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Adoptive T-Cell Therapy

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https://www.readbyqxmd.com/read/28635517/a-primer-for-oncoimmunology-immunooncology
#1
Brad Bolon, Famke Aeffner
Oncoimmunology (or immunooncology) is a burgeoning specialty of precision ("personalized") medicine designed to heighten the antitumor response of the immune system against molecules expressed excessively or only by tumor cells. This focus is necessary, as cancers are polyclonal tissues comprised of antigenically heterogeneous cells, the exact composition of which is shaped by the balance between antitumor immunity and tumor-promoting inflammation. Key targets include enhancing immune system (especially T cell) reactivity, inhibiting immune checkpoints, and promoting tumor cytolysis...
January 1, 2017: Toxicologic Pathology
https://www.readbyqxmd.com/read/28633756/immunotherapy-the-wave-of-the-future-in-bladder-cancer
#2
Daniel P Petrylak
Urothelial cell carcinoma (UC) is one of the most common cancers and one of the most deadly. Metastatic UC is particularly hard to treat, because it is typically diagnosed when patients are elderly and have medical comorbidities. Many patients with metastatic UC are unable to receive cisplatin-based chemotherapy, due to older age at diagnosis and comorbidities, and even when platinum chemotherapy can be administered, it has limited success in prolonging survival. Recently, improved understanding of molecular targets and immunologic characteristics of urothelial tumor cells has resulted in new therapeutic approaches that may help optimize first- and second-line therapy...
June 2017: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/28629762/targeting-the-tumor-and-its-associated-stroma-one-and-one-can-make-three-in-adoptive-t-cell-therapy-of-solid-tumors
#3
Anna Mondino, Gerlanda Vella, Laura Icardi
Adoptive T cell therapy (ACT) has become a promising immunotherapeutic option for cancer patients. The proof for ACT therapeutic efficacy was first obtained with allogenic T cells and then reproduced with T cells isolated from patients' tumor samples (i.e. tumor-infiltrating lymphocytes). It is now clear that specificity of ACT products can be educated by genetically engineering T cells with classical T Cell Receptors (TCR) or chimeric antigen receptors (CAR). To date a poor accessibility of the tumor mass and a hostile microenvironment, influenced by genetic and epigenetic instability, mainly limit ACT therapeutic efficacy in the case of solid tumors...
June 15, 2017: Cytokine & Growth Factor Reviews
https://www.readbyqxmd.com/read/28629761/cytokines-for-the-induction-of-antitumor-effectors-the-paradigm-of-cytokine-induced-killer-cik-cells
#4
Elisa Cappuzzello, Roberta Sommaggio, Paola Zanovello, Antonio Rosato
Cytokine-Induced killer (CIK) cells are raising growing interest in cellular antitumor therapy, as they can be easily expanded with a straightforward and inexpensive protocol, and are safe requiring only GMP-grade cytokines to obtain very high amounts of cytotoxic cells. CIK cells do not need antigen-specific stimuli to be activated and proliferate, as they recognize and destroy tumor cells in an HLA-independent fashion through the engagement of NKG2D. In several preclinical studies and clinical trials, CIK cells showed a reduced alloreactivity compared to conventional T cells, even when challenged across HLA-barriers; only in a few patients, a mild GVHD occurred after treatment with allogeneic CIK cells...
June 3, 2017: Cytokine & Growth Factor Reviews
https://www.readbyqxmd.com/read/28615711/identification-and-characterization-of-a-rich-population-of-cd34-mesenchymal-stem-stromal-cells-in-human-parotid-sublingual-and-submandibular-glands
#5
Padma Priya Togarrati, Robson T Sasaki, Mohamed Abdel-Mohsen, Nuntana Dinglasan, Xutao Deng, Shivani Desai, Elaine Emmerson, Elizabeth Yee, William R Ryan, Marcelo C P da Silva, Sarah M Knox, Satish K Pillai, Marcus O Muench
Mesenchymal stem/stromal cells (MSCs) play crucial roles in maintaining tissue homeostasis during physiological turnovers and injuries. Very little is known about the phenotype, distribution and molecular nature of MSCs in freshly isolated human salivary glands (SGs) as most reports have focused on the analysis of cultured MSCs. Our results demonstrate that the cell adhesion molecule CD34 was widely expressed by the MSCs of human major SGs, namely parotid (PAG), sublingual (SLG) and submandibular (SMG) glands...
