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CAR-T and brain tumor

Christopher T Petersen, Giedre Krenciute
High grade gliomas (HGG) comprise a heterogeneous group of brain malignancies with dismal prognosis. Current standard-of-care includes radiation, chemotherapy, and surgical resection when possible. Despite advances in each of these treatment modalities, survival rates for pediatric and adult HGG patients has remained largely unchanged over the course of several years. This is in stark contrast to the significant survival increases seen recently for a variety of hematological and other solid malignancies. The introduction and widespread use of immunotherapies have contributed significantly to these survival increases, and as such these therapies have been explored for use in the treatment of HGG...
2019: Frontiers in Oncology
Javier Redondo-Muñoz, Angeles García-Pardo, Joaquin Teixidó
The trafficking of neoplastic cells represents a key process that contributes to progression of hematologic malignancies. Diapedesis of neoplastic cells across endothelium and perivascular cells is facilitated by adhesion molecules and chemokines, which act in concert to tightly regulate directional motility. Intravital microscopy provides spatio-temporal views of neoplastic cell trafficking, and is crucial for testing and developing therapies against hematologic cancers. Multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia (ALL) are hematologic malignancies characterized by continuous neoplastic cell trafficking during disease progression...
2019: Frontiers in Immunology
Robbie G Majzner, Johanna L Theruvath, Anandani Nellan, Sabine Heitzeneder, Yongzhi Cui, Christopher W Mount, Skyler P Rietberg, Miles H Linde, Peng Xu, Christopher Rota, Elena Sotillo, Louai Labanieh, Daniel W Lee, Rimas J Orentas, Dimiter S Dimitrov, Zhongyu Zhu, Brad St Croix, Alberto Delaidelli, Alla Sekunova, Ezio Bonvini, Siddhartha S Mitra, Martha M Quezado, Ravindra Majeti, Michelle Monje, Poul Hb Sorensen, John M Maris, Crystal L Mackall
PURPOSE: Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T cell therapy of pediatric solid tumors, including those arising in the central nervous system...
January 17, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Bryan D Choi, Marcela V Maus, Carl H June, John H Sampson
Glioblastoma (GBM) is a devastating disease with an extremely poor prognosis. Immune therapy via adoptive cell transfer (ACT), especially with T cells engineered to express chimeric antigen receptors (CARs), represents a particularly promising approach. Despite the recent success of CAR T cells for blood cancers, the question remains whether this powerful anti-cancer therapy will ultimately work for brain tumors, and if the primary immunologic challenges in this disease-which include antigenic heterogeneity, immune suppression and T-cell exhaustion-can be adequately addressed...
November 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Antonia Rotolo, Valentina S Caputo, Monika Holubova, Nicoleta Baxan, Olivier Dubois, Mohammed Suhail Chaudhry, Xiaolin Xiao, Katerina Goudevenou, David S Pitcher, Kyriaki Petevi, Carolina Kachramanoglou, Sandra Iles, Kikkeri Naresh, John Maher, Anastasios Karadimitris
Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival...
October 8, 2018: Cancer Cell
(no author information available yet)
In a recent study, researchers investigated why brain cancers are impervious to T cells, and used their findings to create reengineered T cells that are better able to move into tumors. Their "homing system" could improve CAR T-cell therapies for brain cancers, including glioblastoma and medulloblastoma.
November 2018: Cancer Discovery
Christopher DeRenzo, Giedre Krenciute, Stephen Gottschalk
Adoptive cell therapy with genetically modified T cells holds the promise to improve outcomes for children with recurrent/refractory solid tumors and has the potential to reduce treatment complications for all patients. Although T cells that express chimeric antigen receptors (CARs) specific for CD19 have had remarkable success for B-cell-derived malignancies, which has led to their approval by the U.S. Food and Drug Administration, CAR T cells have been less effective for solid tumors and brain tumors. Lack of efficacy is most likely multifactorial, but heterogeneous antigen expression; limited migration of T cells to tumor sites; and the immunosuppressive, hostile tumor microenvironment have emerged as major roadblocks that must be addressed...
May 23, 2018: American Society of Clinical Oncology Educational Book
Sanne W Ten Broeke, Heleen M van der Klift, Carli M J Tops, Stefan Aretz, Inge Bernstein, Daniel D Buchanan, Albert de la Chapelle, Gabriel Capella, Mark Clendenning, Christoph Engel, Steven Gallinger, Encarna Gomez Garcia, Jane C Figueiredo, Robert Haile, Heather L Hampel, John L Hopper, Nicoline Hoogerbrugge, Magnus von Knebel Doeberitz, Loic Le Marchand, Tom G W Letteboer, Mark A Jenkins, Annika Lindblom, Noralane M Lindor, Arjen R Mensenkamp, Pål Møller, Polly A Newcomb, Theo A M van Os, Rachel Pearlman, Marta Pineda, Nils Rahner, Egbert J W Redeker, Maran J W Olderode-Berends, Christophe Rosty, Hans K Schackert, Rodney Scott, Leigha Senter, Liesbeth Spruijt, Verena Steinke-Lange, Manon Suerink, Stephen Thibodeau, Yvonne J Vos, Anja Wagner, Ingrid Winship, Frederik J Hes, Hans F A Vasen, Juul T Wijnen, Maartje Nielsen, Aung Ko Win
PURPOSE: Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants...
October 10, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Lisa R Sun, Stacy Cooper
Neurological complications resulting from childhood cancer treatments are common. Treatment for childhood neoplastic disorders is often multimodal and may include procedures, cranial irradiation, chemotherapy, transplant, and immunotherapy, each of which carries distinct neurological risks. Procedures, such as lumbar punctures, are commonly used in this population for diagnostic purposes as well as intrathecal medication administration. Surgery is associated with an array of potential neurological complications, with posterior fossa syndrome being a common cause of morbidity in pediatric brain tumor patients after neurosurgical resection...
August 2018: Pediatric Neurology
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
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...
October 2018: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
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
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
Michael R Weist, Renate Starr, Brenda Aguilar, Junie Chea, Joshua K Miles, Erasmus Poku, Ethan Gerdts, Xin Yang, Saul J Priceman, Stephen J Forman, David Colcher, Christine E Brown, John E Shively
Chimeric antigen receptor (CAR) T cell therapy is a promising clinical approach for reducing tumor progression and prolonging patient survival. However, improvements in both the safety and the potency of CAR T cell therapy demand quantitative imaging techniques to determine the distribution of cells after adoptive transfer. The purpose of this study was to optimize 89 Zr-oxine labeling of CAR T cells and evaluate PET as a platform for imaging adoptively transferred CAR T cells. Methods: CAR T cells were labeled with 0-1...
October 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
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
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
(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
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
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
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
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