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CAR-T and brain tumor

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https://www.readbyqxmd.com/read/30076299/the-chimeric-tac-receptor-co-opts-the-t-cell-receptor-yielding-robust-anti-tumor-activity-without-toxicity
#1
Christopher W Helsen, Joanne A Hammill, Vivian W C Lau, Kenneth A Mwawasi, Arya Afsahi, Ksenia Bezverbnaya, Lisa Newhook, Danielle L Hayes, Craig Aarts, Bojana Bojovic, Galina F Denisova, Jacek M Kwiecien, Ian Brain, Heather Derocher, Katy Milne, Brad H Nelson, Jonathan L Bramson
Engineering T cells with chimeric antigen receptors (CARs) is an effective method for directing T cells to attack tumors, but may cause adverse side effects such as the potentially lethal cytokine release syndrome. Here the authors show that the T cell antigen coupler (TAC), a chimeric receptor that co-opts the endogenous TCR, induces more efficient anti-tumor responses and reduced toxicity when compared with past-generation CARs. TAC-engineered T cells induce robust and antigen-specific cytokine production and cytotoxicity in vitro, and strong anti-tumor activity in a variety of xenograft models including solid and liquid tumors...
August 3, 2018: Nature Communications
https://www.readbyqxmd.com/read/30041899/hyaluronic-acid-based-low-viscosity-hydrogel-as-a-novel-carrier-for-convection-enhanced-delivery-of-car-t-cells
#2
Ahmet F Atik, Carter M Suryadevara, Ryan M Schweller, Jennifer L West, Patrick Healy, James E Herndon Ii, Kendra L Congdon, Luis Sanchez-Perez, Roger E McLendon, Gerald E Archer, Peter Fecci, John H Sampson
Convection Enhanced Delivery (CED) infuses therapeutic agents directly into the intracranial area continuously under pressure. The convection improves the distribution of therapeutics such as those aimed at brain tumors. Although CED successfully delivers small therapeutic agents, this technique fails to effectively deliver cells largely due to cell sedimentation during delivery. To overcome this limitation, we have developed a low viscosity hydrogel (LVHydrogel), which is capable of retaining cells in suspension...
July 21, 2018: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
https://www.readbyqxmd.com/read/29975720/development-of-third-generation-anti-egfrviii-chimeric-t-cells-and-egfrviii-expressing-artificial-antigen-presenting-cells-for-adoptive-cell-therapy-for-glioma
#3
Ayguen Sahin, Carlos Sanchez, Szofia Bullain, Peter Waterman, Ralph Weissleder, Bob S Carter
Glioblastoma multiforme (GBM) is the most aggressive and deadly form of adult brain cancer. Despite of many attempts to identify potential therapies for this disease, including promising cancer immunotherapy approaches, it remains incurable. To address the need of improved persistence, expansion, and optimal antitumor activity of T-cells in the glioma milieu, we have developed an EGFRvIII-specific third generation (G3-EGFRvIII) chimeric antigen receptor (CAR) that expresses both co-stimulatory factors CD28 and OX40 (MR1-CD8TM-CD28-OX40-CD3ζ)...
2018: PloS One
https://www.readbyqxmd.com/read/29872570/temozolomide-lymphodepletion-enhances-car-abundance-and-correlates-with-antitumor-efficacy-against-established-glioblastoma
#4
Carter M Suryadevara, Rupen Desai, Melissa L Abel, Katherine A Riccione, Kristen A Batich, Steven H Shen, Pakawat Chongsathidkiet, Patrick C Gedeon, Aladine A Elsamadicy, David J Snyder, James E Herndon, Patrick Healy, Gary E Archer, Bryan D Choi, Peter E Fecci, John H Sampson, Luis Sanchez-Perez
Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is an effective immunotherapy for B-cell malignancies but has failed in some solid tumors clinically. Intracerebral tumors may pose challenges that are even more significant. In order to devise a treatment strategy for patients with glioblastoma (GBM), we evaluated CARs as a monotherapy in a murine model of GBM. CARs exhibited poor expansion and survival in circulation and failed to treat syngeneic and orthotopic gliomas. We hypothesized that CAR engraftment would benefit from host lymphodepletion prior to immunotherapy and that this might be achievable by using temozolomide (TMZ), which is standard treatment for these patients and has lymphopenia as its major side effect...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29728514/positron-emission-tomography-of-adoptively-transferred-chimeric-antigen-receptor-t-cells-with-zirconium-89-oxine
#5
Michael Ryan Weist, Renate Starr, Brenda Aguilar, Junie Chea, Joshua Miles, Erasmus Poku, Ethan Gerdts, Xin Yang, Saul Priceman, Stephen Forman, David Colcher, Christine Brown, John Shively
CAR T cell therapy is a promising clinical approach for reducing tumor progression and prolonging patient survival. However, improvements in both the safety and potency of CAR T cell therapy demand quantitative imaging techniques to determine the distribution of cells following adoptive transfer. The purpose of this study is to optimize zirconium-89-oxine (89 Zr-oxine) labeling of chimeric antigen receptor (CAR) T cells and evaluate positron emission tomography (PET) as a platform for imaging adoptively transferred CAR T cells...
