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https://www.readbyqxmd.com/read/29789639/fludarabine-and-neurotoxicity-in-engineered-t-cell-therapy
#1
Kate L Lowe, Crystal L Mackall, Elliot Norry, Rafael Amado, Bent K Jakobsen, Gwendolyn Binder
Adoptive T-cell therapy, incorporating engineered T cell receptors (TCRs) or chimeric antigen receptors (CARs), target tumor antigens with high affinity and specificity. To increase the potency of adoptively transferred T cells, patients are conditioned with lymphodepleting chemotherapy regimens prior to adoptive T-cell transfer (ACT), and data suggest that fludarabine is an important component of an effective regimen. In a recent clinical trial using CAR-T cells engineered to target the CD19 B-cell antigen to treat acute lymphoblastic leukemia, JCAR-015 (NCT02535364), two patient deaths due to cerebral edema led to trial suspension...
May 7, 2018: Gene Therapy
https://www.readbyqxmd.com/read/29780254/are-ovarian-cancer-stem-cells-the-target-for-innovative-immunotherapy
#2
REVIEW
Liang Wang, Tianmin Xu, Manhua Cui
Cancer stem cells (CSCs), a subpopulation of cancer cells with the ability of self-renewal and differentiation, are believed to be responsible for tumor generation, progression, metastasis, and relapse. Ovarian cancer, the most malignant gynecological cancer, has consistent pathology behavior with CSC model, which suggests that therapies based on ovarian cancer stem cells (OCSCs) can gain a more successful prognosis. Much evidence has proved that epigenetic mechanism played an important role in tumor formation and sustainment...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29772559/gitr-domain-inside-car-co-stimulates-activity-of-car-t-cells-against-cancer
#3
Vita M Golubovskaya, Robert Berahovich, Qumiao Xu, Hua Zhou, Shirley Xu, Jasper Guan, Hizkia Harto, Le Li, Lijun Wu
T cells expressing Chimeric antigen receptors or CAR-T cells are used as a novel treatment against hematological and solid cancers. In this report, we designed CAR with glucocorticoid-induced TNFR-related protein (GITR) co-stimulatory domain to study its ability to co-activate CAR-T cells. EGFR-GITR-CD3 CAR-T cells were cytotoxic against EGFR-positive: pancreatic and ovarian cancer cells but not against EGFR-negative cancer cells. The cytotoxic activity of EGFR-GITR-CD3 CAR-T cells was comparable or better than EGFR-28-CD3 or EGFR-41BB-CD3 CAR-T cells...
June 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/29772538/targeting-fibroblast-activation-protein-in-cancer-prospects-and-caveats
#4
Petr Busek, Rosana Mateu, Michal Zubal, Lenka Kotackova, Aleksi Sedo
Fibroblast activation protein (FAP, seprase) is a serine protease with post-proline dipeptidyl peptidase and endopeptidase enzymatic activity. FAP is upregulated in several tumor types, while its expression in healthy adult tissues is scarce. FAP molecule itself and FAP+ stromal cells play an important although probably context-dependent and tumor type-specific pathogenetic role in tumor progression. We provide an overview of FAP expression under both physiological and pathological conditions with focus on human malignancies...
June 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/29769444/glioblastoma-targeted-cd4-car-t-cells-mediate-superior-antitumor-activity
#5
Dongrui Wang, Brenda Aguilar, Renate Starr, Darya Alizadeh, Alfonso Brito, Aniee Sarkissian, Julie R Ostberg, Stephen J Forman, Christine E Brown
Chimeric antigen receptor-modified (CAR-modified) T cells have shown promising therapeutic effects for hematological malignancies, yet limited and inconsistent efficacy against solid tumors. The refinement of CAR therapy requires an understanding of the optimal characteristics of the cellular products, including the appropriate composition of CD4+ and CD8+ subsets. Here, we investigated the differential antitumor effect of CD4+ and CD8+ CAR T cells targeting glioblastoma-associated (GBM-associated) antigen IL-13 receptor α2 (IL13Rα2)...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769201/in-vitro-priming-of-adoptively-transferred-t-cells-with-a-ror%C3%AE-agonist-confers-durable-memory-and-stemness-in-vivo
#6
Xiao Hu, Kinga Majchrzak, Xikui Liu, Megan M Wyatt, Chauncey Spooner, Jacques Moisan, Weiping Zou, Laura L Carter, Chrystal M Paulos
Adoptive T cell transfer therapy is an FDA-approved treatment for leukemia that relies on the ex vivo expansion and re-infusion of a patient's immune cells, which can be engineered with a chimeric antigen receptor (CAR) for more efficient tumor recognition. Type 17 T cells, controlled transcriptionally by RORγ, have been reported to mediate potent anti-tumor effects superior to those observed with conventionally expanded T cells. Here we demonstrate that addition of a synthetic, small molecule RORγ agonist during ex vivo expansion potentiates the anti-tumor activity of human Th17 and Tc17 cells redirected with a CAR...
