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Yi Tian Png, Natasha Vinanica, Takahiro Kamiya, Noriko Shimasaki, Elaine Coustan-Smith, Dario Campana
Effective immunotherapies for T-cell malignancies are lacking. We devised a novel approach based on chimeric antigen receptor (CAR)-redirected T lymphocytes. We selected CD7 as a target because of its consistent expression in T-cell acute lymphoblastic leukemia (T-ALL), including the most aggressive subtype, early T-cell precursor (ETP)-ALL. In 49 diagnostic T-ALL samples (including 14 ETP-ALL samples), median CD7 expression was >99%; CD7 expression remained high at relapse (n = 14), and during chemotherapy (n = 54)...
November 28, 2017: Blood Advances
Fenlu Zhu, Nirav Shah, Huiqing Xu, Dina Schneider, Rimas Orentas, Boro Dropulic, Parameswaran Hari, Carolyn A Keever-Taylor
BACKGROUND AIMS: Multiple steps are required to produce chimeric antigen receptor (CAR)-T cells, involving subset enrichment or depletion, activation, gene transduction and expansion. Open processing steps that increase risk of contamination and production failure are required. This complex process requires skilled personnel and costly clean-room facilities and infrastructure. Simplified, reproducible CAR-T-cell manufacturing with reduced labor intensity within a closed-system is highly desirable for increased availability for patients...
December 26, 2017: Cytotherapy
J Bae, T Hideshima, G L Zhang, J Zhou, D B Keskin, N C Munshi, K C Anderson
XBP1 (X-box binding protein 1), CD138 (Syndecan-1), and CS1 (SLAMF7) are highly expressed antigens in cancers including multiple myeloma (MM). Here we identify and characterize immunogenic HLA-A24 peptides derived from these antigens for potential vaccination therapy of HLA-A24+ patients with MM. The identified immunogenic HLA-A24-specific XBP1 unspliced (UN)185-193 (I S P W I L A V L), XBP1 spliced (SP)223-231 (V Y P E G P S S L), CD138265-273 (I F A V C L V G F) and CS1240-248 (L F V L G L F L W) peptides induced antigen-specific CTL with anti-MM activity in an HLA-A24 restricted manner...
November 1, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Ingunn M Stromnes, Ayaka Hulbert, Robert H Pierce, Philip D Greenberg, Sunil R Hingorani
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to most therapies, including immune checkpoint blockade. To elucidate mechanisms of immunotherapy resistance, we assessed immune parameters in resected human PDA. We demonstrate significant interpatient variability in T-cell number, localization, and phenotype. CD8+ T cells, Foxp3+ regulatory T cells, and PD-1+ and PD-L1+ cells were preferentially enriched in tertiary lymphoid structures that were found in most tumors compared with stroma and tumor cell nests...
November 2017: Cancer Immunology Research
Mireya Paulina Velasquez, Arpad Szoor, Abishek Vaidya, Aarohi Thakkar, Phuong Nguyen, Meng-Fen Wu, Hao Liu, Stephen Gottschalk
T cells expressing CD19-specific chimeric antigen receptors (CARs) with endodomains that encode a signaling domain derived from CD3ζ and CD28 or 41BB have potent antitumor activity in early-phase clinical studies for B-cell malignancies. Besides CD19-specific CARs, other approaches are actively being pursued to redirect T cells to CD19, including recombinant bispecific T-cell engager (BiTE) proteins or T cells genetically modified to express BiTEs [engager (ENG) T cells]. As BiTEs provide no costimulation, we investigated here if provision of costimulation through CD28 and 41BB enhances the effector function of CD19-ENG T cells...
October 2017: Cancer Immunology Research
Alec J Walker, Robbie G Majzner, Ling Zhang, Kelsey Wanhainen, Adrienne H Long, Sang M Nguyen, Paola Lopomo, Marc Vigny, Terry J Fry, Rimas J Orentas, Crystal L Mackall
We explored the utility of targeting anaplastic lymphoma kinase (ALK), a cell surface receptor overexpressed on pediatric solid tumors, using chimeric antigen receptor (CAR)-based immunotherapy. T cells expressing a CAR incorporating the single-chain variable fragment sequence of the ALK48 mAb linked to a 4-1BB-CD3ζ signaling domain lysed ALK-expressing tumor lines and produced interferon-gamma upon antigen stimulation but had limited anti-tumor efficacy in two xenograft models of human neuroblastoma. Further exploration demonstrated that cytokine production was highly dependent upon ALK target density and that target density of ALK on neuroblastoma cell lines was insufficient for maximal activation of CAR T cells...
