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cytotoxic t cell therapy

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https://www.readbyqxmd.com/read/28087047/rational-design-of-low-immunogenic-anti-cd25-recombinant-immunotoxin-for-t-cell-malignancies-by-elimination-of-t-cell-epitopes-in-pe38
#1
Ronit Mazor, Gilad Kaplan, Dong Park, Youjin Jang, Fred Lee, Robert Kreitman, Ira Pastan
LMB-2, is a potent recombinant immunotoxin (RIT) that is composed of scFv antibody that targets CD25 (Tac) and a toxin fragment (PE38). It is used to treat T cell leukemias and lymphomas. To make LMB-2 less immunogenic, we introduced a large deletion in domain II and six point mutations in domain III that were previously shown to reduce T cell activation in other RITs. We found that unlike other RITs, deletion of domain II from LMB-2 severely compromised its activity. Rather than deletion, we identified T cell epitopes in domain II and used alanine substitutions to identify point mutations that diminished those epitopes...
January 5, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28079009/emerging-roles-of-calreticulin-in-cancer-implications-for-therapy
#2
Kavya Venkateswaran, Amit Verma, Anant Narayan Bhatt, Anju Shrivastava, Kailash Manda, Hanumantharao G Raj, Ashok Prasad, Christophe Len, Virinder S Parmar, Bilikere Dwarakanath
Calreticulin (CRT), initially identified as a ubiquitous calcium-binding protein in the endoplasmic reticulum, has emerged as a multifunctional protein with roles in calcium homeostasis, molecular chaperoning and cell adhesion. Emerging evidence suggests its involvement in tumorigenesis facilitating proliferation, migration, and adhesion. CRT translocated to the cell surface (ecto-CRT) serves as a phagocytic signal for immunogenic cell death (ICD) mediated through dendritic cells (DCs) and cytotoxic T-cell activation thereby making tumors susceptible to immunotherapy-based anti-cancer strategies...
January 11, 2017: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/28076376/increased-natural-killer-cell-activation-in-hiv-infected-immunologic-non-responders-correlates-with-cd4-t-cell-recovery-after-antiretroviral-therapy-and-viral-suppression
#3
Zhenwu Luo, Zhen Li, Lisa Martin, Zhiliang Hu, Hao Wu, Zhuang Wan, Michael Kilby, Sonya L Heath, Lei Huang, Wei Jiang
The role of natural killer (NK) cell function in HIV disease especially in the setting of long-term antiretroviral therapy (ART) and viral suppression is not fully understood. In the current study, we have investigated NK cell activation in healthy controls and aviremic ART-treated HIV+ subjects with different degrees of immune restoration. We performed a cross sectional study in 12 healthy controls and 24 aviremic ART-treated HIV-infected subjects including 13 HIV+ subjects with CD4+ T cells above 500 cells/μL defined as "immunologic responders" and 11 HIV+ subjects with CD4+ T cells below 350 cells/μL defined as "immunologic non-responders"...
2017: PloS One
https://www.readbyqxmd.com/read/28075524/topk-t-lak-cell-originated-protein-kinase-inhibitor-exhibits-growth-suppressive-effect-on-small-cell-lung-cancer
#4
Jae-Hyun Park, Hiroyuki Inoue, Taigo Kato, Makda Zewde, Takashi Miyamoto, Yo Matsuo, Ravi Salgia, Yusuke Nakamura
T-lymphokine-activated killer cell-originated protein kinase (TOPK) plays critical roles in cancer cell proliferation as well as maintenance of cancer stem cells (CSC). Small cell lung cancer (SCLC) has highly aggressive phenotype, reveals early spread to distant sites, and results in dismal prognosis with little effective treatment. In this study, we demonstrate that TOPK expression was highly upregulated in both SCLC cell lines and primary tumors. Similar to siRNA-mediated TOPK knockdown effects, treatment with a potent TOPK inhibitor, OTS514, effectively suppressed growth of SCLC cell lines (IC50 ; 0...
January 11, 2017: Cancer Science
https://www.readbyqxmd.com/read/28075442/increased-expression-of-pd%C3%A2-l1-by-the-human-papillomavirus-16-e7-oncoprotein-inhibits-anticancer-immunity
#5
Chaoqi Liu, Jiao Lu, Huiqun Tian, Wei Du, Lin Zhao, Jing Feng, Ding Yuan, Zhiying Li
Cytotoxic T lymphocyte dysfunction is frequently associated with PD‑L1/PD‑1 pathway activation, and is a principal obstacle in cancer therapy. In the present study, the mechanisms underlying the human papillomavirus (HPV)‑induced evasion of cervical cancer cells to the host immune system via the programmed death ligand  1/programmed death 1 (PD‑L1/PD‑1) signaling pathway was investigated. A significant increase in the expression of the HPV16E7 viral protein and PD‑L1 in cervical tissues was observed when compared with normal cervical tissues...