May 16, 2018: Cancer Research
https://www.readbyqxmd.com/read/29769134/advances-on-chimeric-antigen-receptor-modified-t-cell-therapy-for-oncotherapy
#7
REVIEW
Yanyu Pang, Xiaoyang Hou, Chunsheng Yang, Yanqun Liu, Guan Jiang
Tumor treatment is still complicated in the field of medicine. Tumor immunotherapy has been the most interesting research field in cancer therapy. Application of chimeric antigen receptor T (CAR-T) cell therapy has recently achieved excellent clinical outcome in patients, especially those with CD19-positive hematologic malignancies. This phenomenon has induced intense interest to develop CAR-T cell therapy for cancer, especially for solid tumors. However, the performance of CAR-T cell treatment in solid tumor is not as satisfactory as that in hematologic disease...
May 16, 2018: Molecular Cancer
https://www.readbyqxmd.com/read/29768210/engineered-tumor-targeted-t-cells-mediate-enhanced-anti-tumor-efficacy-both-directly-and-through-activation-of-the-endogenous-immune-system
#8
Mauro P Avanzi, Oladapo Yeku, Xinghuo Li, Dinali P Wijewarnasuriya, Dayenne G van Leeuwen, Kenneth Cheung, Hyebin Park, Terence J Purdon, Anthony F Daniyan, Matthew H Spitzer, Renier J Brentjens
Chimeric antigen receptor (CAR) T cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T cells, antigen-negative relapses, and impairment by an immunosuppressive tumor microenvironment. Improvements in CAR T cell design are required to enhance clinical efficacy, as well as broaden the applicability of this technology...
May 15, 2018: Cell Reports
https://www.readbyqxmd.com/read/29766234/the-severe-cytokine-release-syndrome-in-phase-i-trials-of-cd19-car-t-cell-therapy-a-systematic-review
#9
REVIEW
Zhen Jin, Rufang Xiang, Kai Qing, Xiaoyang Li, Yunxiang Zhang, Lining Wang, Hongming Zhu, Yuanfei Mao, Zizhen Xu, Junmin Li
CD19 chimeric antigen receptor (CAR) T cell therapy has shown impressive results in treating acute lymphoblastic leukemia (B-ALL), chronic lymphoblastic leukemia (B-CLL), and B-cell non-Hodgkin lymphoma (B-NHL) over the past few years. Meanwhile, the cytokine release syndrome (CRS), which could be moderate or even life-threatening, has emerged as the most significant adverse effect in the clinical course of this novel targeting immunotherapy. In this systematic review, we analyzed the incidence of severe CRS in 19 clinical trials selected from studies published between 2010 and 2017...
May 15, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29760047/nanoparticles-that-reshape-the-tumor-milieu-create-a-therapeutic-window-for-effective-t-cell-therapy-in-solid-malignancies
#10
Fan Zhang, Sirkka B Stephan, Chibawanye I Ene, Tyrel T Smith, Eric C Holland, Matthias T Stephan
A major obstacle to the success rate of chimeric antigen receptor (CAR-) T cell therapy against solid tumors is the microenvironment antagonistic to T cells that solid tumors create. Conventional checkpoint blockade can silence lymphocyte anti-survival pathways activated by tumors, but because they are systemic, these treatments disrupt immune homeostasis and induce autoimmune side effects. Thus, new technologies are required to remodel the tumor milieu without causing systemic toxicities. Here we demonstrate that targeted nanocarriers that deliver a combination of immune-modulatory agents can remove pro-tumor cell populations and simultaneously stimulate anti-tumor effector cells...
