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Adoptive T cell therapy

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https://www.readbyqxmd.com/read/28331617/current-approaches-to-increase-car-t-cell-potency-in-solid-tumors-targeting-the-tumor-microenvironment
#1
REVIEW
Irene Scarfò, Marcela V Maus
Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary treatment for haematological malignancies (i.e. B-ALL). However, the success of this type of treatment has not yet been achieved in solid tumors. One hypothesis is that the immunosuppressive nature of the tumor microenvironment (TME) influences and affects the efficacy of adoptive immunotherapy. Understanding the role of the TME and its interaction with CAR T-cells is crucial to improve the potency of adoptive immunotherapy. In this review, we discuss the strategies and potential combinatorial approaches recently developed in mouse models to enhance the efficacy of CAR T-cells, with particular emphasis on the translational potential of these approaches...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28331616/ex-vivo-akt-inhibition-promotes-the-generation-of-potent-cd19car-t-cells-for-adoptive-immunotherapy
#2
Ryan Urak, Miriam Walter, Laura Lim, ChingLam W Wong, Lihua E Budde, Sandra Thomas, Stephen J Forman, Xiuli Wang
BACKGROUND: Insufficient persistence and effector function of chimeric antigen receptor (CAR)-redirected T cells have been challenging issues for adoptive T cell therapy. Generating potent CAR T cells is of increasing importance in the field. Studies have demonstrated the importance of the Akt pathway in the regulation of T cell differentiation and memory formation. We now investigate whether inhibition of Akt signaling during ex vivo expansion of CAR T cells can promote the generation of CAR T cells with enhanced antitumor activity following adoptive therapy in a murine leukemia xenograft model...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28331613/systematic-evaluation-of-immune-regulation-and-modulation
#3
REVIEW
David F Stroncek, Lisa H Butterfield, Michael A Cannarile, Madhav V Dhodapkar, Tim F Greten, Jean Charles Grivel, David R Kaufman, Heidi H Kong, Firouzeh Korangy, Peter P Lee, Francesco Marincola, Sergio Rutella, Janet C Siebert, Giorgio Trinchieri, Barbara Seliger
Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28321811/interleukin-2-old-and-new-approaches-to-enhance-immune-therapeutic-efficacy
#4
Pooja Dhupkar, Nancy Gordon
Interleukin-2 (IL-2) is a very well-known cytokine that has been studied for the past 35 years. It plays a major role in the growth and proliferation of many immune cells such NK and T cells. It is an important immunotherapy cytokine for the treatment of various diseases including cancer. Systemic delivery of IL-2 has shown clinical benefit in renal cell carcinoma and melanoma patients. However, its use has been limited by the numerous toxicities encountered with the systemic delivery. Intravenous IL-2 causes the well-known "capillary leak syndrome," or the leakage of fluid from the circulatory system to the interstitial space resulting in hypotension (low blood pressure), edema, and dyspnea that can lead to circulatory shock and eventually cardiopulmonary collapse and multiple organ failure...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28320444/ox40-signaling-is-involved-in-the-autoactivation-of-cd4-cd28-t-cells-and-contributes-to-the-pathogenesis-of-autoimmune-arthritis
#5
Juean Jiang, Cuiping Liu, Mi Liu, Yu Shen, Xiaohan Hu, Qin Wang, Jian Wu, Min Wu, Qi Fang, Xueguang Zhang
BACKGROUND: CD4(+)CD28(-) T cells exhibit autoreactive potential in autoimmune disorders, including rheumatoid arthritis (RA). It is not well known which costimulator functions as an alternative second signal in the activation of this subset after CD28 expression is downregulated. Tumor necrosis factor receptor superfamily member OX40 is a key costimulator in the activation of T cells. The aim of this study was to investigate the costimulatory effects of OX40 on CD4(+)CD28(-) T cells in autoimmune arthritis...
March 21, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28318492/-brain-tumor-immunotherapy-illusion-or-hope
#6
REVIEW
Denis Migliorini, Valérie Dutoit, Paul R Walker, Pierre-Yves Dietrich
Immunotherapy has proven efficient for many tumors and is now part of standard of care in many indications. What is the picture for brain tumors? The recent development of anti-CTLA-4 and PD1 immune checkpoint inhibitors, which have the ability to restore T lymphocytes activity, has gathered enthusiasm and is now paving the way towards more complex models of immune system manipulation. These models include, among others, vaccination and adoptive T cell transfer technologies. Complementary to those strategies, molecules capable of reshaping the immune tumor microenvironment are currently being investigated in early phase trials...