September 6, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
Qiong J Wang, Zhiya Yu, Ken-Ichi Hanada, Krishna Patel, David Kleiner, Nicholas P Restifo, James C Yang
Purpose: CD70 expression in normal tissues is restricted to activated lymphoid tissues. Targeting CD70 on CD70-expressing tumors could mediate "on-target, off-tumor" toxicity. This study was to evaluate the feasibility and safety of using anti-human CD70 CARs to treat cancer patients whose tumors express CD70.Experimental Design: Seven anti-human CD70 CARs with binding moieties from human CD27 combined with CD3-zeta and different costimulatory domains from CD28 and/or 41BB were constructed. In vitro functionality of these receptors was compared and in vivo treatment efficacy was evaluated in a xenograft mouse model...
May 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
MacLean Hall, Hao Liu, Mokenge Malafa, Barbara Centeno, Pamela J Hodul, José Pimiento, Shari Pilon-Thomas, Amod A Sarnaik
BACKGROUND: We evaluated whether tumor infiltrating lymphocytes (TIL) could be expanded from surgically resected tumors from pancreatic cancer patients. METHODS: Tumors were resected from pancreatic cancer patients. Tumors were minced into fragments and cultured in media containing high dose interleukin-2 (IL-2) for up to 6 weeks. T cell phenotype, activation markers, and reactivity were measured. RESULTS: TIL expansion was measured in 19 patient samples...
2016: Journal for Immunotherapy of Cancer
Wolfgang Merkt, Hanns-Martin Lorenz, Carsten Watzl
BACKGROUND: Rituximab has broad and increasing application in rheumatic diseases. It is known from lymphoma studies that natural killer (NK) cells can lyse rituximab-coated transformed B cells. However, the role of NK cells in mediating rituximab-induced depletion of non-malignant B cells is unknown. The purpose of this study was to provide fundamental data on rituximab-mediated effects on NK cells in PBMCs without tumor cells, in order to simulate effects that could be relevant in patients with rheumatic disease...
September 15, 2016: Arthritis Research & Therapy
Wolfgang Merkt, Maren Claus, Norbert Blank, Michael Hundemer, Adelheid Cerwenka, Hanns-Martin Lorenz, Carsten Watzl
BACKGROUND: The role of natural killer (NK) cells in granulomatosis with polyangiitis (GPA) is poorly understood. We recently reported that peripheral blood NK cell percentages correlate with the suppression of GPA activity (cohort I). The purpose of the current study was to further characterize NK cell subsets, phenotype and function in a second GPA cohort (cohort II). METHODS: Peripheral blood lymphocyte subsets were analyzed at a clinical diagnostic laboratory...
September 13, 2016: Arthritis Research & Therapy
Hans Hammers
PURPOSE OF REVIEW: Kidney cancer, in particular clear cell renal cell carcinoma (ccRCC) has long been considered to be sensitive to immunotherapies. With the recent breakthroughs in immunotherapy for solid tumors and the recent approval of the first immune checkpoint inhibitor for ccRCC, we are reviewing the history of immunotherapy in kidney cancer, describing its current state and look into the future of a rapidly evolving landscape in immunotherapy for kidney cancer. RECENT FINDINGS: Systemic treatment options over the past decade have been dominated by targeted therapies inhibiting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways...
November 2016: Current Opinion in Urology
Wei Wang, Amy K Erbe, Kory A Alderson, Emily Phillips, Mikayla Gallenberger, Jacek Gan, Dario Campana, Jacquelyn A Hank, Paul M Sondel
Infusion of allogeneic NK cells is a potential immunotherapy for both hematopoietic malignancies and solid tumors. Interactions between killer immunoglobulin-like receptors (KIR) on human NK cells and KIR-ligands on tumor cells influence the magnitude of NK function. To obtain sufficient numbers of activated NK cells for infusion, one potent method uses cells from the K562 human erythroleukemia line that have been transfected to express activating 41BB ligand (41BBL) and membrane-bound interleukin 15 (mbIL15)...
September 2016: Cancer Immunology, Immunotherapy: CII
Marie T Kim, Martin J Richer, Brett P Gross, Lyse A Norian, Vladimir P Badovinac, John T Harty
U.S. Food and Drug Administration-approved high-dose IL-2 therapy and dendritic cell (DC) immunization offer time-tested treatments for malignancy, but with defined issues of short in vivo t1/2, toxicity, and modest clinical benefit. Complexes of IL-2 with specific mAbs (IL-2c) exhibit improved stability in vivo with reduced toxicity and are capable of stimulating NK cell and memory phenotype CD8 T cell proliferation. In this study, we demonstrate that IL-2c treatment in tumor-bearing mice can enhance NK cell and tumor-specific CD8 T cell numbers...
