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CAR T-Cell

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https://www.readbyqxmd.com/read/29025771/endothelial-activation-and-blood-brain-barrier-disruption-in-neurotoxicity-after-adoptive-immunotherapy-with-cd19-car-t-cells
#1
Juliane Gust, Kevin A Hay, Laïla-Aïcha Hanafi, Daniel Li, David Myerson, Luis F Gonzalez-Cuyar, Cecilia Yeung, W Conrad Liles, Mark Wurfel, Jose A Lopez, Junmei Chen, Dominic Chung, Susanna Harju-Baker, Tahsin Özpolat, Kathleen R Fink, Stanley R Riddell, David G Maloney, Cameron J Turtle
Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19(+) cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability...
October 12, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29025766/car-t-therapy-targeting-icam-1-eliminates-advanced-human-thyroid-tumors
#2
Irene M Min, Enda Shevlin, Yogindra Vedvyas, Marjan Zaman, Brian Wyrwas, Theresa Scognamiglio, Maureen D Moore, Weibin Wang, Susan Park, Spencer Park, Suraj Panjwani, Katherine D Gray, Andrew B Tassler, Rasa Zarnegar, Thomas J Fahey, Moonsoo M Jin
PURPOSE: Poorly-differentiated thyroid cancer and anaplastic thyroid cancer (ATC) are rare yet lethal malignancies with limited treatment options. Many malignant tumors including papillary thyroid cancer (PTC) and ATC are associated with increased expression of ICAM-1, providing a rationale for utilizing ICAM-1-targeting agents for the treatment of aggressive cancer. We developed a third-generation CAR targeting ICAM-1 to leverage adoptive T cell therapy as a new treatment modality. EXPERIMENTAL DESIGN: ICAM-1 CAR T cells were applied on multiple malignant and non-malignant target cells to investigate specific target cell death and 'off-tumor' toxicity in vitro...
October 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29025266/the-abcs-of-immunotherapy-for-adult-patients-with-b-cell-acute-lymphoblastic-leukemia
#3
Troy Z Horvat, Amanda N Seddon, Adebayo Ogunniyi, Amber C King, Larry W Buie, Ryan J Daley
OBJECTIVE: To review the pharmacology, efficacy, and safety of Food and Drug Administration approved and promising immunotherapy agents used in the treatment of acute lymphoblastic leukemia (ALL). DATA SOURCES: A literature search was performed of PubMed and MEDLINE databases (1950 to July 2017) and of abstracts from the American Society of Hematology and the American Society of Clinical Oncology. Searches were performed utilizing the following key terms: rituximab, blinatumomab, inotuzumab, ofatumumab, obinutuzumab, Blincyto, Rituxan, Gazyva, Arzerra, CAR T-cell, and chimeric antigen receptor (CAR)...
October 1, 2017: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/29024301/emerging-principles-from-the-clinical-application-of-chimeric-antigen-receptor-car-t-cell-therapies-for-b-cell-malignancies
#4
REVIEW
Michael D Jain, Marco L Davila
Gene-engineered T cell therapies are soon to be FDA approved for at least two types of B cell malignancies in pediatric and adult patients, in the form of CD19 targeted chimeric antigen receptor T (CAR T) cell therapy. This represents a triumph of a true bench to bedside clinical translation of a therapy that was conceived of in the early 1990s. Clinical results have demonstrated efficacious responses in patients with the CD19 positive diseases B cell acute lymphoblastic leukemia (B-ALL) and diffuse large B cell lymphoma (DLBCL)...
October 11, 2017: Stem Cells
https://www.readbyqxmd.com/read/29023549/supraphysiologic-control-over-hiv-1-replication-mediated-by-cd8-t-cells-expressing-a-re-engineered-cd4-based-chimeric-antigen-receptor
#5
Rachel S Leibman, Max W Richardson, Christoph T Ellebrecht, Colby R Maldini, Joshua A Glover, Anthony J Secreto, Irina Kulikovskaya, Simon F Lacey, Sarah R Akkina, Yanjie Yi, Farida Shaheen, Jianbin Wang, Keith A Dufendach, Michael C Holmes, Ronald G Collman, Aimee S Payne, James L Riley
HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs...