March 16, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/28317871/insights-into-molecular-therapy-of-glioma-current-challenges-and-next-generation-blueprint
#7
REVIEW
Y Rajesh, Ipsita Pal, Payel Banik, Sandipan Chakraborty, Sachin A Borkar, Goutam Dey, Ahona Mukherjee, Mahitosh Mandal
Glioma accounts for the majority of human brain tumors. With prevailing treatment regimens, the patients have poor survival rates. In spite of current development in mainstream glioma therapy, a cure for glioma appears to be out of reach. The infiltrative nature of glioma and acquired resistance substancially restrict the therapeutic options. Better elucidation of the complicated pathobiology of glioma and proteogenomic characterization might eventually open novel avenues for the design of more sophisticated and effective combination regimens...
March 20, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28316970/dgk-%C3%AE-a-checkpoint-in-cancer-mediated-immuno-inhibition-and-target-for-immunotherapy
#8
Elfriede Noessner
Immunotherapy is moving to the forefront of cancer treatments owing to impressive durable responses achieved with checkpoint blockade antibodies and adoptive T-cell therapy. Still, improvements are necessary since, overall, only a small percentage of patients benefit from current therapies. Here, I summarize evidence that DGK-α may represent an immunological checkpoint suppressing the activity of cytotoxic immunocytes in the tumor microenvironment. DGK-inhibitors can restore the antitumor function of tumor-suppressed adaptive and innate cytotoxic immunocytes...
2017: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/28302023/anti-egfrviii-chimeric-antigen-receptor-modified-t-cells-for-adoptive-cell-therapy-of-glioblastoma
#9
Pei-Pei Ren, Ming Li, Tian-Fang Li, Shuang-Yin Han
Glioblastoma (GBM) is one of the most devastating brain tumors with poor prognosis and high mortality. Although radical surgical treatment with subsequent radiation and chemotherapy can improve the survival, the efficacy of such regimens is insufficient because the GBM cells can spread and destroy normal brain structures. Moreover, these non-specific treatments may damage adjacent healthy brain tissue. It is thus imperative to develop novel therapies to precisely target invasive tumor cells without damaging normal tissues...
March 16, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28301281/cell-based-immunotherapy-with-cytokine-induced-killer-cik-cells-from-preparation-and-testing-to-clinical-application
#10
Yiming Meng, Zhifu Yu, Yefeng Wu, Tianzhao Du, Shi Chen, Fanjuan Meng, Nan Su, Yushu Ma, Xiaoxi Li, Sulan Sun, Guirong Zhang
Cell-based immunotherapy holds promise in the quest for the treatment of cancer, having potential synergy with surgery, chemotherapy and radiotherapy. As a novel approach for adoptive cell-based immunotherapy, cytokine-induced killer (CIK) cells have moved from the 'bench to bedside'. CIK cells are a heterogeneous subset of ex-vitro expanded, polyclonal T-effector cells with both natural killer (NK) and T-cell properties, which present potent non-major histocompatibility complex-restricted cytotoxicity against a variety of tumor target cells...
February 22, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28301076/clinical-development-of-anti-cd19-chimeric-antigen-receptor-t-cell-therapy-for-b-cell-non-hodgkin-lymphoma
#11
Shinichi Makita, Kiyoshi Yoshimura, Kensei Tobinai
B-cell non-Hodgkin lymphoma (B-NHL) is the most frequent hematological malignancy. Although refined chemotherapy regimens and several new therapeutics including rituximab, a chimeric anti-CD20 monoclonal antibody, have improved its prognosis in recent decades, there are still a substantial number of patients with chemorefractory B-NHL. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is expected to be an effective adoptive cell treatment and has the potential to overcome the chemorefractoriness of B-cell leukemia and lymphoma...
