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adoptive cell transfer

Paul Zolkind, Gavin P Dunn, Tianxiang Lin, Malachi Griffith, Obi L Griffith, Ravindra Uppaluri
The recent success of immunotherapies has demonstrated the potency of tumor-specific immune cells in mediating tumor rejection and generating durable tumor immunity. Our understanding of the scientific basis of these responses results from the confluence of a better comprehension of the cancer immunoediting process and the revolution in next generation sequencing of cancer genomes. Recent evidence suggests that T cell specificity for cancer cell expressed mutant proteins - termed neoantigens - is an important component of immune mediated tumor rejection...
October 14, 2016: Oral Oncology
Alireza Bolourian, Zahra Mojtahedi
Mammalian target of rapamycin (mTOR) inhibitors are strong anti-tumor drugs; however, they have adverse immunosuppressive side effects in some cancer patients. Animal studies have provided evidence that mTOR inhibitors improved tumor-specific T-cells adoptive transfer in which the quality of CD8+ T-cells is a major factor for predicting success. Interestingly, mTOR inhibitors are capable of stimulating cytotoxic CD8+ T-cell if their dose/duration is adjusted. Rapamycin-induced CD8+ T-cells have also been associated with tumor immunity in animal models...
July 2016: Archives of Medical Research
Pravin Kesarwani, Paramita Chakraborty, Radhika Gudi, Shilpak Chatterjee, Gina Scurti, Kyle Toth, Patt Simms, Mahvash Husain, Kent Armeson, Shahid Husain, Elizabeth Garrett-Mayer, Chethamarakshan Vasu, Michael I Nishimura, Shikhar Mehrotra
Advancements in adoptive cell transfer therapy (ACT) has led to the use of T cells engineered with tumor specific T cell receptors, which after rapid expansion can be obtained in sufficient numbers for treating patients. However, due to massive proliferation these cells are close to replicative senescence, exhibit exhausted phenotype, and also display increased susceptibility to activation induced cell death. We have previously shown that tumor reactive T cells undergo caspase-independent cell death upon TCR restimulation with cognate antigen, which involves reactive oxygen species and c-jun N-terminal kinase...
October 14, 2016: Oncotarget
Yifeng Cai, Shoubao Ma, Yuejun Liu, Huanle Gong, Qiao Cheng, Bo Hu, Yan Wu, Xiao Yu, Chen Dong, Kai Sun, Depei Wu, Haiyan Liu
The role of IL-17 and IL-17-producing CD4(+) T cells in acute graft-versus-host disease (GVHD) has been controversial in recent mouse and human studies. We carried out studies in a murine acute GVHD model of fully major histocompatibility complex-mismatched myeloablative bone marrow transplantation. We showed that donor wild-type CD4(+) T cells exacerbated acute GVHD compared with IL-17(-/-) CD4(+) T cells, while IL-17 reduced the severity of acute GVHD. The augmentation of acute GVHD by transferred donor IL-17-producing CD4(+) T cells was associated with increased Th1 responses, while IL-17 decreased the percentages of Th1 cells in the GVHD target organs...
October 17, 2016: Cellular & Molecular Immunology
Fahima Madouri, Pauline Chenuet, Chloé Beuraud, Louis Fauconnier, Tiffany Marchiol, Nathalie Rouxel, Aurélie Ledru, Margaux Gallerand, Vincent Lombardi, Laurent Mascarell, Quentin Marquant, Lionel Apetoh, François Erard, Marc Le Bert, Fabrice Trovero, Valérie F J Quesniaux, Bernhard Ryffel, Dieudonnée Togbe
BACKGROUND: Protein Kinase C theta (PKC-θ), a serine/threonine kinase is involved in T helper 2 (Th2) cell activation and proliferation. Innate lymphoid cells 2 (ILC2) resemble Th2 cells; produce the Th2 cytokines IL-5 and IL-13, but lack antigen specific receptors. The mechanism by which PKC-θ drives innate immune cells to instruct Th2 responses in allergic lung inflammation remains unknown. OBJECTIVES: We hypothesized that PKC-θ contributes to ILC2 activation and may be necessary for ILC2 to instruct Th2 response...