May 4, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/29662203/potent-antitumor-efficacy-of-anti-gd2-car-t-cells-in-h3-k27m-diffuse-midline-gliomas
#6
Christopher W Mount, Robbie G Majzner, Shree Sundaresh, Evan P Arnold, Meena Kadapakkam, Samuel Haile, Louai Labanieh, Esther Hulleman, Pamelyn J Woo, Skyler P Rietberg, Hannes Vogel, Michelle Monje, Crystal L Mackall
Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10 , and recent results suggest benefit in central nervous system malignancies11-13 . Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2...
May 2018: Nature Medicine
https://www.readbyqxmd.com/read/29552579/optimizing-epha2-car-t-cells-for-the-adoptive-immunotherapy-of-glioma
#7
Zhongzhen Yi, Brooke L Prinzing, Felicia Cao, Stephen Gottschalk, Giedre Krenciute
Glioblastoma is the most aggressive primary brain tumor in humans and is virtually incurable with conventional therapies. Chimeric antigen receptor (CAR) T cell therapy targeting the glioblastoma antigen EphA2 is an attractive approach to improve outcomes because EphA2 is expressed highly in glioblastoma but only at low levels in normal brain tissue. Building upon our previous findings in this area, we generated and evaluated a panel of EphA2-specific CARs. We demonstrate here that T cells expressing CD28...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29540359/cspg4-shows-promise-for-glioblastoma-car-t-therapy
#8
(no author information available yet)
CAR T cells directed against CSPG4 limit the growth of brain tumors in cultured neurospheres and glioma xenograft mouse models, with no signs of immune escape owing to loss of antigen expression.
May 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29222400/nkg2d-based-car-t-cells-and-radiotherapy-exert-synergistic-efficacy-in-glioblastoma
#9
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 anticancer treatments. We addressed these questions using a NKG2D-based chimeric antigen receptor construct (chNKG2D) in fully immunocompetent orthotopic glioblastoma mouse models...
February 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29180536/high-affinity-gd2-specific-car-t-cells-induce-fatal-encephalitis-in-a-preclinical-neuroblastoma-model
#10
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 under way. 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 We included the E101K mutation of GD2 scFv (GD2-E101K) that has enhanced antitumor activity against a GD2+ human neuroblastoma xenograft in vivo However, this enhanced antitumor efficacy in vivo was concomitantly associated with lethal central nervous system (CNS) toxicity comprised of extensive CAR T-cell infiltration and proliferation within the brain and neuronal destruction...
January 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29167820/engineering-chimeric-antigen-receptor-t-cells-to-treat-glioblastoma
#11
Bryan D Choi, Donald M O'Rourke, Marcela V Maus
Immunotherapy has emerged as a promising strategy for glioblastoma (GBM), a disease that remains universally fatal despite currently available standard-of-care. Adoptive T cell therapy has been shown to produce potent antitumor immunity while obviating the need for traditional antigen presentation and primary immune responses. Chimeric antigen receptors (CARs) are specialized molecules that can be expressed on the surface of T cells allowing for redirected cytotoxicity against tumor antigens of interest. To date, the application of CAR T cells for GBM has been relatively limited, in large part due to a dearth of well-described tumor specific antigens that are both homogenously and frequently expressed...
August 2017: The journal of targeted therapies in cancer
https://www.readbyqxmd.com/read/29158268/car-t-cell-therapies-in-glioblastoma-a-first-look
#12
Denis Migliorini, Pierre-Yves Dietrich, Roger Stupp, Gerald P Linette, Avery D Posey, Carl H June
Glioblastoma is an aggressive malignancy with a poor prognosis. The current standard of care for newly diagnosed glioblastoma patients includes surgery to the extent, temozolomide combined with radiotherapy, and alternating electric fields therapy. After recurrence, there is no standard therapy and survival is less than 9 months. Recurrent glioblastoma offers a unique opportunity to investigate new treatment approaches in a malignancy known for remarkable genetic heterogeneity, an immunosuppressive microenvironment, and a partially permissive anatomic blood-brain barrier...
February 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29061641/regional-delivery-of-chimeric-antigen-receptor-engineered-t-cells-effectively-targets-her2-breast-cancer-metastasis-to-the-brain
#13
Saul J Priceman, Dileshni Tilakawardane, Brook Jeang, Brenda Aguilar, John P Murad, Anthony K Park, Wen-Chung Chang, Julie R Ostberg, Josh Neman, Rahul Jandial, Jana Portnow, Stephen J Forman, Christine E Brown
Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease...
January 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29016929/trivalent-car-t-cells-overcome-interpatient-antigenic-variability-in-glioblastoma
#14
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 2 glioma antigens offsets antigen escape and enhances T-cell effector functions, the interpatient variability in surface antigen expression between patients hinders the clinical impact of targeting 2 antigen pairs. This study addresses targeting 3 antigens using a single CAR T-cell product for broader application...
