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Lorenz Jahn, Renate S Hagedoorn, Dirk M van der Steen, Pleun Hombrink, Michel G D Kester, Marjolein P Schoonakker, Daniëlle de Ridder, Peter A van Veelen, J H Frederik Falkenburg, Mirjam H M Heemskerk
CD22 is currently evaluated as a target-antigen for the treatment of B-cell malignancies using chimeric antigen receptor (CAR)-engineered T-cells or monoclonal antibodies (mAbs). CAR- and mAbs-based immunotherapies have been successfully applied targeting other antigens, however, occurrence of refractory disease to these interventions urges the identification of additional strategies. Here, we identified a TCR recognizing the CD22-derived peptide RPFPPHIQL (CD22RPF) presented in human leukocyte antigen (HLA)-B*07:02...
September 26, 2016: Oncotarget
Cameron J Turtle, Laïla-Aïcha Hanafi, Carolina Berger, Michael Hudecek, Barbara Pender, Emily Robinson, Reed Hawkins, Colette Chaney, Sindhu Cherian, Xueyan Chen, Lorinda Soma, Brent Wood, Daniel Li, Shelly Heimfeld, Stanley R Riddell, David G Maloney
CD19-specific chimeric antigen receptor (CAR)-modified T cells have antitumor activity in B cell malignancies, but factors that affect toxicity and efficacy have been difficult to define because of differences in lymphodepletion and heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 CD4(+)/CD8(+) ratio of CAR-T cells to 32 adults with relapsed and/or refractory B cell non-Hodgkin's lymphoma after cyclophosphamide (Cy)-based lymphodepletion chemotherapy with or without fludarabine (Flu)...
September 7, 2016: Science Translational Medicine
Bingfeng Liu, Fan Zou, Lijuan Lu, Cancan Chen, Dalian He, Xu Zhang, Xiaoping Tang, Chao Liu, Linghua Li, Hui Zhang
: Despite the advent of combined antiretroviral therapy (cART), the persistence of viral reservoirs remains a major barrier to curing human immunodeficiency virus type 1 (HIV-1) infection. Recently, the shock and kill strategy, by which such reservoirs are eradicated following reactivation of latent HIV-1 by latency-reversing agents (LRAs), has been extensively practiced. It is important to reestablish virus-specific and reliable immune surveillance to eradicate the reactivated virus-harboring cells...
November 1, 2016: Journal of Virology
Annette Künkele, Agne Taraseviciute, Laura S Finn, Adam J Johnson, Carolina Berger, Olivia Finney, Cindy A Chang, Lisa S Rolczynski, Christopher Brown, Stephanie Mgebroff, Michael Berger, Julie R Park, Michael C Jensen
PURPOSE: The identification and vetting of cell surface tumor restricted epitopes for chimeric antigen receptor (CAR) redirected T cell immunotherapy is the subject of intensive investigation. We have focused on CD171 (L1-CAM), an abundant cell surface molecule on neuroblastomas and, specifically, on the glycosylation dependent tumor-specific epitope recognized by the CE7 monoclonal antibody. EXPERIMENTAL DESIGN: CD171 expression was assessed by IHC using CE7 mAb in tumor microarrays of primary, metastatic, and recurrent neuroblastoma, as well as human and rhesus macaque tissue arrays...
July 7, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Reona Sakemura, Seitaro Terakura, Keisuke Watanabe, Jakrawadee Julamanee, Erina Takagi, Kotaro Miyao, Daisuke Koyama, Tatsunori Goto, Ryo Hanajiri, Tetsuya Nishida, Makoto Murata, Hitoshi Kiyoi
T cells genetically modified with a CD19 chimeric antigen receptor (CD19CAR) are remarkably effective against B-cell malignancies in clinical trials. However, major concerns remain regarding toxicities, such as hypogammaglobulinemia, due to B-cell aplasia or severe cytokine release syndrome after overactivation of CAR T cells. To resolve these adverse events, we aimed to develop an inducible CAR system by using a tetracycline regulation system that would be activated only in the presence of doxycycline (Dox)...