June 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28615225/enhanced-therapeutic-efficacy-and-memory-of-tumor-specific-cd8-t-cells-by-ex-vivo-pi3k-%C3%AE-inhibition
#6
Rasha Abu-Eid, Shamim Ahmad, Yuan Lin, Mason Webb, Zuzana Berrong, Rajeev K Shrimali, Takumi Kumai, Sudha Ananth, Paulo C Rodriguez, Esteban Celis, John E Janik, Mikayel Mkrtichyan, Samir N Khleif
Inhibition of specific Akt isoforms in CD8+ T cells promotes favored differentiation into memory versus effector cells, the former of which are superior in mediating anti-tumor immunity. In this study, we investigated the role of upstream PI3K isoforms in CD8+ T cell differentiation and assessed the potential use of PI3K isoform-specific inhibitors to favorably condition CD8+ T cells for adoptive cell therapy. The phenotype and proliferative ability of tumor antigen specific CD8+ T cells was assessed in the presence of PI3K-α, -β, or -δ inhibitors...
June 14, 2017: Cancer Research
https://www.readbyqxmd.com/read/28614908/adenoviral-production-of-interleukin-2-at-the-tumor-site-removes-the-need-for-systemic-postconditioning-in-adoptive-cell-therapy
#7
Joao Manuel Santos, Riikka Havunen, Mikko Siurala, Víctor Cervera-Carrascon, Siri Tähtinen, Suvi Sorsa, Marjukka Anttila, Pauliina Karell, Anna Kanerva, Akseli Hemminki
Systemic high-dose interleukin-2 (IL-2) postconditioning has long been utilized in boosting the efficacy of T cells in adoptive cell therapy (ACT) of solid tumors. The resulting severe off-target toxicity of these regimens renders local production at the tumor an attractive concept with possible safety gains. We evaluated the efficacy and safety of intratumorally administered IL-2-coding adenoviruses in combination with tumor-infiltrating lymphocyte therapy in syngeneic Syrian hamsters bearing HapT1 pancreatic tumors and with T cell receptor transgenic ACT in B16...
June 14, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28614795/a-3d-microfluidic-model-for-preclinical-evaluation-of-tcr-engineered-t-cells-against-solid-tumors
#8
Andrea Pavesi, Anthony T Tan, Sarene Koh, Adeline Chia, Marta Colombo, Emanuele Antonecchia, Carlo Miccolis, Erica Ceccarello, Giulia Adriani, Manuela T Raimondi, Roger D Kamm, Antonio Bertoletti
The tumor microenvironment imposes physical and functional constraints on the antitumor efficacy of adoptive T cell immunotherapy. Preclinical testing of different T cell preparations can help in the selection of efficient immune therapies, but in vivo models are expensive and cumbersome to develop, while classical in vitro 2D models cannot recapitulate the spatiotemporal dynamics experienced by T cells targeting cancer. Here, we describe an easily customizable 3D model, in which the tumor microenvironment conditions are modulated and the functionality of different T cell preparations is tested...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28604557/antigen-presentation-by-individually-transferred-hla-class-i-genes-in-hla-a-hla-b-hla-c-null-human-cell-line-generated-using-the-multiplex-crispr-cas9-system
#9
Cheol-Hwa Hong, Hyun-Jung Sohn, Hyun-Joo Lee, Hyun-Il Cho, Tai-Gyu Kim
Human leukocyte antigens (HLAs) are essential immune molecules that affect transplantation and adoptive immunotherapy. When hematopoietic stem cells or organs are transplanted with HLA-mismatched recipients, graft-versus-host disease or graft rejection can be induced by allogeneic immune responses. The function of each HLA allele has been studied using HLA-deficient cells generated from mutant cell lines or by RNA interference, zinc finger nuclease, and the CRISPR/Cas9 system. To improve HLA gene editing, we attempted to generate an HLA class I null cell line using the multiplex CRISPR/Cas9 system by targeting exons 2 and 3 of HLA-A, HLA-B, and HLA-C genes simultaneously...