May 14, 2018: Cancer Research
https://www.readbyqxmd.com/read/29748183/aberrant-lck-signal-via-cd28-co-stimulation-augments-antigen-specific-functionality-and-tumor-control-by-redirected-t-cells-with-pd-1-blockade-in-humanized-mice
#11
Pratiksha Gulati, Julia Rühl, Abhilash Kannan, Magdalena Pircher, Petra Schuberth, Katarzyna Jozefa Nytko, Martin N Pruschy, Simon Sulser, Mark D Haefner, Shawn M Jensen, Alex Soltermann, Wolfgang Jungraithmayr, Maya Eisenring, Thomas Winder, Panagiotis Samaras, Annett Tabor, Rene Rs Stenger, Roger Stupp, Walter Weder, Christoph Renner, Christian Münz, Ulf Petrausch
PURPOSE: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. EXPERIMENTAL DESIGN: Fibroblast Activation Protein (FAP)-specific CARs with different co-stimulatory domains including CD28, Δ-CD28 (lacking lck binding moiety) or 4-1BB were established...
May 10, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29747685/car-t-cell-therapy-for-breast-cancer-harnessing-the-tumor-milieu-to-drive-t-cell-activation
#12
Pradip Bajgain, Supannikar Tawinwung, Lindsey D'Elia, Sujita Sukumaran, Norihiro Watanabe, Valentina Hoyos, Premal Lulla, Malcolm K Brenner, Ann M Leen, Juan F Vera
BACKGROUND: The adoptive transfer of T cells redirected to tumor via chimeric antigen receptors (CARs) has produced clinical benefits for the treatment of hematologic diseases. To extend this approach to breast cancer, we generated CAR T cells directed against mucin1 (MUC1), an aberrantly glycosylated neoantigen that is overexpressed by malignant cells and whose expression has been correlated with poor prognosis. Furthermore, to protect our tumor-targeted cells from the elevated levels of immune-inhibitory cytokines present in the tumor milieu, we co-expressed an inverted cytokine receptor linking the IL4 receptor exodomain with the IL7 receptor endodomain (4/7ICR) in order to transform the suppressive IL4 signal into one that would enhance the anti-tumor effects of our CAR T cells at the tumor site...
May 10, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29735365/human-cd19-targeted-mouse-t-cells-induce-b-cell-aplasia-and-toxicity-in-human-cd19-transgenic-mice
#13
Christopher A Pennell, Jessie L Barnum, Cameron S McDonald-Hyman, Angela Panoskaltsis-Mortari, Megan J Riddle, Zhengming Xiong, Michael Loschi, Govindarajan Thangavelu, Heather M Campbell, Meghan D Storlie, Yosef Refaeli, Scott N Furlan, Michael C Jensen, Leslie S Kean, Jeffrey S Miller, Jakub Tolar, Mark J Osborn, Bruce R Blazar
The clinical success of chimeric antigen receptor (CAR) T cell therapy for CD19+ B cell malignancies can be limited by acute toxicities and immunoglobulin replacement needs due to B cell aplasia from persistent CAR T cells. Life-threatening complications include cytokine release syndrome and neurologic adverse events, the exact etiologies of which are unclear. To elucidate the underlying toxicity mechanisms and test potentially safer CAR T cells, we developed a mouse model in which human CD19 (hCD19)-specific mouse CAR T cells were adoptively transferred into mice whose normal B cells express a hCD19 transgene at hemizygous levels...
April 7, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29730801/challenges-and-prospects-of-chimeric-antigen-receptor-t-cell-therapy-in-solid-tumors
#14
REVIEW
Vishal Jindal, Ena Arora, Sorab Gupta
Chimeric antigen receptor (CAR) T cell therapy is a novel and innovative immunotherapy. CAR-T cells are genetically engineered T cells, carrying MHC independent specific antigen receptor and co-stimulatory molecule which can activate an immune response to a cancer specific antigen. This therapy showed great results in hematological malignancies but were unable to prove their worth in solid tumors. Likely reasons for their failure are lack of antigens, poor trafficking, and hostile tumor microenvironment. Excessive amount of research is going on to improve the efficacy of CAR T cell therapy in solid tumors...