August 2016: Cancer Immunology Research
Marianna Sabatino, Jinhui Hu, Michele Sommariva, Sanjivan Gautam, Vicki Fellowes, James D Hocker, Sean Dougherty, Haiying Qin, Christopher A Klebanoff, Terry J Fry, Ronald E Gress, James N Kochenderfer, David F Stroncek, Yun Ji, Luca Gattinoni
Long-lived, self-renewing, multipotent T memory stem cells (TSCM) can trigger profound and sustained tumor regression but their rareness poses a major hurdle to their clinical application. Presently, clinically compliant procedures to generate relevant numbers of this T-cell population are undefined. Here, we provide a strategy for deriving large numbers of clinical-grade tumor-redirected TSCM starting from naive precursors. CD8(+)CD62L(+)CD45RA(+) naive T cells enriched by streptamer-based serial-positive selection were activated by CD3/CD28 engagement in the presence of interleukin-7 (IL-7), IL-21, and the glycogen synthase-3β inhibitor TWS119, and genetically engineered to express a CD19-specific chimeric antigen receptor (CD19-CAR)...
July 28, 2016: Blood
Ayub Ali, Scott G Kitchen, Irvin S Y Chen, Hwee L Ng, Jerome A Zack, Otto O Yang
UNLABELLED: Although the use of chimeric antigen receptors (CARs) based on single-chain antibodies for gene immunotherapy of cancers is increasing due to promising recent results, the earliest CAR therapeutic trials were done for HIV-1 infection in the late 1990s. This approach utilized a CAR based on human CD4 as a binding domain and was abandoned for a lack of efficacy. The growing number of HIV-1 broadly neutralizing antibodies (BNAbs) offers the opportunity to generate novel CARs that may be more active and revisit this modality for HIV-1 immunotherapy...
August 1, 2016: Journal of Virology
Hillary G Caruso, Hiroki Torikai, Ling Zhang, Sourindra Maiti, Jianliang Dai, Kim-Anh Do, Harjeet Singh, Helen Huls, Dean A Lee, Richard E Champlin, Amy B Heimberger, Laurence J N Cooper
Potential for on-target, but off-tissue toxicity limits therapeutic application of genetically modified T cells constitutively expressing chimeric antigen receptors (CARs) from tumor-associated antigens expressed in normal tissue, such as epidermal growth factor receptor (EGFR). Curtailing expression of CAR through modification of T cells by in vitro-transcribed mRNA species is one strategy to mitigate such toxicity. We evaluated expression of an EGFR-specific CAR coded from introduced mRNA in human T cells numerically expanded ex vivo to clinically significant numbers through coculture with activating and propagating cells (AaPC) derived from K562 preloaded with anti-CD3 antibody...
June 2016: Journal of Immunotherapy
Carmen S M Yong, Liza B John, Christel Devaud, Miles H Prince, Ricky W Johnstone, Joseph A Trapani, Phillip K Darcy, Michael H Kershaw
While adoptive immunotherapy using chimeric antigen receptor (CAR)-modified T cells can induce remission of some tumors, the role of other CAR-modified leukocytes is not well characterized. In this study, we characterize the function of leukocytes including natural killer (NK) cells, macrophages and CAR T cells from transgenic mice expressing a CAR under the control of the pan-hematopoietic promoter, vav, and determine the ability of these mice to respond to ERB expressing tumors. We demonstrate the anti-tumor functions of leukocytes, including antigen specific cytotoxicity and cytokine secretion...
June 7, 2016: Oncotarget
Xiuli Wang, Leslie L Popplewell, Jamie R Wagner, Araceli Naranjo, M Suzette Blanchard, Michelle R Mott, Adam P Norris, ChingLam W Wong, Ryan Z Urak, Wen-Chung Chang, Samer K Khaled, Tanya Siddiqi, Lihua E Budde, Jingying Xu, Brenda Chang, Nikita Gidwaney, Sandra H Thomas, Laurence J N Cooper, Stanley R Riddell, Christine E Brown, Michael C Jensen, Stephen J Forman
Myeloablative autologous hematopoietic stem cell transplantation (HSCT) is a mainstay of therapy for relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high. In phase 1 studies designed to improve long-term remission rates, we administered adoptive T-cell immunotherapy after HSCT, using ex vivo-expanded autologous central memory-enriched T cells (TCM) transduced with lentivirus expressing CD19-specific chimeric antigen receptors (CARs). We present results from 2 safety/feasibility studies, NHL1 and NHL2, investigating different T-cell populations and CAR constructs...