July 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/28594388/gene-therapy-for-pancreatic-cancer-specificity-issues-and-hopes
#10
REVIEW
Marie Rouanet, Marine Lebrin, Fabian Gross, Barbara Bournet, Pierre Cordelier, Louis Buscail
A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments of therapeutic innovations in combination with conventional chemotherapy are needed urgently. Among innovative treatments the gene therapy offers a promising avenue. The present review gives an overview of the general strategy of gene therapy as well as the limitations and stakes of the different experimental in vivo models, expression vectors (synthetic and viral), molecular tools (interference RNA, genome editing) and therapeutic genes (tumor suppressor genes, antiangiogenic and pro-apoptotic genes, suicide genes)...
June 8, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28586310/effective-control-of-acute-myeloid-leukaemia-and-acute-lymphoblastic-leukaemia-progression-by-telomerase-specific-adoptive-t-cell-therapy
#11
Sara Sandri, Francesco De Sanctis, Alessia Lamolinara, Federico Boschi, Ornella Poffe, Rosalinda Trovato, Alessandra Fiore, Sara Sartori, Andrea Sbarbati, Attilio Bondanza, Simone Cesaro, Mauro Krampera, Maria T Scupoli, Michael I Nishimura, Manuela Iezzi, Silvia Sartoris, Vincenzo Bronte, Stefano Ugel
Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28586044/noninvasive-detection-of-acute-renal-allograft-rejection-by-measurement-of-soluble-tim-3-in-urine
#12
Dajin Chen, Wenhan Peng, Hong Jiang, Hao Yang, Jianyong Wu, Huiping Wang, Jianghua Chen
The purpose of the present study was to assess whether urinary soluble T-cell immunoglobulin and mucin domain-containing protein 3 (sTim-3) could be adopted as a novel non‑invasive biomarker for acute rejection (AR) following renal transplantation. A total of 156 patients were enrolled between January 2006 and December 2009, comprising 49 patients with biopsy‑proven AR, 58 patients with stable grafts and no abnormal histological findings (NO‑AR), 10 patients with subclinical rejection (SCR) in protocol biopsies, 10 patients with acute tubular necrosis (ATN) and 29 patients with chronic allograft nephropathy (CAN)...
July 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28582800/regulation-of-cd4-t-cells-and-their-effects-on-immunopathological-inflammation-following-viral-infection
#13
Mitra Bhattacharyya, Patrick Madden, Nathan Henning, Shana Gregory, Malika Aid, Amanda Martinot, Dan H Barouch, Pablo Penaloza-MacMaster
CD4 T cells help immune responses, but knowledge of how memory CD4 T cells are regulated and how they regulate adaptive immune responses and induce immunopathology is limited. Using adoptive transfer of virus-specific CD4 T cells, we show that naïve CD4 T cells undergo substantial expansion following infection, but can induce lethal TH1-driven inflammation. In contrast, memory CD4 T cells exhibit a biased proliferation of T follicular helper (Tfh) cell subsets and were able to improve adaptive immune responses in the context of minimal tissue damage...
