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Jiao Wang, Kyle B Lupo, Andrea M Chambers, Sandro Matosevic
BACKGROUND: The anti-tumor immunity of natural killer (NK) cells can be paralyzed by the CD73-induced generation of immunosuppressive adenosine from precursor ATP within the hypoxic microenvironment of solid tumors. In an effort to redirect purinergic immunosuppression of NK cell anti-tumor function, we showed, for the first time, that immunometabolic combination treatment with NKG2D-engineered CAR-NK cells alongside blockade of CD73 ectonucleotidase activity can result in significant anti-tumor responses in vivo...
December 4, 2018: Journal for Immunotherapy of Cancer
Florian Douam, Carly G K Ziegler, Gabriela Hrebikova, Bruno Fant, Robert Leach, Lance Parsons, Wei Wang, Jenna M Gaska, Benjamin Y Winer, Brigitte Heller, Alex K Shalek, Alexander Ploss
Mice engrafted with components of a human immune system have become widely-used models for studying aspects of human immunity and disease. However, a defined methodology to objectively measure and compare the quality of the human immune response in different models is lacking. Here, by taking advantage of the highly immunogenic live-attenuated yellow fever virus vaccine YFV-17D, we provide an in-depth comparison of immune responses in human vaccinees, conventional humanized mice, and second generation humanized mice...
November 28, 2018: Nature Communications
Qing Zhang, Haixu Zhang, Jiage Ding, Hongyan Liu, Huizhong Li, Hailong Li, Mengmeng Lu, Yangna Miao, Liantao Li, Junnian Zheng
Adoptive chimeric antigen receptor-modified T or NK cells (CAR-T or CAR-NK) offer new options for cancer treatment. CAR-T therapy has achieved encouraging breakthroughs in the treatment of hematological malignancies. However, their therapeutic efficacy against solid tumors is limited. New regimens, including combinations with chemical drugs, need to be studied to enhance the therapeutic efficacy of CAR-T or NK cells for solid tumors. An epithelial cell adhesion molecule- (EpCAM-) specific second-generation CAR was constructed and transduced into NK-92 cells by lentiviral vectors...
2018: Journal of Immunology Research
A Quaiser, U Köhl
Cell and gene therapy as part of immuno-oncology has reached an important milestone in medicine. After decades of experience stem cell transplantation is well established with worldwide >1 million transplantations to date. Due to the improved success of the last years using chimeric antigen receptor (CAR) T cells for CD19 positive leukemia and lymphomas, the interest in cellular therapies is continuously increasing. The current review also gives a short overview about donor lymphocytes, antigen-specific T cells, regulatory T cells, natural killer (NK) cells, mesenchymal stromal cells and induced pluripotent stem (iPS) cells in immuno-oncology...
December 2018: Der Internist
Michelle L Saetersmoen, Quirin Hammer, Bahram Valamehr, Dan S Kaufman, Karl-Johan Malmberg
Cell therapy is emerging as a very promising therapeutic modality against cancer, spearheaded by the clinical success of chimeric antigen receptor (CAR) modified T cells for B cell malignancies. Currently, FDA-approved CAR-T cell products are based on engineering of autologous T cells harvested from the patient, typically using a central manufacturing facility for gene editing before the product can be delivered to the clinic and infused to the patients. For a broader implementation of advanced cell therapy and to reduce costs, it would be advantageous to use allogeneic "universal" cell therapy products that can be stored in cell banks and provided upon request, in a manner analogous to biopharmaceutical drug products...
October 25, 2018: Seminars in Immunopathology
Joseph D Malaer, Armando M Marrufo, Porunelloor A Mathew
Signaling Lymphocyte Activation Molecule (SLAM) family receptors are expressed on different types of hematopoietic cells and play important role in immune regulation in health and disease. 2B4 (CD244, SLAMF4) and CS1 (CD319, CRACC, SLAMF7) were originally identified as NK cell receptors regulating NK cell cytolytic activity. 2B4 is expressed on all NK cells, a subpopulation of T cells, monocytes and basophils. Unlike other activating and inhibitory receptors, 2B4 (CD244) interaction with its ligand CD48 has been shown to mediate both activating and inhibitory functions...
October 19, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
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
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