October 13, 2016: Journal of Allergy and Clinical Immunology
Matthew J Scheffel, Gina Scurti, Patricia Simms, Elizabeth Garrett-Mayer, Shikhar Mehrotra, Michael I Nishimura, Christina Voelkel-Johnson
Although adoptive transfer of autologous tumor antigen-specific T-cell immunotherapy can produce remarkable clinical efficacy, most patients do not achieve durable complete responses. We hypothesized that reducing susceptibility of T cells to activation-induced cell death (AICD), which increases during the rapid in vitro expansion of therapeutic T cells before their infusion, might improve the persistence of adoptively transferred cells. Our investigations revealed that repetitive stimulation of the T-cell receptor (TCR) induced AICD, as a result of activating the DNA damage response pathway through ATM-mediated Ser15 phosphorylation of p53...
October 15, 2016: Cancer Research
Umberto Maggiore, Julio Pascual
Cancer immunotherapy, especially the use of checkpoint inhibitors, is expanding and can be efficacious in organ transplant recipients with malignant neoplasia. In this review, we summarize clinical findings and evolution of several patients treated with CTL4-4 or PD-1 inhibitors reported in the literature. The CTL-4 inhibitor ipilimumab has been safely used in several liver and kidney allograft recipients. PD1-inhibitors look promising for tumor shrinking, but acute rejection is the rule, so they should be avoided in recipients of life-saving organs...
September 2016: Advances in Chronic Kidney Disease
Catherine Daniel, Marie Titecat, Sabine Poiret, Delphine Cayet, Denise Boutillier, Michel Simonet, Jean-Claude Sirard, Nadine Lemaître, Florent Sebbane
BACKGROUND: Pseudotuberculosis is an infection caused by the bacterial enteropathogen Yersinia pseudotuberculosis and is considered to be a significant problem in veterinary medicine. We previously found that intranasal administration of a recombinant Lactococcus lactis strain that secretes the low-calcium response V (LcrV) antigen from Y. pseudotuberculosis (Ll-LcrV) confers protection against a lethal Y. pseudotuberculosis infection. Here, we aimed at characterizing the immunological basis of this LcrV-elicited protective response and at determining the duration of vaccine-induced immunity...
October 11, 2016: Vaccine
Siri Tähtinen, Carolin Blattner, Markus Vähä-Koskela, Dipongkor Saha, Mikko Siurala, Suvi Parviainen, Jochen Utikal, Anna Kanerva, Viktor Umansky, Akseli Hemminki
The immunosuppressive microenvironment of solid tumors renders adoptively transferred T cells hypofunctional. However, adenoviral delivery of immunostimulatory cytokines IL2 and TNFα can significantly improve the efficacy of adoptive T-cell therapy. Using ret transgenic mice that spontaneously develop skin malignant melanoma, we analyzed the mechanism of action of adenoviruses coding for IL2 and TNFα in combination with adoptive transfer of TCR-transgenic TRP-2-specific T cells. Following T-cell therapy and intratumoral virus injection, a significant increase in antigen-experienced, tumor-reactive PD-1 CD8 T cells was seen in both cutaneous lesions and in metastatic lymph nodes...
November 2016: Journal of Immunotherapy
Young Uk Kim, Byung-Seok Kim, Hoyong Lim, Rick A Wetsel, Yeonseok Chung
CXCR5⁺ T follicular helper (Tfh) cells are associated with aberrant autoantibody production in patients with antibody-mediated autoimmune diseases including lupus. Follicular regulatory T (Tfr) cells expressing CXCR5 and Bcl6 have been recently identified as a specialized subset of Foxp3⁺ regulatory T (Treg) cells that control germinal center reactions. In this study, we show that retroviral transduction of CXCR5 gene in Foxp3⁺ Treg cells induced a stable expression of functional CXCR5 on their surface...