May 5, 2018: Medical Oncology
https://www.readbyqxmd.com/read/29730057/adoptive-t-cell-therapy-points-to-consider
#15
REVIEW
Cassian Yee
Adoptive Cell Therapy (ACT) has enjoyed a revival in recent years with the approval of CAR T cells for the treatment of patients with B cell malignancies. Advancing the use of adoptively transferred T cells for the treatment of patients with solid tumor and other hematologic malignancies however, will require addressing numerous effector cell intrinsic as well as tumor micro environmental hurdles and exploiting a broader ACT platform that includes not only engineered CAR-T cells, but also other forms of ACT including Endogenous T Cell (ETC) and Tumor-infiltrating Lymphocyte (TIL) therapy...
May 2, 2018: Current Opinion in Immunology
https://www.readbyqxmd.com/read/29729210/enhanced-car-t-cell-therapy-a-novel-approach-for-head-and-neck-cancers
#16
Songlin Wang, Zhao Zhu
Head and neck cancer that presents in locally advanced stages often results in a bad prognosis with an increased recurrence rate even after curative resections. Radiation therapy is then applied, with multiple side effects, as adjuvant regional therapy. Because of the high rate of recurrence and mortality, new therapies are needed for patients suffering from head and neck malignant tumors.CAR (chimeric antigen receptor) T cell therapy, which was first devised about 25 years ago, causes the killing or apoptosis of target tumor cells through inducing the secretion of cytokines and granzymes by T cells (Cheadle et al...
May 5, 2018: Oral Diseases
https://www.readbyqxmd.com/read/29728788/chimeric-antigen-receptor-t-cell-therapy-in-pancreatic-cancer-from-research-to-practice
#17
REVIEW
Vishal Jindal, Ena Arora, Muhammad Masab, Sorab Gupta
Chimeric antigen receptor (CAR) T cell therapy is genetically engineered tumor antigen-specific anticancer immunotherapy, which after showing great success in hematological malignancies is currently being tried in advanced solid tumors like pancreatic cancer. Immunosuppressive tumor microenvironment and dense fibrous stroma are some of the limitation in the success of this novel therapy. However, genetic modifications and combination therapy is the topic of the research to improve its efficacy. In this article, we summarize the current state of knowledge, limitations, and future prospects for CAR T cell therapy in pancreatic cancer...
May 4, 2018: Medical Oncology
https://www.readbyqxmd.com/read/29728514/positron-emission-tomography-of-adoptively-transferred-chimeric-antigen-receptor-t-cells-with-zirconium-89-oxine
#18
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/29728402/chimeric-antigen-receptor-modified-t-cells-cd19-and-the-road-beyond
#19
Alexander I Salter, Margot J Pont, Stanley R Riddell
The ability to harness a patient's immune system to target malignant cells is now transforming the treatment of many cancers, including hematologic malignancies. The adoptive transfer of T cells selected for tumor reactivity, or engineered with natural or synthetic receptors has emerged as an effective modality, even for patients with tumors that are refractory to conventional therapies. The most notable example of adoptive cell therapy is with T cells engineered to express synthetic chimeric antigen receptors (CARs) that reprogram their specificity to target CD19...
May 4, 2018: Blood
https://www.readbyqxmd.com/read/29727246/strategies-for-enhancing-adoptive-t-cell-immunotherapy-against-solid-tumors-using-engineered-cytokine-signaling-and-other-modalities
#20
Thomas Shum, Robert L Kruse, Cliona M Rooney
Cancer therapy has been transformed by the demonstration that tumor-specific T-cells can eliminate tumor cells in a clinical setting with minimal long-term toxicity. However, significant success in the treatment of leukemia and lymphoma with T-cells using native receptors or redirected with chimeric antigen receptors (CARs) has not been recapitulated in the treatment of solid tumors. This lack of success is likely related to the paucity of costimulatory and cytokine signaling available in solid tumors, in addition to a range of inhibitory mechanisms...
May 4, 2018: Expert Opinion on Biological Therapy
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