified T‑cell immunotherapy (CAR‑T) and programmed cell death protein-1 blockade (PD‑1 blockade). CAR‑T has emerged as a promising regimen for the treatment of a range of types of cancer, including chronic lymphoid leukemia and neuroblastoma, with studies of long term remission in certain patients...
November 22, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29203440/car-t-cells-and-combination-therapies-what-s-next-in-the-immunotherapy-revolution
#12
Maria C Ramello, Eric B Haura, Daniel Abate-Daga
Cancer immunotherapies are dramatically reshaping the clinical management of oncologic patients. For many of these therapies, the guidelines for administration, monitoring, and management of associated toxicities are still being established. This is especially relevant for adoptively transferred, genetically-modified T cells, which have unique pharmacokinetic properties, due to their ability to replicate and persist long-term, following a single administration. Furthermore, in the case of CAR-T cells, the use of synthetic immune receptors may impact signaling pathways involved in T cell function and survival in unexpected ways...
December 1, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29200207/human-antibody-based-chemically-induced-dimerizers-for-cell-therapeutic-applications
#13
Zachary B Hill, Alexander J Martinko, Duy P Nguyen, James A Wells
Chemically induced dimerizers (CIDs) have emerged as one of the most powerful tools for artificially regulating signaling pathways in cells; however, currently available CID systems lack the properties desired for use in regulating cellular therapies. Here, we report the development of human antibody-based chemically induced dimerizers (AbCIDs) from known small-molecule-protein complexes by selecting for synthetic antibodies that recognize the chemical epitope created by the bound small molecule. We demonstrate this concept by generating three antibodies that are highly selective for the BCL-xL-ABT-737 complex compared to BCL-xL alone...
December 4, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29196452/constant-attack-on-t-cell-lymphomas
#14
Gabriel K Griffin
A proof-of-principle study generates CAR-T cells against T cell lymphoma by selectively targeting the T cell receptor β-chain constant region 1.
December 1, 2017: Science Immunology
https://www.readbyqxmd.com/read/29189429/new-developments-in-immunotherapy-for-pediatric-solid-tumors
#15
Liora M Schultz, Robbie Majzner, Kara L Davis, Crystal Mackall
PURPOSE OF REVIEW: Building upon preclinical advances, we are uncovering immunotherapy strategies that are translating into improved outcomes in tumor subsets. Advanced pediatric solid tumors carry poor prognoses and resultant robust efforts to apply immunotherapy advances to pediatric solid tumors are in progress. Here, we discuss recent developments in the field using mAb and mAb-based therapies including checkpoint blockade and chimeric antigen receptors (CARs). RECENT FINDINGS: The pediatric solid tumor mAb experience targeting the diganglioside, GD2, for patients with neuroblastoma has been the most compelling to date...
November 20, 2017: Current Opinion in Pediatrics
https://www.readbyqxmd.com/read/29186979/the-need-for-immune-biomarkers-for-treatment-prognosis-and-response-in-genitourinary-malignancies
#16
Susan F Slovin
Immune biomarkers encompass a wide range of blood-borne and cell-associated molecules whose detection or expression may change in response to an immune therapy. These immune therapies encompass a range of platforms including autologous cellular products, in other words, dendritic cells, prime boost DNA vaccines, chimeric antigen receptor (CAR) T cells and checkpoint inhibitors. The response to checkpoint inhibitors by a particular cancer may not be necessarily associated with a change in a particular immune biomarker; other immune biomarkers are needed to assess their association with treatment response or a change in the biology that can impact on the immunologic milieu...