March 16, 2017: Cancer Science
https://www.readbyqxmd.com/read/28289713/th17-cells-are-refractory-to-senescence-and-retain-robust-antitumor-activity-after-long-term-ex-vivo-expansion
#12
Jacob S Bowers, Michelle H Nelson, Kinga Majchrzak, Stefanie R Bailey, Baerbel Rohrer, Andrew D M Kaiser, Carl Atkinson, Luca Gattinoni, Chrystal M Paulos
Adoptive immunotherapy for solid tumors relies on infusing large numbers of T cells to mediate successful antitumor responses in patients. While long-term rapid-expansion protocols (REPs) produce sufficient numbers of CD8(+) T cells for treatment, they also cause decline in the cell's therapeutic fitness. In contrast, we discovered that IL-17-producing CD4(+) T cells (Th17 cells) do not require REPs to expand 5,000-fold over 3 weeks. Also, unlike Th1 cells, Th17 cells do not exhibit hallmarks of senescence or apoptosis, retaining robust antitumor efficacy in vivo...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28284008/effective-and-persistent-antitumor-activity-of-her2-directed-car-t-cells-against-gastric-cancer-cells-in-vitro-and-xenotransplanted-tumors-in-vivo
#13
Yanjing Song, Chuan Tong, Yao Wang, Yunhe Gao, Hanren Dai, Yelei Guo, Xudong Zhao, Yi Wang, Zizheng Wang, Weidong Han, Lin Chen
Human epidermal growth factor receptor 2 (HER2) proteins are overexpressed in a high proportion of gastric cancer (GC) cases and affect the maintenance of cancer stem cell (CSC) subpopulations, which are used as targets for the clinical treatment of patients with HER2-positive GC. Despite improvements in survival, numerous HER2-positive patients fail treatment with trastuzumab, highlighting the need for more effective therapies. In this study, we generated a novel type of genetically modified human T cells, expressing a chimeric antigen receptor (CAR), and targeting the GC cell antigen HER2, which harbors the CD137 and CD3ζ moieties...
March 10, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28280853/murine-th17-cells-utilize-il-2-receptor-gamma-chain-cytokines-but-are-resistant-to-cytokine-withdrawal-induced-apoptosis
#14
Daniel J Neitzke, Jacob S Bowers, Kristina Andrijauskaite, Nathaniel S O'Connell, Elizabeth Garrett-Mayer, John Wrangle, Zihai Li, Chrystal M Paulos, David J Cole, Mark P Rubinstein
Adoptive cellular therapy (ACT) with the Th17 subset of CD4(+) T cells can cure established melanoma in preclinical models and holds promise for treating human cancer. However, little is known about the growth factors necessary for optimal engraftment and anti-tumor activity of Th17 cells. Due to the central role of IL-2 receptor gamma chain (IL2Rγ-chain) cytokines (IL-2, IL-7, and IL-15) in the activity and persistence of many T cell subsets after adoptive transfer, we hypothesized that these cytokines are important for Th17 cells...
March 9, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28280089/successful-transfer-of-umbilical-cord-blood-cd34-hematopoietic-stem-and-progenitor-derived-nk-cells-in-older-acute-myeloid-leukemia-patients
#15
Harry Dolstra, Mieke W H Roeven, Jan Spanholtz, Basav N Hangalapura, Marleen Tordoir, Frans Maas, Marij Leenders, Fenna Bohme, Nina Kok, Carel Trilsbeek, Jos Paardekooper, Anniek B van der Waart, Peter E Westerweel, Tjeerd J F Snijders, Jan J Cornelissen, Gerard M J Bos, Hans F M Pruijt, Aniek O De Graaf, Bert van der Reijden, Joop H Jansen, Arnold van der Meer, Gerwin Huls, Jeannette Cany, Frank Preijers, Nicole M A Blijlevens, Nicolaas M Schaap
PURPOSE: Older acute myeloid leukemia (AML) patients have a poor prognosis, therefore novel therapies are needed. Allogeneic natural killer (NK) cells have been adoptively transferred with promising clinical results. Here, we report the first-in-human study exploiting an unique scalable NK cell product generated ex vivo from CD34+ hematopoietic stem and progenitor cells (HSPCs) from partially HLA-matched umbilical cord blood units. EXPERIMENTAL DESIGN: Ten older AML patients in morphologic complete remission received an escalating HSPC-NK cell dose (between 3 and 30x10^6/kg body weight) after lymphodepleting chemotherapy without cytokine boosting...