June 16, 2016: Blood
Cameron J Turtle, Laïla-Aïcha Hanafi, Carolina Berger, Theodore A Gooley, Sindhu Cherian, Michael Hudecek, Daniel Sommermeyer, Katherine Melville, Barbara Pender, Tanya M Budiarto, Emily Robinson, Natalia N Steevens, Colette Chaney, Lorinda Soma, Xueyan Chen, Cecilia Yeung, Brent Wood, Daniel Li, Jianhong Cao, Shelly Heimfeld, Michael C Jensen, Stanley R Riddell, David G Maloney
BACKGROUND: T cells that have been modified to express a CD19-specific chimeric antigen receptor (CAR) have antitumor activity in B cell malignancies; however, identification of the factors that determine toxicity and efficacy of these T cells has been challenging in prior studies in which phenotypically heterogeneous CAR-T cell products were prepared from unselected T cells. METHODS: We conducted a clinical trial to evaluate CD19 CAR-T cells that were manufactured from defined CD4+ and CD8+ T cell subsets and administered in a defined CD4+:CD8+ composition to adults with B cell acute lymphoblastic leukemia after lymphodepletion chemotherapy...
June 1, 2016: Journal of Clinical Investigation
Ann Ager, H Angharad Watson, Sophie C Wehenkel, Rebar N Mohammed
The success of adoptive T-cell therapies for the treatment of cancer patients depends on transferred T-lymphocytes finding and infiltrating cancerous tissues. For intravenously transferred T-cells, this means leaving the bloodstream (extravasation) from tumour blood vessels. In inflamed tissues, a key event in extravasation is the capture, rolling and arrest of T-cells inside blood vessels which precedes transmigration across the vessel wall and entry into tissues. This depends on co-ordinated signalling of selectins, integrins and chemokine receptors on T-cells by their respective ligands which are up-regulated on inflamed blood vessels...
April 15, 2016: Biochemical Society Transactions
Vita Golubovskaya, Lijun Wu
This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy--a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities against tumor cells. Recently, differences in T cell functions and the role of memory and effector T cells were shown to be important in CAR-T cell immunotherapy. The CD4⁺ subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh) and CD8⁺ memory and effector subsets differ in extra-cellular (CD25, CD45RO, CD45RA, CCR-7, L-Selectin [CD62L], etc...
2016: Cancers
Franco Rongioletti, Giulia Merlo, Carla Carli, Bernard Cribier, Dieter Metze, Eduardo Calonje, Werner Kempf, Catherine M Stefanato, Eduardo Marinho, Jean Kanitakis
BACKGROUND: Few histologic studies describe the histopathologic aspects of scleromyxedema. OBJECTIVE: We sought to describe the histopathologic and immunohistochemical features of scleromyxedema in a large series of patients. METHODS: We studied all the cases with scleromyxedema diagnosed between 2000 and 2014 at participating centers. Sections with hematoxylin-eosin and special stains were examined. Immunohistochemistry for CD3, CD4, CD8, CD20, CD68, and factor XIIIa was performed in 10 cases...
June 2016: Journal of the American Academy of Dermatology
Omkar U Kawalekar, Roddy S O'Connor, Joseph A Fraietta, Lili Guo, Shannon E McGettigan, Avery D Posey, Prachi R Patel, Sonia Guedan, John Scholler, Brian Keith, Nathaniel W Snyder, Nathaniel Snyder, Ian A Blair, Ian Blair, Michael C Milone, Carl H June
Chimeric antigen receptors (CARs) redirect T cell cytotoxicity against cancer cells, providing a promising approach to cancer immunotherapy. Despite extensive clinical use, the attributes of CAR co-stimulatory domains that impact persistence and resistance to exhaustion of CAR-T cells remain largely undefined. Here, we report the influence of signaling domains of coreceptors CD28 and 4-1BB on the metabolic characteristics of human CAR T cells. Inclusion of 4-1BB in the CAR architecture promoted the outgrowth of CD8(+) central memory T cells that had significantly enhanced respiratory capacity, increased fatty acid oxidation and enhanced mitochondrial biogenesis...
