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https://www.readbyqxmd.com/read/28932644/romidepsin-alone-or-in-combination-with-anti-cd20-chimeric-antigen-receptor-expanded-natural-killer-cells-targeting-burkitt-lymphoma-in-vitro-and-in-immunodeficient-mice
#1
Yaya Chu, Ashlin Yahr, Brian Huang, Janet Ayello, Matthew Barth, Mitchell S Cairo
Facilitating the development of alternative targeted therapeutic strategies is urgently required to improve outcome or circumvent chemotherapy resistance in children, adolescents, and adults with recurrent/refractory de novo mature B-cell (CD20) non-Hodgkin lymphoma, including Burkitt lymphoma (BL). Romidepsin, a histone deacetylase inhibitor (HDACi), has been used to treat cutaneous T-cell lymphoma. We have demonstrated the significant anti-tumor effect of anti-CD20 chimeric antigen receptor (CAR) modified expanded peripheral blood natural killer (exPBNK) against rituximab-sensitive and -resistant BL...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28931402/recent-advances-of-bispecific-antibodies-in-solid-tumors
#2
REVIEW
Shengnan Yu, Anping Li, Qian Liu, Xun Yuan, Hanxiao Xu, Dechao Jiao, Richard G Pestell, Xinwei Han, Kongming Wu
Cancer immunotherapy is the most exciting advancement in cancer therapy. Similar to immune checkpoint blockade and chimeric antigen receptor T cell (CAR-T), bispecific antibody (BsAb) is attracting more and more attention as a novel strategy of antitumor immunotherapy. BsAb not only offers an effective linkage between therapeutics (e.g., immune effector cells, radionuclides) and targets (e.g., tumor cells) but also simultaneously blocks two different oncogenic mediators. In recent decades, a variety of BsAb formats have been generated...
September 20, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28924019/kinetics-and-biomarkers-of-severe-cytokine-release-syndrome-after-cd19-chimeric-antigen-receptor-modified-t-cell-therapy
#3
Kevin A Hay, Laïla-Aïcha Hanafi, Daniel Li, Juliane Gust, W Conrad Liles, Mark M Wurfel, José A López, Junmei Chen, Dominic Chung, Susanna Harju-Baker, Sindhu Cherian, Xueyan Chen, Stanley R Riddell, David G Maloney, Cameron J Turtle
Lymphodepletion chemotherapy followed by infusion of CD19-specific chimeric antigen receptor-modified T cells (CAR-T) has produced impressive antitumor responses in patients with refractory CD19(+) B cell malignancies, but is often associated with cytokine release syndrome (CRS). Our understanding of CRS continues to evolve, and identification of the kinetics of CRS and predictive clinical and laboratory biomarkers of severity are needed to evaluate strategies to mitigate toxicity. We report the clinical presentation and identify biomarkers of severe CRS in 133 adult patients who received CD19 CAR-T cells...
September 18, 2017: Blood
https://www.readbyqxmd.com/read/28912137/enhanced-cancer-immunotherapy-by-chimeric-antigen-receptor-modified-t-cells-engineered-to-secrete-checkpoint-inhibitors
#4
Pin Wang, Si Li, Natnaree Siriwon, Xiaoyang Zhang, Shuai Yang, Tao Jin, Feng He, Yu Jeong Kim, John Mac, Zhengfei Lu, Sijie Wang, Xiaolu Han
PURPOSE: Despite favorable responses of CAR-engineered T cell therapy in patients with hematologic malignancies, the outcome has been far from satisfactory in the treatment of solid tumors, partially owing to the development of an immunosuppressive tumor microenvironment. To overcome this limitation, we engineered CAR-T cells secreting checkpoint inhibitors (CPIs) targeting PD-1 (CAR.αPD1-T) and evaluated their efficacy in a human lung carcinoma xenograft mouse model. EXPERIMENTAL DESIGN: To evaluate the effector function and expansion capacity of CAR...
