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Xiaowen Tang, Lin Yang, Zheng Li, Ansel P Nalin, Haiping Dai, Ting Xu, Jia Yin, Fengtao You, Mingqing Zhu, Wenhong Shen, Guanghua Chen, Xiaming Zhu, Depei Wu, Jianhua Yu
[This corrects the article on p. 1083 in vol. 8, PMID: 30034945.].
2018: American Journal of Cancer Research
Qing Zhang, Jinjing Xu, Jiage Ding, Hongyan Liu, Huizhong Li, Hailong Li, Mengmeng Lu, Yangna Miao, Zhenzhen Wang, Qiang Fu, Junnian Zheng
Adoptive chimeric antigen receptor (CAR) T or NK cells offer new options for cancer treatment. Clinical results indicate that CAR‑modified T cell (CAR‑T) therapy has curative therapeutic efficacy for hematological malignancies. However, the efficacy of the therapy in most solid tumors, including advanced renal cell carcinoma (RCC), remains highly limited. New regimens, including combination of CAR‑T cells with chemical drugs, must be studied to enhance the therapeutic efficacy of CAR‑T or NK cells for solid tumors...
September 24, 2018: Oncology Reports
Toshiharu Murakami, Tsutomu Nakazawa, Atsushi Natsume, Fumihiko Nishimura, Mitsutoshi Nakamura, Ryosuke Matsuda, Koji Omoto, Yoshitaka Tanaka, Youichi Shida, Young-Soo Park, Yasushi Motoyama, Ichiro Nakagawa, Shuichi Yamada, Kentaro Tamura, Yasuhiro Takeshima, Yoshiaki Takamura, Toshihiko Wakabayashi, Hiroyuki Nakase
BACKGROUND/AIM: Natural killer (NK) cells are considered potential antitumor effector cells. The aim of this study was to establish a novel type of a chimeric antigen receptor (CAR) NK cell line (CAR-KHYG-1) specific for epidermal growth factor receptor variant III (EGFRvIII)-expressing tumors and investigate the anti-tumor activity of EGFRvIII-specific-CAR-KHYG-1 (EvCAR-KHYG-1). MATERIALS AND METHODS: EvCAR-KHYG-1 was established by self-inactivated lentiviral-based transduction of the EvCAR gene and magnetic bead-based purification of EvCAR-expressing NK cells...
September 2018: Anticancer Research
Janine E Melsen, Gertjan Lugthart, Carly Vervat, Szymon M Kielbasa, Sander A J van der Zeeuw, Henk P J Buermans, Monique M van Ostaijen-Ten Dam, Arjan C Lankester, Marco W Schilham
Human lymphoid tissues harbor, in addition to CD56bright and CD56dim natural killer (NK) cells, a third NK cell population: CD69+ CXCR6+ lymphoid tissue (lt)NK cells. The function and development of ltNK cells remain poorly understood. In this study, we performed RNA sequencing on the three NK cell populations derived from bone marrow (BM) and blood. In ltNK cells, 1,353 genes were differentially expressed compared to circulating NK cells. Several molecules involved in migration were downregulated in ltNK cells: S1PR1, SELPLG and CD62L ...
2018: Frontiers in Immunology
Ping Zhang, Songbo Zhao, Chao Wu, Jialu Li, Zixuan Li, Chunmei Wen, Siyi Hu, Gangli An, Huimin Meng, Xingding Zhang, Lin Yang
Tumor immunotherapy has shown great progress for the treatment of cancer; however, both endogenous and exogenous T cells are inhibited by the immunosuppressive tumor microenvironment. Tumor-associated macrophages (TAMs) in the microenvironment play pivotal and complex roles in tumor development and progression. Macrophages are categorized as M1 and M2 types. Relevant studies suggest that M2 TAMs correlate with poor prognosis. Colony-stimulating factor 1 receptor (CSF1R) controls the formation, differentiation and function of M2 macrophages, which helps tumors grow, metastasize and secrete immunosuppressive cytokines...
August 2018: Immunotherapy
Bianca Simon, Manuel Wiesinger, Johannes März, Kilian Wistuba-Hamprecht, Benjamin Weide, Beatrice Schuler-Thurner, Gerold Schuler, Jan Dörrie, Ugur Uslu
Natural killer T (NKT) cells represent a cell subpopulation that combines characteristics of natural killer (NK) cells and T cells. Through their endogenous T-cell receptors (TCRs), they reveal a pronounced intrinsic anti-tumor activity. Thus, a NKT cell transfected with a chimeric antigen receptor (CAR), which recognizes a tumor-specific surface antigen, could attack tumor cells antigen-specifically via the CAR and additionally through its endogenous TCR. NKT cells were isolated from peripheral blood mononuclear cells (PBMCs), expanded, and electroporated with mRNA encoding a chondroitin sulfate proteoglycan 4 (CSPG4)-specific CAR...