October 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29017060/integrating-proteomics-and-transcriptomics-for-systematic-combinatorial-chimeric-antigen-receptor-therapy-of-aml
#6
Fabiana Perna, Samuel H Berman, Rajesh K Soni, Jorge Mansilla-Soto, Justin Eyquem, Mohamad Hamieh, Ronald C Hendrickson, Cameron W Brennan, Michel Sadelain
Chimeric antigen receptor (CAR) therapy targeting CD19 has yielded remarkable outcomes in patients with acute lymphoblastic leukemia. To identify potential CAR targets in acute myeloid leukemia (AML), we probed the AML surfaceome for overexpressed molecules with tolerable systemic expression. We integrated large transcriptomics and proteomics datasets from malignant and normal tissues, and developed an algorithm to identify potential targets expressed in leukemia stem cells, but not in normal CD34(+)CD38(-) hematopoietic cells, T cells, or vital tissues...
October 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29016929/trivalent-car-t-cells-overcome-interpatient-antigenic-variability-in-glioblastoma
#7
Kevin Bielamowicz, Kristen Fousek, Tiara T Byrd, Hebatalla Samaha, Malini Mukherjee, Nikita Aware, Meng-Fen Wu, Jordan S Orange, Pavel Sumazin, Tsz-Kwong Man, Sujith K Joseph, Meenakshi Hegde, Nabil Ahmed
Background: Glioblastoma (GBM) is the most common primary malignant brain cancer, and is currently incurable. Chimeric Antigen Receptor (CAR) T-cells have shown promise in GBM treatment. While we have shown that combinatorial targeting of two glioma antigens offsets antigen escape and enhances T-cell effector functions, the inter-patient variability in surface antigen expression between patients hinders the clinical impact of targeting two antigen pairs. This study addresses targeting 3 antigens using a single CAR T-cell product for broader application...
September 16, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28993773/targeting-malignant-brain-tumors-with-antibodies
#8
REVIEW
Rok Razpotnik, Neža Novak, Vladka Čurin Šerbec, Uros Rajcevic
Antibodies have been shown to be a potent therapeutic tool. However, their use for targeting brain diseases, including neurodegenerative diseases and brain cancers, has been limited, particularly because the blood-brain barrier (BBB) makes brain tissue hard to access by conventional antibody-targeting strategies. In this review, we summarize new antibody therapeutic approaches to target brain tumors, especially malignant gliomas, as well as their potential drawbacks. Many different brain delivery platforms for antibodies have been studied such as liposomes, nanoparticle-based systems, cell-penetrating peptides (CPPs), and cell-based approaches...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28988742/chimeric-antigen-receptor-t-cell-therapy-for-hematological-malignancies-and-solid-tumors-clinical-data-to-date-current-limitations-and-perspectives
#9
REVIEW
J Gauthier, I Yakoub-Agha
Progress in our understanding of basic immunology along with the advent of bioengineering technologies have made possible the production of human T-cells expressing Chimeric Antigen Receptors (CAR T-cells). These CAR T-cells are designed to target specific antigens presented by cancer cells. Once CARs are bound to these antigens, CAR T-cells get activated and can initiate potent anti-tumor effects. We will here overview the bioengineering advances which made possible the clinical application of CAR T-cell therapy...