September 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28903456/tumor-reductive-therapies-and-antitumor-immunity
#5
REVIEW
Huiqin Guo, Kangla Tsung
Tumor reductive therapy is to reduce tumor burden through direct killing of tumor cells. So far, there is no report on the connection between antitumor immunity and tumor reductive therapies. In the last few years, a new category of cancer treatment, immunotherapy, emerged and they are categorized separately from classic cytotoxic treatments (chemo and radiation therapy). The most prominent examples include cellular therapies (LAK and CAR-T) and immune checkpoint inhibitors (anti-PD-1 and CTLA-4). Recent advances in clinical immunotherapy and our understanding of the mechanism behind them revealed that these therapies have a closer relationship with classic cancer treatments than we thought...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28900984/-targeted-therapy-combined-with-immunotherapy-in-gastrointestinal-stromal-tumor-a-new-era-of-hope-and-challenges
#6
Wenyi Zhao, Hui Cao
New immunotherapy represented by immune checkpoint inhibitor therapy and chimeric antigen receptor T-Cell immunotherapy (CAR-T) has already become hot trend in the treatment of malignant tumors. In gastrointestinal stromal tumor (GIST), with notable tumor-infiltrating immune cells existing in GIST tissues and immunological effects reported in imatinib mesylate (IM) treatment, the clinicians and researchers started to realize the possibilities of immunotherapy in GIST. Recent studies reported that PD-1/PD-L1 or CTLA-4 blockade may enhance the T-cell activity and anti-tumor effect of targeted therapy, which can be applied in advanced GIST, and anti-KIT CAR T-cells indicated a new immunotherapeutic targeted strategy for GIST patients with TKI resistance...
September 25, 2017: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
https://www.readbyqxmd.com/read/28880014/chimeric-antigen-receptor-car-transduced-natural-killer-cells-in-tumor-immunotherapy
#7
REVIEW
Yuan Hu, Zhi-Gang Tian, Cai Zhang
Natural killer (NK) cells are potential effector cells in cell-based cancer immunotherapy, particularly in the control of hematological malignancies. The chimeric antigen receptor (CAR) is an artificially modified fusion protein that consists of an extracellular antigen recognition domain fused to an intracellular signaling domain. T cells genetically modified with a CAR have demonstrated remarkable success in the treatment of hematological cancers. Compared to T cells, CAR-transduced NK cells (CAR-NK) exhibit several advantages, such as safety in clinical use, the mechanisms by which they recognize cancer cells, and their abundance in clinical samples...
September 7, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28874817/armored-car-t-cells-enhance-antitumor-efficacy-and-overcome-the-tumor-microenvironment
#8
Oladapo O Yeku, Terence J Purdon, Mythili Koneru, David Spriggs, Renier J Brentjens
Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy for the management of solid tumor malignancies. In ovarian cancer, this is in part due to an immunosuppressive cytokine and cellular tumor microenvironment which suppresses adoptively transferred T cells. We engineered an armored CAR T cell capable of constitutive secretion of IL-12, and delineate the mechanisms via which these CAR T cells overcome a hostile tumor microenvironment. In this report, we demonstrate enhanced proliferation, decreased apoptosis and increased cytotoxicity in the presence of immunosuppressive ascites...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28871274/paired-expression-analysis-of-tumor-cell-surface-antigens
#9
Rimas J Orentas, Sivasish Sindiri, Christine Duris, Xinyu Wen, Jianbin He, Jun S Wei, Jason Jarzembowski, Javed Khan
Adoptive immunotherapy with antibody-based therapy or with T cells transduced to express chimeric antigen receptors (CARs) is useful to the extent that the cell surface membrane protein being targeted is not expressed on normal tissues. The most successful CAR-based (anti-CD19) or antibody-based therapy (anti-CD20) in hematologic malignancies has the side effect of eliminating the normal B cell compartment. Targeting solid tumors may not provide a similar expendable marker. Beyond antibody to Her2/NEU and EGFR, very few antibody-based and no CAR-based therapies have seen broad clinical application for solid tumors...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28868758/programmed-cell-death-ligand-1-pd-l1-expression-is-not-a-predominant-feature-in-ewing-sarcomas
#10
Christian Spurny, Sareetha Kailayangiri, Silke Jamitzky, Bianca Altvater, Eva Wardelmann, Uta Dirksen, Jendrik Hardes, Wolfgang Hartmann, Claudia Rossig
BACKGROUND: Programmed cell death 1 (PD-1) receptor engagement on T cells by its ligand programmed cell death ligand 1 (PD-L1) is a key mechanism of immune escape, and antibody blockade of the interaction has emerged as an effective immunotherapeutic strategy in some cancers. The role and relevance of the PD-1 checkpoint in Ewing sarcoma (EwS) is not yet understood. PROCEDURE: Here, we investigated expression of PD-L1 and PD-1 in EwS by immunohistochemistry analysis of pretherapeutic tumor biopsies and in tumor xenografts following treatment with human T cells engineered to express a chimeric antigen receptor (CAR) against the tumor-associated antigen GD2 ...