February 16, 2016: Immunity
M Khadhar, H Jebali, R Kheder, L Ben Fatma, L Raïs, W Smaoui, M Krid, F Ben Moussa, S Beji, K Zouaghi
OBJECTIFS: La granulomatose rénale est une infiltration inflammatoire de l'interstitium rénal. Elle réalise un tableau de néphropathie tubulo-interstitielle dans la plupart des cas. L'hypertension artérielle complique exceptionnellement cette atteinte. MéTHODES: Nous rapportons une observation d'une granulomatose rénale compliquée d'hypertension artérielle maligne et d'insuffisance rénale aigue. RéSULTATS: Nous rapportons le cas de la patiente A. S âgée de 18 ans, sans antécédents notables, hospitalisée pour prise en charge d'une sarcoïdose sys-témique...
December 2015: Annales de Cardiologie et D'angéiologie
Chunchun Meng, Xiao Zhi, Chao Li, Chuanfeng Li, Zongyan Chen, Xusheng Qiu, Chan Ding, Lijun Ma, Hongmin Lu, Di Chen, Guangqing Liu, Daxiang Cui
Current studies have revealed the immune effects of graphene oxide (GO) and have utilized them as vaccine carriers and adjuvants. However, GO easily induces strong oxidative stress and inflammatory reaction at the site of injection. It is very necessary to develop an alternative adjuvant based on graphene oxide derivatives for improving immune responses and decreasing side effects. Carnosine (Car) is an outstanding and safe antioxidant. Herein, the feasibility and efficiency of ultrasmall graphene oxide decorated with carnosine as an alternative immune adjuvant were explored...
February 23, 2016: ACS Nano
Ylva Terelius, Robert A Figler, Svetlana Marukian, Maria S Collado, Mark J Lawson, Aaron J Mackey, David Manka, Charles W Qualls, Brett R Blackman, Brian R Wamhoff, Ajit Dash
Drug induced liver injury (DILI), a major cause of pre- and post-approval failure, is challenging to predict pre-clinically due to varied underlying direct and indirect mechanisms. Nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) and Ritonavir, a protease inhibitor, are antiviral drugs that cause clinical DILI with different phenotypes via different mechanisms. Assessing DILI in vitro in hepatocyte cultures typically requires drug exposures significantly higher than clinical plasma Cmax concentrations, making clinical interpretations of mechanistic pathway changes challenging...
August 5, 2016: Chemico-biological Interactions
K Pinz, H Liu, M Golightly, A Jares, F Lan, G W Zieve, N Hagag, M Schuster, A E Firor, X Jiang, Y Ma
Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with no effective upfront standard treatment and ineffective options in relapsed disease, resulting in poorer clinical outcomes as compared with B-cell lymphomas. The adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) is a promising new approach for treatment of hematological malignancies. However, preclinical reports of targeting T-cell lymphoma with CARs are almost non-existent. Here we have designed a CAR, CD4CAR, which redirects the antigen specificity of CD8+ cytotoxic T cells to CD4-expressing cells...
March 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Ling-Ling Yin, Su-Hong Ruan, Yu Tian, Kai Zhao, Kai Lin Xu
OBJECTIVE: To clone the variable region genes of human anti-IL1RAP (IL-1 receptor accessory protein) monoclonal antibodies (McAb) and to construct IL1RAP chimeric antigen receptors (CARs). METHODS: The VH and VL DNA of IL1RAP single chain antibodies were amplified by RACE and overlap extension PCR from total RNA extracted from 3H6E10 and 10D8A7 hybridoma and ligated into specific IL1RAP single-chain variable fragments (scFv). CD8α transmembrane domain, CD137 intracellular domain, TCR ζ chain, human CD8α signal peptide and scFv-anti-IL1RAP were cloned into plasmid LV-lac...
October 2015: Zhongguo Shi Yan Xue Ye Xue za Zhi
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