November 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Susann Szmania, Natalia Lapteva, Tarun Garg, Amy Greenway, Joshuah Lingo, Bijay Nair, Katie Stone, Emily Woods, Junaid Khan, Justin Stivers, Susan Panozzo, Dario Campana, William T Bellamy, Molly Robbins, Joshua Epstein, Shmuel Yaccoby, Sarah Waheed, Adrian Gee, Michele Cottler-Fox, Cliona Rooney, Bart Barlogie, Frits van Rhee
Highly activated/expanded natural killer (NK) cells can be generated by stimulation with the human leukocyte antigen-deficient cell line K562, genetically modified to express 41BB-ligand and membrane-bound interleukin (IL)15. We tested the safety, persistence, and activity of expanded NK cells generated from myeloma patients (auto-NK) or haploidentical family donors (allo-NK) in heavily pretreated patients with high-risk relapsing myeloma. The preparative regimen comprised bortezomib only or bortezomib and immunosuppression with cyclophosphamide, dexamethasone, and fludarabine...
January 2015: Journal of Immunotherapy
Daniel Abate-Daga, Kiran H Lagisetty, Eric Tran, Zhili Zheng, Luca Gattinoni, Zhiya Yu, William R Burns, Anne M Miermont, Yaroslav Teper, Udo Rudloff, Nicholas P Restifo, Steven A Feldman, Steven A Rosenberg, Richard A Morgan
Despite advances in the understanding of its molecular pathophysiology, pancreatic cancer remains largely incurable, highlighting the need for novel therapies. We developed a chimeric antigen receptor (CAR) specific for prostate stem cell antigen (PSCA), a glycoprotein that is overexpressed in pancreatic cancer starting at early stages of malignant transformation. To optimize the CAR design, we used antigen-recognition domains derived from mouse or human antibodies, and intracellular signaling domains containing one or two T cell costimulatory elements, in addition to CD3zeta...
December 2014: Human Gene Therapy
Sujin Lee, Robert S Mittler, Martin L Moore
Respiratory syncytial virus (RSV) causes significant morbidity and mortality in children and the elderly. No vaccines for RSV are in use. Because of immunosenescence, the immunologic requirements for a successful RSV vaccine in the elderly might differ from a RSV vaccine for young children. Using an aged mouse model of RSV pathogenesis, we found that aged mice had impaired Ag-specific CD8(+) T cell responses and delayed RSV clearance compared with young mice. To study vaccine-elicited RSV-specific CD8(+) T cells in aged mice, we used a peptide vaccine approach...
January 1, 2014: Journal of Immunology: Official Journal of the American Association of Immunologists
Andreas A Hombach, Hinrich Abken
No abstract text is available yet for this article.
July 2013: Immunotherapy
Álvaro Teijeira, Asís Palazón, Saray Garasa, Diego Marré, Cristina Aubá, Anne Rogel, Ohiana Murillo, Iván Martínez-Forero, François Lang, Ignacio Melero, Ana Rouzaut
CD137/TNFR9/41BB was originally described as a surface molecule present on activated T and NK cells. However, its expression is broader among leukocytes, and it is also detected on hypoxic endothelial cells and inflamed blood vessels, as well as in atherosclerotic lesions. Here, we demonstrate that lymphatic endothelial cells (LECs) up-regulate CD137 expression from undetectable baseline levels on stimulation with TNF-α, LPS, and IL-1β. CD137 cross-linking with an agonistic mAb results in NF-κB nuclear translocation, followed by up-regulation of VCAM and a 3-fold increase in the production of the chemokine CCL21...
August 2012: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
John Stagg, Sherene Loi, Upulie Divisekera, Shin Foong Ngiow, Helene Duret, Hideo Yagita, Michele W Teng, Mark J Smyth
Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor-2 (HER2/ErbB-2), has become the mainstay of treatment for HER2-positive breast cancer. Nevertheless, its exact mechanism of action has not been fully elucidated. Although several studies suggest that Fc receptor-expressing immune cells are involved in trastuzumab therapy, the relative contribution of lymphocyte-mediated cellular cytotoxicity and antitumor cytokines remains unknown. We report here that anti-ErbB-2 mAb therapy is dependent on the release of type I and type II IFNs but is independent of perforin or FasL...
April 26, 2011: Proceedings of the National Academy of Sciences of the United States of America
Hiroyuki Fujisaki, Harumi Kakuda, Noriko Shimasaki, Chihaya Imai, Jing Ma, Timothy Lockey, Paul Eldridge, Wing H Leung, Dario Campana
Infusions of natural killer (NK) cells are an emerging tool for cancer immunotherapy. The development of clinically applicable methods to produce large numbers of fully functional NK cells is a critical step to maximize the potential of this approach. We determined the capacity of the leukemia cell line K562 modified to express a membrane-bound form of interleukin (IL)-15 and 41BB ligand (K562-mb15-41BBL) to generate human NK cells with enhanced cytotoxicity. Seven-day coculture with irradiated K562-mb15-41BBL induced a median 21...
May 1, 2009: Cancer Research
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