October 17, 2016: Biomolecules & Therapeutics
Christine Gonzales, Hikari A I Yoshihara, Nahzli Dilek, Julie Leignadier, Melita Irving, Pascal Mieville, Lothar Helm, Olivier Michielin, Juerg Schwitter
BACKGROUND: 19F-MRI and 19F-MRS can identify specific cell types after in-vitro or in-vivo 19F-labeling. Knowledge on the potential to track in-vitro 19F-labeled immune cells in tumor models by 19F-MRI/MRS is scarce. AIM: To study 19F-based MR techniques for in-vivo tracking of adoptively transferred immune cells after in-vitro 19F-labeling, i.e. to detect and monitor their migration non-invasively in melanoma-bearing mice. METHODS: Splenocytes (SP) were labeled in-vitro with a perfluorocarbon (PFC) and IV-injected into non-tumor bearing mice...
2016: PloS One
Hajera Amatullah, Yuexin Shan, Brittany L Beauchamp, Patricia L Gali, Sahil Gupta, Tatiana Maron-Gutierrez, Edwin R Speck, Alison E Fox-Robichaud, Jennifer L Y Tsang, Shirley H J Mei, Tak W Mak, Patricia Rm Rocco, John W Semple, Haibo Zhang, Pingzhao Hu, John C Marshall, Duncan J Stewart, Mary-Ellen Harper, Patricia C Liaw, W Conrad Liles, Claudia C Dos Santos
RATIONALE & OBJECTIVES: Effective and rapid bacterial clearance is a fundamental determinant of outcome(s) in sepsis. DJ-1 is a well-established reactive oxygen species (ROS) scavenger. As cellular ROS status is pivotal to inflammation and bacterial killing, we determined the role of DJ-1 in bacterial sepsis. METHODS: We used cell and murine models with gain and loss of function experiments, plasma and cells from septic patients. MEASUREMENTS & RESULTS: Stimulation of bone marrow derived macrophages (BMM) with endotoxin resulted in increased DJ-1 mRNA and protein expression...
October 13, 2016: American Journal of Respiratory and Critical Care Medicine
Epameinondas Gousopoulos, Steven T Proulx, Samia B Bachmann, Jeannette Scholl, Dimitris Dionyssiou, Efterpi Demiri, Cornelia Halin, Lothar C Dieterich, Michael Detmar
Secondary lymphedema is a common postcancer treatment complication, but the underlying pathological processes are poorly understood and no curative treatment exists. To investigate lymphedema pathomechanisms, a top-down approach was applied, using genomic data and validating the role of a single target. RNA sequencing of lymphedematous mouse skin indicated upregulation of many T cell-related networks, and indeed depletion of CD4(+) cells attenuated lymphedema. The significant upregulation of Foxp3, a transcription factor specifically expressed by regulatory T cells (Tregs), along with other Treg-related genes, implied a potential role of Tregs in lymphedema...
October 6, 2016: JCI Insight
Kerstin Renner, Sonja Hellerbrand, Fabian Hermann, Christine Riedhammer, Yvonne Talke, Gabriela Schiechl, Manuel Rodriguez Gomez, Simone Kutzi, Dagmar Halbritter, Nicole Goebel, Hilke Brühl, Robert Weissert, Matthias Mack
Little is known about the role of IL-3 in multiple sclerosis (MS) in humans and in experimental autoimmune encephalomyelitis (EAE). Using myelin oligodendrocyte glycoprotein (MOG) peptide-induced EAE, we show that CD4(+) T cells are the main source of IL-3 and that cerebral IL-3 expression correlates with the influx of T cells into the brain. Blockade of IL-3 with monoclonal antibodies, analysis of IL-3 deficient mice, and adoptive transfer of leukocytes demonstrate that IL-3 plays an important role for development of clinical symptoms of EAE, for migration of leukocytes into the brain, and for cerebral expression of adhesion molecules and chemokines...
October 6, 2016: JCI Insight
Emilio Brunetti, Steven Moerkerke, Johan Wouters, Kristin Bartik, Ivan Jabin
The development of chemosensors that can selectively detect phosphatidylcholines (PCs) in biological samples is of medical relevance considering the importance of these phospholipids in cell growth and survival. Their selective sensing over phosphatidylethanolamines (PEs) is however a challenging task. We report here on the chemosensing capacities of calix[6]tris-pyrenylurea 1, which is able to selectively interact with phosphatidylcholine-type lipids in organic media. Host 1 also binds them in a biphasic chloroform/water solution, opening the way to the design of selective chemosensors for these lipids in biological media...