October 5, 2017: Current Research in Translational Medicine
https://www.readbyqxmd.com/read/28983300/human-tregs-made-antigen-specific-by-gene-modification-the-power-to-treat-autoimmunity-and-antidrug-antibodies-with-precision
#10
REVIEW
Patrick R Adair, Yong Chan Kim, Ai-Hong Zhang, Jeongheon Yoon, David W Scott
Human regulatory CD4(+) T cells (Tregs) are potent immunosuppressive lymphocytes responsible for immune tolerance and homeostasis. Since the seminal reports identifying Tregs, vast research has been channeled into understanding their genesis, signature molecular markers, mechanisms of suppression, and role in disease. This research has opened the doors for Tregs as a potential therapeutic for diseases and disorders such as multiple sclerosis, type I diabetes, transplantation, and immune responses to protein therapeutics, like factor VIII...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28978841/treatment-of-relapsed-or-refractory-acute-lymphoblastic-leukemia
#11
Kiyotoshi Imai
Most patients with adult acute lymphoblastic leukemia (ALL) undergo relapse, despite the achievement of complete remission with chemotherapy. Among patients with relapsed or refractory ALL, remission rates are 18-44% with the use of standard salvage chemotherapy, but the duration of remission is short. A major goal in this population is to induce remission with a sufficient duration to prepare for stem cell transplantation. The poor outcomes and lack of durable responses seen with conventional chemotherapy have led to the development of several novel agents, including clofarabine and nelarabine...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28978471/tonic-4-1bb-costimulation-in-chimeric-antigen-receptors-impedes-t-cell-survival-and-is-vector-dependent
#12
Diogo Gomes-Silva, Malini Mukherjee, Madhuwanti Srinivasan, Giedre Krenciute, Olga Dakhova, Yueting Zheng, Joaquim M S Cabral, Cliona M Rooney, Jordan S Orange, Malcolm K Brenner, Maksim Mamonkin
Antigen-independent tonic signaling by chimeric antigen receptors (CARs) can increase differentiation and exhaustion of T cells, limiting their potency. Incorporating 4-1BB costimulation in CARs may enable T cells to resist this functional exhaustion; however, the potential ramifications of tonic 4-1BB signaling in CAR T cells remain unclear. Here, we found that tonic CAR-derived 4-1BB signaling can produce toxicity in T cells via continuous TRAF2-dependent activation of the nuclear factor κB (NF-κB) pathway and augmented FAS-dependent cell death...
October 3, 2017: Cell Reports
https://www.readbyqxmd.com/read/28978241/treating-hematological-malignancies-with-cell-therapy-where-are-we-now
#13
Elisa Landoni, Barbara Savoldo
Adoptive cell therapy (ACT) is becoming an increasingly successful and widespread form of treatment for different types of cancer. Compared to chemotherapy or monoclonal antibodies, ACT is an active biological strategy, with infused immune cells featuring dynamic migration, expansion and long-term persistence properties. ACT in hematological malignancies offered the initial proof of principle of the feasibility for this innovative 'live-drug'. Areas covered: In this review, the authors summarize the clinical results achieved with two specific strategies in hematological malignancies: chimeric antigen receptor (CAR) and T cell receptor (transgenic TCR) redirected T cells...
October 5, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28977984/driving-better-and-safer-her2-specific-cars-for-cancer-therapy
#14
Xianqiang Liu, Nan Zhang, Huan Shi
Given the clinical efficacy of chimeric antigen receptor (CAR)-based therapy in hematological malignancies, CAR T-cell therapy for a number of solid tumors has been actively investigated. Human epidermal growth factor receptor 2 (HER2) is a well-established therapeutic target in breast, as well as other types of cancer. However, HER2 CAR T cells pose a risk of lethal toxicity including cytokine release syndrome from "on-target, off-tumor" recognition of HER2. In this review, we summarize the development of conventional HER2 CAR technology, the alternative selection of CAR hosts, the novel HER2 CAR designs, clinical studies and toxicity...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28975930/immunotherapy-tisagenlecleucel-the-first-approved-car-t-cell-therapy-implications-for-payers-and-policy-makers
#15
Vinay Prasad
No abstract text is available yet for this article.