June 5, 2017: Immunology
https://www.readbyqxmd.com/read/28571578/immunotherapy-in-head-and-neck-cancer-aiming-at-extreme-precision
#14
Petr Szturz, Jan B Vermorken
BACKGROUND: Locoregionally advanced, recurrent, and metastatic squamous cell carcinomas of the head and neck (SCCHN) remain difficult to treat disease entities, in which systemic treatment often forms an integral part of their management. Immunotherapy is based on functional restoration of the host immune system, helping to counteract various tumour evasion strategies. Broadly, immunotherapeutic approaches encompass tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating agents...
June 2, 2017: BMC Medicine
https://www.readbyqxmd.com/read/28570507/trends-in-prevalence-of-advanced-hiv-disease-at-antiretroviral-therapy-enrollment-10-countries-2004-2015
#15
Andrew F Auld, Ray W Shiraishi, Ikwo Oboho, Christine Ross, Moses Bateganya, Valerie Pelletier, Jacob Dee, Kesner Francois, Nirva Duval, Mayer Antoine, Chris Delcher, Gracia Desforges, Mark Griswold, Jean Wysler Domercant, Nadjy Joseph, Varough Deyde, Yrvel Desir, Joelle Deas Van Onacker, Ermane Robin, Helen Chun, Isaac Zulu, Ishani Pathmanathan, E Kainne Dokubo, Spencer Lloyd, Rituparna Pati, Jonathan Kaplan, Elliot Raizes, Thomas Spira, Kiren Mitruka, Aleny Couto, Eduardo Samo Gudo, Francisco Mbofana, Melissa Briggs, Charity Alfredo, Carla Xavier, Alfredo Vergara, Ndapewa Hamunime, Simon Agolory, Gram Mutandi, Naemi N Shoopala, Souleymane Sawadogo, Andrew L Baughman, Adebobola Bashorun, Ibrahim Dalhatu, Mahesh Swaminathan, Dennis Onotu, Solomon Odafe, Oseni Omomo Abiri, Henry H Debem, Hank Tomlinson, Velephi Okello, Peter Preko, Trong Ao, Caroline Ryan, George Bicego, Peter Ehrenkranz, Harrison Kamiru, Harriet Nuwagaba-Biribonwoha, Gideon Kwesigabo, Angela A Ramadhani, Kahemele Ng'wangu, Patrick Swai, Mohamed Mfaume, Ramadhani Gongo, Deborah Carpenter, Timothy D Mastro, Carol Hamilton, Julie Denison, Fred Wabwire-Mangen, Olivier Koole, Kwasi Torpey, Seymour G Williams, Robert Colebunders, Julius N Kalamya, Alice Namale, Michelle R Adler, Bridget Mugisa, Sundeep Gupta, Sharon Tsui, Eric van Praag, Duc B Nguyen, Sheryl Lyss, Yen Le, Abu S Abdul-Quader, Nhan T Do, Modest Mulenga, Sebastian Hachizovu, Owen Mugurungi, Beth A Tippett Barr, Elizabeth Gonese, Tsitsi Mutasa-Apollo, Shirish Balachandra, Stephanie Behel, Trista Bingham, Duncan Mackellar, David Lowrance, Tedd V Ellerbrock
Monitoring prevalence of advanced human immunodeficiency virus (HIV) disease (i.e., CD4+ T-cell count <200 cells/μL) among persons starting antiretroviral therapy (ART) is important to understand ART program outcomes, inform HIV prevention strategy, and forecast need for adjunctive therapies.*(,)(†)(,)(§) To assess trends in prevalence of advanced disease at ART initiation in 10 high-burden countries during 2004-2015, records of 694,138 ART enrollees aged ≥15 years from 797 ART facilities were analyzed...
June 2, 2017: MMWR. Morbidity and Mortality Weekly Report
https://www.readbyqxmd.com/read/28561728/adoptive-t-cell-therapy-for-solid-tumors
#16
Oladapo Yeku, Xinghuo Li, Renier J Brentjens
Chimeric antigen receptor (CAR) T-cell therapy is an innovative form of immunotherapy wherein autologous T cells are genetically modified to express chimeric receptors encoding an antigen-specific single-chain variable fragment and various costimulatory molecules. Upon administration, these modified T cells traffic to, and recognize, cancer cells in an HLA-independent manner. CAR T-cell therapy has shown remarkable success in the treatment of CD-19-expressing B-cell acute lymphocytic leukemia. However, clinical gains to the same magnitude have not been reported in solid tumors...