August 11, 2018: International Journal of Molecular Sciences
Ye Li, David L Hermanson, Branden S Moriarity, Dan S Kaufman
Chimeric antigen receptors (CARs) significantly enhance the anti-tumor activity of immune effector cells. Although most studies have evaluated CAR expression in T cells, here we evaluate different CAR constructs that improve natural killer (NK) cell-mediated killing. We identified a CAR containing the transmembrane domain of NKG2D, the 2B4 co-stimulatory domain, and the CD3ζ signaling domain to mediate strong antigen-specific NK cell signaling. NK cells derived from human iPSCs that express this CAR (NK-CAR-iPSC-NK cells) have a typical NK cell phenotype and demonstrate improved anti-tumor activity compared with T-CAR-expressing iPSC-derived NK cells (T-CAR-iPSC-NK cells) and non-CAR-expressing cells...
August 2, 2018: Cell Stem Cell
Masayuki Shiozawa, Chuan-Hsin Chang, Yi-Chun Huang, Yi-Ching Chen, Mau-Shin Chi, Hsu-Chao Hao, Yue-Cune Chang, Satoru Takeda, Kwan-Hwa Chi, Yu-Shan Wang
BACKGROUND: The natural killer cell line, NK-92MI, is cytotoxic against various types of cancer. The aim of this study was to develop chimeric antigen receptor-modified (CAR) NK-92MI cells targeting carcinoembryonic antigen-expressing (CEA) tumours and increase killing efficacy by pharmacologically modifying CEA-expression. RESULT: We generated anti-CEA-CAR NK-92MI cells by retroviral vector transduction. This genetically-modified cell line recognised and lysed high CEA-expressing tumour cell lines (LS174T) at 47...
August 3, 2018: BMC Immunology
Elizabeth L Siegler, Yanni Zhu, Pin Wang, Lili Yang
CAR-T therapy has shown great success treating blood cancers, but drawbacks include high manufacturing costs and potentially fatal toxicities such as cytokine release syndrome. In this issue of Cell Stem Cell, Li et al. (2018) describe how engineered iPSC-derived NK cells armed with NK-tailored CAR constructs (CAR-iPSC-NK cells) provide better options for anti-cancer immunotherapy.
August 2, 2018: Cell Stem Cell
Xiaowen Tang, Lin Yang, Zheng Li, Ansel P Nalin, Haiping Dai, Ting Xu, Jia Yin, Fengtao You, Mingqing Zhu, Wenhong Shen, Guanghua Chen, Xiaming Zhu, Depei Wu, Jianhua Yu
CAR T cells have shown clinical efficacy for acute lymphoblastic leukemia, but this therapy has not been effective for acute myeloid leukemia (AML), and other treatment options are needed. Theoretically, CAR-NK cells have a more favorable toxicity profile compared to CAR T cells, especially in avoiding adverse effects such as cytokine release syndrome. However, the clinical evidence for this has not yet been reported. In the current study, we tested the safety of CD33-CAR NK cells in patients with relapsed and refractory AML...
2018: American Journal of Cancer Research
Hua-Ping Wei, Nan Yang, Zhen-Yang Gu, Sha-Sha Zhao, Fei-Yan Wang, Lan Luo, Li-Xun Guan, Chun-Ji Gao
OBJECTIVE: To explore the killing effect of CAR (CD138-CD28-CD3ζ)-NK cells on myeloma cells through construction of CAR(CD138-CD28-CD3)-NK cells. METHODS: The antiCD138scFv-CD28-CD3 zeta plasmid pcDNA3.1 was constructed, which then together with 3 plasmid lentiviral packaging system were transfected into 293T cells, the virus was collected. Furthermore, in order to get the stably transfected cell line, the NK92MI cell line was infected by the virus, then the positive cells were screened by puromycin...
June 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Rohin K Iyer, Paul A Bowles, Howard Kim, Aaron Dulgar-Tulloch
Cell therapy has proven to be a burgeoning field of investigation, evidenced by hundreds of clinical trials being conducted worldwide across a variety of cell types and indications. Many cell therapies have been shown to be efficacious in humans, such as modified T-cells and natural killer (NK) cells. Adoptive immunotherapy has shown the most promise in recent years, with particular emphasis on autologous cell sources. Chimeric Antigen Receptor (CAR)-based T-cell therapy targeting CD19-expressing B-cell leukemias has shown remarkable efficacy and reproducibility in numerous clinical trials...
2018: Frontiers in Medicine
Yangxi Li, Rui Sun
A group of impressive immunotherapies for cancer treatment, including immune checkpoint-blocking antibodies, gene therapy and immune cell adoptive cellular immunotherapy, have been established, providing new weapons to fight cancer. Natural killer (NK) cells are a component of the first line of defense against tumors and virus infections. Studies have shown dysfunctional NK cells in patients with cancer. Thus, restoring NK cell antitumor functionality could be a promising therapeutic strategy. NK cells that are activated and expanded ex vivo can supplement malfunctional NK cells in tumor patients...