October 4, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28974431/adenovirotherapy-delivering-cytokine-and-checkpoint-inhibitor-augments-car-t-cells-against-metastatic-head-and-neck-cancer
#16
Amanda Rosewell Shaw, Caroline E Porter, Norihiro Watanabe, Kiyonori Tanoue, Andrew Sikora, Stephen Gottschalk, Malcolm K Brenner, Masataka Suzuki
In solid tumors, chimeric antigen receptor (CAR)-modified T cells must overcome the challenges of the immunosuppressive tumor microenvironment. We hypothesized that pre-treating tumors with our binary oncolytic adenovirus (CAd), which produces local oncolysis and expresses immunostimulatory molecules, would enhance the antitumor activity of HER2-specific CAR T cells, which alone are insufficient to cure solid tumors. We tested multiple cytokines in conjunction with PD-L1-blocking antibody and found that Ad-derived IL-12p70 prevents the loss of HER2...
September 14, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28971751/anti-cd-19-and-anti-cd-20-car-modified-t-cells-for-b-cell-malignancies-a-systematic-review-and-meta-analysis
#17
Irbaz Bin Riaz, Umar Zahid, Muhammad Umar Kamal, Muhammad Husnain, Ali McBride, Anh Hua, Auon Abbas Hamadani, Laeth George, Ali Zeeshan, Qurat-Ul-Ain Riaz Sipra, Ammad Raina, Bushra Rahman, Soham Puvvada, Faiz Anwer
Chimeric antigen receptor modified T cells targeting CD19 and CD20 have shown activity in Phase I, II trials of patients with hematological malignancies. We conducted a systematic review and meta-analysis of all published clinical trials studying the role of efficacy as well as safety of CD-19 and CD-20 chimeric antigen receptor-T therapy for B-cell hematologic malignancies. A total of 16 studies with 195 patients were identified. The pooled analysis showed an overall response rate of 61% (118/195) with complete response of 42% (81/195) and partial response of 19% (37/195)...
September 2017: Immunotherapy
https://www.readbyqxmd.com/read/28969098/car-t-cell-therapy-in-ovarian-cancer-from-the-bench-to-the-bedside
#18
REVIEW
Xinxin Zhu, Han Cai, Ling Zhao, Li Ning, Jinghe Lang
Ovarian cancer (OC) is the most lethal gynecological malignancy and is responsible for most gynecological cancer deaths. Apart from conventional surgery, chemotherapy, and radiotherapy, chimeric antigen receptor-modified T (CAR-T) cells as a representative of adoptive cellular immunotherapy have received considerable attention in the research field of cancer treatment. CARs combine antigen specificity and T-cell-activating properties in a single fusion molecule. Several preclinical experiments and clinical trials have confirmed that adoptive cell immunotherapy using typical CAR-engineered T cells for OC is a promising treatment approach with striking clinical efficacy; moreover, the emerging CAR-Ts targeting various antigens also exert great potential...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28964527/gene-therapy-with-the-sleeping-beauty-transposon-system
#19
REVIEW
Partow Kebriaei, Zsuzsanna Izsvák, Suneel A Narayanavari, Harjeet Singh, Zoltán Ivics
The widespread clinical implementation of gene therapy requires the ability to stably integrate genetic information through gene transfer vectors in a safe, effective, and economical manner. The latest generation of Sleeping Beauty (SB) transposon vectors fulfills these requirements, and may overcome limitations associated with viral gene transfer vectors and transient nonviral gene delivery approaches that are prevalent in ongoing clinical trials. The SB system enables high-level stable gene transfer and sustained transgene expression in multiple primary human somatic cell types, thereby representing a highly attractive gene transfer strategy for clinical use...
September 27, 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/28960810/cancer-immunotherapy-using-car-t-cells-from-the-research-bench-to-the-assembly-line
#20
REVIEW
Diogo Gomes-Silva, Carlos A Ramos
The focus of cancer treatment has recently shifted towards targeted therapies, including immunotherapy, which allow better individualization of care and are hoped to increase the probability of success for patients. Specifically, T cells genetically modified to express chimeric antigen receptors (CARs; CAR-T cells) have generated exciting results. Recent clinical successes with this cutting-edge therapy have helped to push CAR-T cells towards approval for wider use. However, several limitations need to be addressed before the widespread use of CAR-T cells as a standard treatment...
September 27, 2017: Biotechnology Journal
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