October 12, 2016: Organic & Biomolecular Chemistry
Hanchao Gao, Chengjiang Zhao, Xi Xiang, Yong Li, Yanli Zhao, Zesong Li, Dengke Pan, Yifan Dai, Hidetaka Hara, David K C Cooper, Zhiming Cai, Lisha Mou
Gene-knockout pigs hold great promise as a solution to the shortage of organs from donor animals for xenotransplantation. Several groups have generated gene-knockout pigs via clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) and somatic cell nuclear transfer (SCNT). Herein, we adopted a simple and micromanipulator-free method, handmade cloning (HMC) instead of SCNT, to generate double gene-knockout pigs. First, we applied the CRISPR/Cas9 system to target α1,3-galactosyltransferase (GGTA1) and cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) genes simultaneously in porcine fetal fibroblast cells (PFFs), which were derived from wild-type Chinese domestic miniature Wuzhishan pigs...
October 8, 2016: Journal of Reproduction and Development
Anning Li, Yue Wu, Jenny Linnoila, Benjamin Pulli, Cuihua Wang, Matthias Zeller, Muhammad Ali, Grant K Lewandrowski, Jinghui Li, Benoit Tricot, Edmund Keliher, Gregory R Wojtkiewicz, Giulia Fulci, Xiaoyuan Feng, Bakhos A Tannous, Zhenwei Yao, John W Chen
Currently, there is no stable and flexible method to label and track cytotoxic T lymphocytes (CTLs) in vivo in CTL immunotherapy. We aimed to evaluate whether the sulfo-hydroxysuccinimide (NHS)-biotin-streptavidin (SA) platform could chemically modify the cell surface of CTLs for in vivo tracking. CD8+ T lymphocytes were labeled with sulfo-NHS-biotin under different conditions and then incubated with SA-Alexa647. Labeling efficiency was proportional to sulfo-NHS-biotin concentration. CD8+ T lymphocytes could be labeled with higher efficiency with sulfo-NHS-biotin in DPBS than in RPMI (P < 0...
October 8, 2016: Cancer Immunology, Immunotherapy: CII
Diamanda Rigas, Gavin Lewis, Jennifer L Aron, Bowen Wang, Homayon Banie, Ishwarya Sankaranarayanan, Lauriane Galle-Treger, Hadi Maazi, Richard Lo, Gordon J Freeman, Arlene H Sharpe, Pejman Soroosh, Omid Akbari
BACKGROUND: Atopic diseases including asthma exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T cells (Tregs) and the emerging group 2 innate lymphoid cells (ILC2s). While ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood. OBJECTIVE: In the present study, we evaluate for the first time how Tregs interact with pulmonary ILC2s and control their function...
October 4, 2016: Journal of Allergy and Clinical Immunology
Maria Pannell, Dominika Labuz, Melih Ö Celik, Jacqueline Keye, Arvind Batra, Britta Siegmund, Halina Machelska
BACKGROUND: During the inflammation which occurs following nerve damage, macrophages are recruited to the site of injury. Phenotypic diversity is a hallmark of the macrophage lineage and includes pro-inflammatory M1 and anti-inflammatory M2 populations. Our aim in this study was to investigate the ability of polarized M0, M1, and M2 macrophages to secrete opioid peptides and to examine their relative contribution to the modulation of neuropathic pain. METHODS: Mouse bone marrow-derived cells were cultured as unstimulated M0 macrophages or were stimulated into an M1 phenotype using lipopolysaccharide and interferon-γ or into an M2 phenotype using interleukin-4...
October 7, 2016: Journal of Neuroinflammation
Sabine Tischer, René Geyeregger, Julian Kwoczek, Albert Heim, Constanca Figueiredo, Rainer Blasczyk, Britta Maecker-Kolhoff, Britta Eiz-Vesper
BACKGROUND: Human adenovirus (HAdV) infections remain a significant cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Efficient antiviral T-cell responses are necessary to clear infection, which is hampered by delayed immune reconstitution and medical immunosuppression after HSCT. Protective immunity may be conferred by adoptive transfer of HAdV-specific T cells. For identification of patients at risk and monitoring of treatment responses diligent assessment of anti-HAdV cellular immune responses is crucial...
October 7, 2016: Journal of Translational Medicine
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