September 4, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28862644/chimeric-antigen-receptor-car-t-cell-therapy-for-malignant-pleural-mesothelioma-mpm
#11
REVIEW
Astero Klampatsa, Andrew R Haas, Edmund K Moon, Steven M Albelda
Cancer immunotherapy has now become a recognized approach to treating cancers. In addition to checkpoint blockade, adoptive T cell transfer (ACT) using chimeric antigen receptors (CARs) has shown impressive clinical outcomes in leukemias and is now being explored in solid tumors. CARs are engineered receptors, stably or transiently transduced into T cells, that aim to enhance T cell effector function by recognizing and binding to a specific tumor-associated antigen. In this review, we provide a summary of CAR T cell preclinical studies and clinical trials for malignant pleural mesothelioma (MPM), a rare, locally invasive pleural cancer with poor prognosis...
September 1, 2017: Cancers
https://www.readbyqxmd.com/read/28862366/redirect-killer-t-cells-via-displaying-azido-sugar-for-tethering-ligands
#12
Weiling Wang, Zhiying Zhao, Ziwei Zhang, Chuanling Zhang, Sulong Xiao, Xinshan Ye, Lihe Zhang, Qing Xia, Demin Zhou
The genetic expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. To broaden the versatility of T cells as tumor-specific killers, we developed a non-genetic approach by which azide-containing sialic acids were metabolically incorporated to modify cellular sialyl glycans. Given displaying such a chemical moiety on T cells, small molecular ligands such as RGD and folate, as proof-of-concept, instead of supersized antibodies were clicked orthogonally, leading to highly selective, time- and dose-dependent cytotoxicity to integrin αvβ3- and folate receptor-positive cells, respectively...
September 1, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28860806/enhancement-of-antitumor-activity-by-using-a-fully-human-gene-encoding-a-single-chain-fragmented-antibody-specific-for-carcinoembryonic-antigen
#13
Hirotomo Shibaguchi, Naixiang Luo, Naoto Shirasu, Motomu Kuroki, Masahide Kuroki
Human leukocyte antigen and/or costimulatory molecules are frequently lacking in metastatic tumor cells, and thus tumor cells are able to escape from the immune system. Although lymphocytes with a chimeric antigen receptor (CAR) is a promising approach for overcoming this challenge in cancer immunotherapy, administration of modified T cells alone often demonstrates little efficacy in patients. Therefore, in order to enhance the antitumor activity of immune cells in the cancer microenvironment, we used lymphocytes expressing CAR in combination with a fusion protein of IL-2 that contained the single-chain fragmented antibody (scFv) specific for the carcinoembryonic antigen...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28843422/redirecting-t-cells-with-chimeric-antigen-receptor-car-for-the-treatment-of-childhood-acute-lymphoblastic-leukemia
#14
REVIEW
Andrea Biondi, Chiara F Magnani, Sarah Tettamanti, Giuseppe Gaipa, Ettore Biagi
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Nowadays the survival rate is around 85%. Nevertheless, an urgent clinical need is still represented by primary refractory and relapsed patients who do not significantly benefit from standard approaches, including chemo-radiotherapy and hematopoietic stem cell transplantation (HSCT). For this reason, immunotherapy has so far represented a challenging novel treatment opportunity, including, as the most validated therapeutic options, cancer vaccines, donor-lymphocyte infusions and tumor-specific immune effector cells...
August 23, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28841215/toll-like-receptor-2-costimulation-potentiates-the-antitumor-efficacy-of-car-t-cells
#15
Y Lai, J Weng, X Wei, L Qin, P Lai, R Zhao, Z Jiang, B Li, S Lin, S Wang, Q Wu, Z Tang, P Liu, D Pei, Y Yao, X Du, P Li
Chimeric antigen receptor (CAR) T-cell immunotherapies have shown unprecedented success in treating leukemia but limited clinical efficacy in solid tumors. Here, we generated 1928zT2 and m28zT2, targeting CD19 and mesothelin, respectively, by introducing the Toll/interleukin-1 receptor domain of Toll-like receptor 2 (TLR2) to 1928z and m28z. T cells expressing 1928zT2 or m28zT2 showed improved expansion, persistency and effector function against CD19(+) leukemia or mesothelin(+) solid tumors respectively in vitro and in vivo...