2017: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/28561703/hematologic-malignancies-plasma-cell-disorders
#17
Madhav V Dhodapkar, Ivan Borrello, Adam D Cohen, Edward A Stadtmauer
Multiple myeloma (MM) is a plasma cell malignancy characterized by the growth of tumor cells in the bone marrow. Properties of the tumor microenvironment provide both potential tumor-promoting and tumor-restricting properties. Targeting underlying immune triggers for evolution of tumors as well as direct attack of malignant plasma cells is an emerging focus of therapy for MM. The monoclonal antibodies daratumumab and elotuzumab, which target the plasma cell surface proteins CD38 and SLAMF7/CS1, respectively, particularly when used in combination with immunomodulatory agents and proteasome inhibitors, have resulted in high response rates and improved survival for patients with relapsed and refractory MM...
2017: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/28544545/cytoprotective-encapsulation-of-individual-jurkat-t-cells-within-durable-tio2-shells-for-t-cell-therapy
#18
Wongu Youn, Eun Hyea Ko, Mi-Hee Kim, Matthew Park, Daewha Hong, Gulaim A Seisenbaeva, Vadim G Kessler, Insung S Choi
Lymphocytes, such as T cells and natural killer (NK) cells, have therapeutic promises in adoptive cell transfer (ACT) therapy, where the cells are activated and expanded in vitro, and then infused into a patient. However, the in vitro preservation of labile lymphocytes during transfer, manipulation, and storage has been one of the bottlenecks in the development and commercialization of therapeutic lymphocytes. Herein, we suggest a "cell-in-shell" (a.k.a. artificial spore) strategy to enhance the cell viability in the practical settings, while maintaining biological activities for therapeutic efficacy...
May 25, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28544101/belatacept-combined-with-transient-calcineurin-inhibitor-therapy-prevents-rejection-and-promotes-improved-long-term-renal-allograft-function
#19
A B Adams, J Goldstein, C Garrett, R Zhang, R E Patzer, K A Newell, N A Turgeon, A S Chami, A Guasch, A D Kirk, S O Pastan, T C Pearson, C P Larsen
Belatacept, a T cell costimulation-blocker demonstrated superior renal function, lower cardiovascular risk, and improved graft/patient survival in renal transplant recipients. Despite the potential benefits, adoption of belatacept has been limited in part due to concerns regarding higher rates and grades of acute rejection in clinical trials. Since July 2011 we have utilized belatacept-based immunosuppression regimens in clinical practice. In this retrospective analysis of 745 patients undergoing renal transplantation at our center, we compared patients treated with belatacept (n=535) to a historical cohort receiving a tacrolimus-based protocol (n=205)...
May 23, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28543698/adoptive-t-cell-therapy-an-overview-of-obstacles-and-opportunities
#20
REVIEW
Erez Nissim Baruch, Amy Lauren Berg, Michal Judith Besser, Jacob Schachter, Gal Markel
The therapeutic potential of adoptive cell therapy (ACT) in cancer patients was first acknowledged 3 decades ago, but it was an esoteric approach at the time. In recent years, technological advancements have transformed ACT into a viable therapeutic option that can be curative in some patients. In fact, current ACT response rates are 80% to 90% for hematological malignancies and 30% for metastatic melanoma refractory to multiple lines of therapy. Although these results are encouraging, there is still much to be done to fulfill ACT's potential, specifically with regard to improving clinical efficacy, expanding clinical indications, reducing toxicity, and increasing production and cost-effectiveness...
June 1, 2017: Cancer
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