March 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28276713/aberrant-function-of-myeloid-derived-suppressor-cells-mdscs-in-experimental-colitis-and-in-inflammatory-bowel-disease-ibd-immune-responses
#16
Eleni Kontaki, Dimitrios T Boumpas, Maria Tzardi, Ioannis A Mouzas, Konstantinos A Papadakis, Panayotis Verginis
BACKGROUND AND AIMS: Myeloid-derived suppressor cells (MDSCs) encompass a novel population of suppressor cells and a potential candidate for cell-based therapies in inflammatory diseases. Herein, we investigated their immunomodulatory properties in experimental inflammatory colitis and T cell-mediated immune responses in inflammatory bowel disease (IBD) patients. METHODS: MDSCs (defined as CD14(-)HLA(-)DR(-/low)CD33(+)CD15(+)) numbers were determined in peripheral blood (PB) from IBD patients...
March 3, 2017: Autoimmunity
https://www.readbyqxmd.com/read/28271325/nebulization-of-rns60-a-physically-modified-saline-attenuates-the-adoptive-transfer-of-experimental-allergic-encephalomyelitis-in-mice-implications-for-multiple-sclerosis-therapy
#17
Susanta Mondal, Suresh B Rangasamy, Supurna Ghosh, Richard L Watson, Kalipada Pahan
Developing a new and effective therapeutic approach against multiple sclerosis (MS) is always an important area of research. RNS60 is a bioactive aqueous solution generated by subjecting normal saline to Taylor-Couette-Poiseuille flow under elevated oxygen pressure. Recently we have demonstrated that RNS60, administered through intraperitoneal injection, ameliorated clinical symptoms and disease progression of experimental allergic encephalomyelitis (EAE), an animal model of MS. Since the intravenous route is not preferred for treating a chronic condition, we tested if nebulization of RNS60 could attenuate the disease process of adoptively-transferred EAE in mice...
March 7, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28268304/cardiac-katp-channel-modulation-by-16hz-magnetic-fields-a-theoretical-study
#18
Yuval Aharonovich, Mickey Scheinowitz, Sharon Zlochiver
Heart exposure to 16Hz magnetic fields (MFs) was shown to be cardio-protective for diseased hearts; still, the mechanism of this effect is unknown. We hypothesize that a possible one mechanism is an increased trans-membrane KATP channel open probability due to modulation of the degree of dissociation between K+ ions, having a resonance frequency of 16Hz, and the channel selectivity filter. The Fan-Makielski Markovian KATP channel model was adopted, and the MF bio-effect was manifested by modulating the open probability of the channel using the predictive MF bio-effect parameter based on Binhi's quantum mechanics model...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28259946/%C3%AE-%C3%AE-tcr-immunoglobulin-constant-region-domain-exchange-in-human-%C3%AE-%C3%AE-tcrs-improves-tcr-pairing-without-altering-tcr-gene-modified-t-cell-function
#19
Changli Tao, Hongwei Shao, Wenfeng Zhang, Huaben Bo, Fenglin Wu, Han Shen, Shulin Huang
The adoptive genetic transfer of T cell receptors (TCRs) has been shown to be overall feasible and offer clinical potential as a treatment for different types of cancer. However, this promising clinical approach is limited by the serious potential consequence that exogenous TCR mispairing with endogenous TCR chains may lead to the risk of self-reactivity. In the present study, domain‑exchange and three‑dimensional modeling strategies were used to create a set of chimeric TCR variants, which were used to exchange the partial or complete constant region of αβTCR with corresponding γδTCR domains...
February 15, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28247187/development-of-novel-immunopet-tracers-to-image-human-pd-1-checkpoint-expression-on-tumor-infiltrating-lymphocytes-in-a-humanized-mouse-model
#20
Arutselvan Natarajan, Aaron T Mayer, Robert E Reeves, Claude M Nagamine, Sanjiv Sam Gambhir
PURPOSE: It is well known that cancers exploit immune checkpoints (programmed death 1 receptor (PD-1) and its ligand (PD-L1)) to evade anti-tumor immune responses. Although immune checkpoint (IC) blockade is a promising approach, not all patients respond. Hence, imaging of tumor-infiltrating lymphocytes (TILs) is of high specific interest, as they are known to express PD-1 during activation and subsequent exhaustion in the tumor microenvironment and are thought to be potentially predictive of therapeutic responses to IC blockade...
February 28, 2017: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
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