March 27, 2018: Neuro-oncology
https://www.readbyqxmd.com/read/28754782/car-t-cells-infiltrate-brain-target-tumors
#15
(no author information available yet)
A single dose of peripherally infused CAR T cells cleared antigen-expressing tumor cells in patients with glioblastoma, a 10-person trial found. However, the cells also triggered an immunosuppressive microenvironment, and the target antigen, EGFR variant III, wasn't expressed uniformly in patients' tumors.
September 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28651374/cd70-a-novel-target-of-car-t-cell-therapy-for-gliomas
#16
Linchun Jin, Haitao Ge, Yu Long, Changlin Yang, Yifan Emily Chang, Luyan Mu, Elias J Sayour, Gabriel De Leon, Qiong J Wang, James C Yang, Paul S Kubilis, Hongbo Bao, Songsong Xia, Dunyue Lu, Yingjun Kong, Li Hu, Yujiao Shang, Chencheng Jiang, Jing Nie, Shimin Li, Yunhe Gu, Jiahang Sun, Duane A Mitchell, Zhiguo Lin, Jianping Huang
Background: Cancer immunotherapy represents a promising treatment approach for malignant gliomas but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified cluster of differentiation (CD)70 as a novel immunosuppressive ligand and glioma target. Methods: Normal tissues derived from 52 different organs and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression...
January 10, 2018: Neuro-oncology
https://www.readbyqxmd.com/read/28649003/targeting-egfrviii-for-glioblastoma-multiforme
#17
REVIEW
Ju Yang, Jing Yan, Baorui Liu
Glioblastoma multiforme (GBM) is the most progressive primary brain tumor. Targeting a novel and highly specific tumor antigen is one of the strategies to overcome tumors. EGFR variant III (EGFRvIII) is present in 25%-33% of all patients with GBM and is exclusively expressed on tumor tissue cells. Currently, there are various approaches to target EGFRvIII, including CAR T-cell therapy, therapeutic vaccines, antibodies, and Bi-specific T Cell Engager. In this review, we focus on the preclinical and clinical findings of targeting EGFRvIII for GBM...
September 10, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28550091/transgenic-expression-of-il15-improves-antiglioma-activity-of-il13r%C3%AE-2-car-t-cells-but-results-in-antigen-loss-variants
#18
Giedre Krenciute, Brooke L Prinzing, Zhongzhen Yi, Meng-Fen Wu, Hao Liu, Gianpietro Dotti, Irina V Balyasnikova, Stephen Gottschalk
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing GBM-specific chimeric antigen receptors (CAR) is an attractive approach to improve outcomes. Although CAR T cells targeting GBM antigens, such as IL13 receptor subunit α2 (IL13Rα2), HER2, and EGFR variant III (EGFRvIII), have had antitumor activity in preclinical models, early-phase clinical testing has demonstrated limited antiglioma activity...
July 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28426845/her2-specific-chimeric-antigen-receptor-modified-virus-specific-t-cells-for-progressive-glioblastoma-a-phase-1-dose-escalation-trial
#19
Nabil Ahmed, Vita Brawley, Meenakshi Hegde, Kevin Bielamowicz, Mamta Kalra, Daniel Landi, Catherine Robertson, Tara L Gray, Oumar Diouf, Amanda Wakefield, Alexia Ghazi, Claudia Gerken, Zhongzhen Yi, Aidin Ashoori, Meng-Fen Wu, Hao Liu, Cliona Rooney, Gianpietro Dotti, Adrian Gee, Jack Su, Yvonne Kew, David Baskin, Yi Jonathan Zhang, Pamela New, Bambi Grilley, Milica Stojakovic, John Hicks, Suzanne Z Powell, Malcolm K Brenner, Helen E Heslop, Robert Grossman, Winfried S Wels, Stephen Gottschalk
Importance: Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited. Objective: To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)-modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity. Design, Setting, and Participants: In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children's Hospital, patients with progressive HER2-positive glioblastoma were enrolled between July 25, 2011, and April 21, 2014...
August 1, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28302023/anti-egfrviii-chimeric-antigen-receptor-modified-t-cells-for-adoptive-cell-therapy-of-glioblastoma
#20
REVIEW
Pei-Pei Ren, Ming Li, Tian-Fang Li, Shuang-Yin Han
Glioblastoma (GBM) is one of the most devastating brain tumors with poor prognosis and high mortality. Although radical surgical treatment with subsequent radiation and chemotherapy can improve the survival, the efficacy of such regimens is insufficient because the GBM cells can spread and destroy normal brain structures. Moreover, these non-specific treatments may damage adjacent healthy brain tissue. It is thus imperative to develop novel therapies to precisely target invasive tumor cells without damaging normal tissues...
2017: Current Pharmaceutical Design
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