August 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28837818/current-strategies-to-improve-the-safety-of-chimeric-antigen-receptor-car-modified-t-cells
#16
REVIEW
Qi-Yu Yang, Jia-Dan Yang, Yong-Sheng Wang
Adoptive immunotherapy adopting chimeric antigen receptor (CAR) modified T cells has arisen attention as a hard-hitting therapy for numerous cancers. CARs are genetically engineered receptors that could stimulate tumor cytotoxicity once binding to the specific tumor epitopes. In spite of current noteworthy achievements in hematologic malignancies, the safety problems have aroused public awareness. In this review, we will focus on recent potential strategies to improve the security of CAR modified T cells.
August 28, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28837681/bispecific-t-cell-engager-bite%C3%A2-antibody-constructs-can-mediate-bystander-tumor-cell-killing
#17
Sandra L Ross, Marika Sherman, Patricia L McElroy, Julie A Lofgren, Gordon Moody, Patrick A Baeuerle, Angela Coxon, Tara Arvedson
For targets that are homogenously expressed, such as CD19 on cells of the B lymphocyte lineage, immunotherapies can be highly effective. Targeting CD19 with blinatumomab, a CD19/CD3 bispecific antibody construct (BiTE®), or with chimeric antigen receptor T cells (CAR-T) has shown great promise for treating certain CD19-positive hematological malignancies. In contrast, solid tumors with heterogeneous expression of the tumor-associated antigen (TAA) may present a challenge for targeted therapies. To prevent escape of TAA-negative cancer cells, immunotherapies with a local bystander effect would be beneficial...
2017: PloS One
https://www.readbyqxmd.com/read/28830878/constitutive-signaling-from-an-engineered-il-7-receptor-promotes-durable-tumor-elimination-by-tumor-redirected-t-cells
#18
Thomas Shum, Bilal Omer, Haruko Tashiro, Robert L Kruse, Dimitrios L Wagner, Kathan Parikh, Zhongzhen Yi, Tim Sauer, Daofeng Liu, Robin Parihar, Paul Castillo, Hao Liu, Malcolm K Brenner, Leonid S Metelitsa, Stephen Gottschalk, Cliona M Rooney
Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but are associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL-7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes...
August 22, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28820501/interleukin-armed-chimeric-antigen-receptor-modified-t-cells-for-cancer-immunotherapy
#19
REVIEW
Y Huang, D Li, D-Y Qin, H-F Gou, W Wei, Y-S Wang, Y-Q Wei, W Wang
Chimeric antigen receptor-modified T cells (CAR-T) are endowed with cytotoxic specificity to tumor cells. Although CAR-T-based cancer immunotherapy presents curable therapeutic potential for hematological malignancies, achieving substantial efficacy for solid tumors remain challenging. Researchers have exploited many strategies to enhance the anti-tumor efficacy of CAR-T cells for solid tumors, among which cytokine-armed CAR-T cells improve the proliferation, survival, homing and other properties of CAR-T cells...
August 18, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28818060/rna-transfection-of-%C3%AE-%C3%AE-t-cells-with-a-chimeric-antigen-receptor-or-an-%C3%AE-%C3%AE-t-cell-receptor-a-safer-alternative-to-genetically-engineered-%C3%AE-%C3%AE-t-cells-for-the-immunotherapy-of-melanoma
#20
Dennis C Harrer, Bianca Simon, Shin-Ichiro Fujii, Kanako Shimizu, Ugur Uslu, Gerold Schuler, Kerstin F Gerer, Stefanie Hoyer, Jan Dörrie, Niels Schaft
BACKGROUND: Adoptive T-cell therapy relying on conventional T cells transduced with T-cell receptors (TCRs) or chimeric antigen receptors (CARs) has caused substantial tumor regression in several clinical trials. However, genetically engineered T cells have been associated with serious side-effects due to off-target toxicities and massive cytokine release. To obviate these concerns, we established a protocol adaptable to GMP to expand and transiently transfect γ/δ T cells with mRNA...
August 17, 2017: BMC Cancer
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