April 2018: Chinese Journal of Cancer Research, Chung-kuo Yen Cheng Yen Chiu
Melissa Mavers, Alice Bertaina
Natural killer (NK) cells are a population of cytotoxic innate lymphocytes that evolved prior to their adaptive counterparts and constitute one of the first lines of defense against infected/mutated cells. Several studies have shown that in patients with acute leukemia given haploidentical hematopoietic stem cell transplantation, donor-derived NK cells play a key role in the eradication of cancer cells. The antileukemic effect is mostly related to the presence of "alloreactive" NK cells, that is, mature KIR+ NK cells that express inhibitory KIR mismatched with HLA class I (KIR-L) of the patient...
2018: Journal of Immunology Research
Fred Falkenburg, Eliana Ruggiero, Chaira Bonini, David Porter, Jeff Miller, Floran Malard, Mohamad Mohty, Nicolaus Kröger, Hans Jochem Kolb
Despite recent advances in reducing therapy-related mortality after allogeneic stem cell transplantation (alloSCT) relapse remains the major cause of treatment failure and little progress has been achieved in the last decades. At the 3rd International Workshop on Biology, Prevention, and Treatment of Relapse held in Hamburg/Germany in November 2016 international experts presented and discussed recent developments in the field. Here, the potential of cellular therapies including unspecific and specific T cells, genetically modified T cells, CAR-T cells, NK-cells, and second allografting in prevention and treatment of relapse after alloSCT are summarized...
May 24, 2018: Bone Marrow Transplantation
Rupert Handgretinger, Patrick Schlegel
Recent developments in cell and gene therapy have a great impact on the new therapeutic approaches in pediatric cancers. Monoclonal antibodies for neuroblastoma and bispecific antibodies for leukemia have induced significant clinical responses for otherwise chemorefractory patients. Moreover, cellular therapeutic approaches including chimeric antigen receptor (CAR) T-cells as well as natural killer (NK) cells have the potential to cure patients with so far incurable malignancies and are the basis for future new therapies for pediatric cancer...
April 2018: Chinese Clinical Oncology
Y Qu, J Z Bi
Objective: To study the cytotoxicity of Robo1-CAR-NK92 cells against U87-MG and SH-SY5Y cells, to explore the effects of IL-15, IL-21 and dexamethasone on the proliferation, survival and cytotoxicity of Robo1-CAR-NK92 cells and to optimize the culture protocol. Methods: Robo1-CAR-NK92 cells were constructed by lentivirus transfection.The Robo1 car positive cells were sorted, expanded and detected by flow cytometry.The levels of Robo1 expression in SH-SY5Y and U87-MG cells were examined by flow cytometry.The cytotoxicity of Robo1-CAR-NK92 or NK92 cells against target cells was tested by CCK-8 and live cell imaging...
March 20, 2018: Zhonghua Yi Xue za Zhi [Chinese medical journal]
May Daher, Katayoun Rezvani
Recent advances in the field of cellular therapy have focused on autologous T cells engineered to express a chimeric antigen receptor (CAR) against tumor antigens. Remarkable responses have been observed in patients receiving autologous CD19-redirected T cells for the treatment of B-lymphoid malignancies. However, the generation of autologous products for each patient is logistically challenging and expensive. Extensive research efforts are ongoing to generate an off-the-shelf cellular product for the treatment of cancer patients...
April 2018: Current Opinion in Immunology
Sergey V Kulemzin, Andrey A Gorchakov, Anton N Chikaev, Valeriya V Kuznetsova, Olga Y Volkova, Daria A Matvienko, Alexey V Petukhov, Andrey Y Zaritskey, Alexandr V Taranin
T and NK cells armed with chimeric antigen receptors (CAR) are promising tools for the specific elimination of cancer cells. In most CAR designs implemented to date, the recognition of target cells is mediated by single-chain variable fragments (scFvs) derived from murine monoclonal antibodies. This format, however, has a number of limitations, including its relatively large size and potential immunogenicity in humans. In this study, we explored the feasibility of using human fibronectin type III domains (Fn3) as the antigen recognition domain in CARs...
February 6, 2018: Oncotarget
Fabio Cerignoli, Yama A Abassi, Brandon J Lamarche, Garret Guenther, David Santa Ana, Diana Guimet, Wen Zhang, Jing Zhang, Biao Xi
A growing understanding of the molecular interactions between immune effector cells and target tumor cells, coupled with refined gene therapy approaches, are giving rise to novel cancer immunotherapeutics with remarkable efficacy in the clinic against both solid and liquid tumors. While immunotherapy holds tremendous promise for treatment of certain cancers, significant challenges remain in the clinical translation to many other types of cancers and also in minimizing adverse effects. Therefore, there is an urgent need for functional potency assays, in vitro and in vivo, that could model the complex interaction of immune cells with tumor cells and can be used to rapidly test the efficacy of different immunotherapy approaches, whether it is small molecule, biologics, cell therapies or combinations thereof...
2018: PloS One
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