November 30, 2017: Biomarkers in Medicine
https://www.readbyqxmd.com/read/29186654/treatment-with-allogenic-mesenchymal-stromal-cells-in-a-murine-model-of-systemic-lupus-erythematosus
#17
Chiara Tani, Sabrina Vagnani, Linda Carli, Francesca Querci, Anja A Kühl, Simone Spieckermann, Constanze Pamela Cieluch, Simone Pacini, Rita Fazzi, Marta Mosca
Objective: Pre-clinical and uncontrolled studies in patients with systemic lupus erythematosus (SLE) showed that mesenchymal stromal cells (MSCs) have a potential therapeutic role in refractory cases. The optimal therapeutic strategy in these patients remain to be elucidated. Our aim was to test the hypothesis that repeated administrations of 1×106/kg body weight of allogenic MSCs, that is a significantly lower dosage with respect to the fixed 1×106 MSC used in animal models, can be effective in improving the clinical course of a murine SLE model...
November 30, 2017: International Journal of Stem Cells
https://www.readbyqxmd.com/read/29185393/chimeric-switch-receptor-switching-for-improved-adoptive-t-cell-therapy-against-cancers
#18
Johan Ck Tay, Shijun Zha, Shu Wang
Adoptive T-lymphocyte transfer-based immunotherapy for cancers has seen huge leaps with both CARs and engineered TCRs. Despite this, issues relating to safety and efficacy persist. To address this, chimeric switch receptors have been created to reverse the outcomes of their original signaling pathways in order to confer immune cells with the ability to overcome the immunosuppressive tumor microenvironment and to allow them to have greater in vivo persistence. Activating switch receptors exploit the inhibitory molecules expressed by cancer cells to further stimulate the tumor antigen-specific T lymphocytes...
December 2017: Immunotherapy
https://www.readbyqxmd.com/read/29183891/tem8-antxr1-specific-car-t-cells-as-a-targeted-therapy-for-triple-negative-breast-cancer
#19
Tiara T Byrd, Kristen Fousek, Antonella Pignata, Christopher Szot, Heba Samaha, Steven Seaman, Lacey Dobrolecki, Vita Salsman, Htoo Zarni Oo, Kevin Bielamowicz, Daniel Landi, Nino Rainusso, John M Hicks, Suzanne Powell, Matthew L Baker, Winfried S Wels, Joachim Koch, Poul Hb Sorensen, Benjamin Deneen, Matthew J Ellis, Michael T Lewis, Meenakshi Hegde, Bradley S Fletcher, Brad St Croix, Nabil Ahmed
Triple-negative breast cancer (TNBC) is an aggressive disease lacking targeted therapy. In this study, we developed a CAR T cell-based immunotherapeutic strategy to target TEM8, a marker initially defined on endothelial cells in colon tumors that was discovered recently to be upregulated in TNBC. CAR T cells were developed that upon specific recognition of TEM8 secreted immunostimulatory cytokines and killed tumor endothelial cells as well as TEM8-positive TNBC cells. Notably, the TEM8 CAR T cells targeted breast cancer stem-like cells, offsetting the formation of mammospheres relative to non-transduced T cells...
November 28, 2017: Cancer Research
https://www.readbyqxmd.com/read/29180536/high-affinity-gd2-specific-car-t-cells-induce-fatal-encephalitis-in-a-preclinical-neuroblastoma-model
#20
Sarah A Richman, Selene Nunez-Cruz, Babak Moghimi, Lucy Z Li, Zachary T Gershenson, Zissimos Mourelatos, David M Barrett, Stephan A Grupp, Michael C Milone
The GD2 ganglioside, which is abundant on the surface of neuroblastoma cells, is targeted by an FDA-approved therapeutic monoclonal antibody and is an attractive tumor-associated antigen for cellular immunotherapy. Chimeric antigen receptor (CAR)-modified T cells can have potent antitumor activity in B-cell malignancies, and trials to harness this cytolytic activity toward GD2 in neuroblastoma are underway. In an effort to enhance the antitumor activity of CAR T cells that target GD2, we generated variant CAR constructs predicted to improve the stability and the affinity of the GD2-binding, 14G2a-based, single-chain variable fragment (scFv) of the CAR, and compared their properties in vivo...
November 27, 2017: Cancer Immunology Research
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