January 5, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28075428/balanced-secretion-of-anti-cea-x-anti-cd3-diabody-chains-using-the-2a-self-cleaving-peptide-maximizes-diabody-assembly-and-tumor-specific-cytotoxicity
#6
K Mølgaard, M Compte, N Nuñez-Prado, S L Harwood, L Sanz, L Alvarez-Vallina
Adoptive transfer of genetically engineered human cells secreting bispecific T cell engagers has shown encouraging therapeutic effects in preclinical models of cancer. However, reducing the toxicity and improving the effectiveness of this emerging immunotherapeutic strategy will be critical to its successful application. We have demonstrated that for gene-based bispecific antibody strategies, two-chain diabodies have a better safety profile than single-chain tandem scFvs, because their reduced tendency to form aggregates reduces the risk of inducing antigen-independent T cell activation...
January 11, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28074218/-autoimmune-diseases-of-the-thyroid-gland
#7
S Allelein, J Feldkamp, M Schott
Autoimmune diseases of the thyroid gland are considered to be the most frequent cause of thyroid gland disorders. Autoimmune thyroid diseases consist of two subgroups: autoimmune thyroiditis (AIT) and Graves' disease. The AIT is the most common human autoimmune disease. Infiltration of the thyroid gland with cytotoxic T‑cells can lead to an initial thyrotoxicosis und during the course to hypothyroidism due to destruction of the thyroid gland. Substitution with Levothyroxine is indicated for manifest hypothyroidism and subclinical hypothyroidism with increased thyroid antibodies with the intention of normalizing the serum thyroid stimulating hormone (TSH)...
January 10, 2017: Der Internist
https://www.readbyqxmd.com/read/28073960/ligand-characterization-of-cyp4b1-isoforms-modified-for-high-level-expression-in-escherichia-coli-and-hepg2-cells
#8
Katharina Roellecke, Vera D Jäger, Veselin H Gyurov, John P Kowalski, Stephanie Mielke, Allan E Rettie, Helmut Hanenberg, Constanze Wiek, Marco Girhard
Human CYP4B1, a cytochrome P450 monooxygenase predominantly expressed in the lung, inefficiently metabolizes classical CYP4B1 substrates, such as the naturally occurring furan pro-toxin 4-ipomeanol (4-IPO). Highly active animal forms of the enzyme convert 4-IPO to reactive alkylating metabolite(s) that bind(s) to cellular macromolecules. By substitution of 13 amino acids, we restored the enzymatic activity of human CYP4B1 toward 4-IPO and this modified cDNA is potentially valuable as a suicide gene for adoptive T-cell therapies...
January 10, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/28073775/dasatinib-changes-immune-cell-profiles-concomitant-with-reduced-tumor-growth-in-several-murine-solid-tumor-models
#9
Can Hekim, Mette Ilander, Jun Yan, Erin Michaud, Richard Smykla, Markus Vähä-Koskela, Paula Savola, Siri Tähtinen, Leena Saikko, Akseli Hemminki, Panu E Kovanen, Kimmo Porkka, Francis Yf Lee, Satu Mustjoki
Dasatinib, a broad range tyrosine kinase inhibitor (TKI), induces rapid mobilization of lymphocytes and clonal expansion of cytotoxic cells in leukemia patients. Here, we investigated whether dasatinib could induce beneficial immunomodulatory effects in solid tumor models. The effects on tumor growth and on the immune system were studied in four different syngeneic mouse models (B16.OVA melanoma, 1956 sarcoma, MC38 colon, and 4T1 breast carcinoma). Both peripheral blood (PB) and tumor samples were immunophenotyped during treatment...
January 10, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28073132/hypothyroidism-in-cancer-patients-on-immune-checkpoint-inhibitors-with-anti-pd1-agents-insights-on-underlying-mechanisms
#10
M Alhusseini, J Samantray
Background: Immune therapy using monoclonal antibodies against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 receptor (PD-1) for various cancers have been reported to cause thyroid dysfunction. Little is known, however, about the underlying pathogenic mechanisms and the course of hypothyroidism that subsequently develops. In this report, we use the change in thyroglobulin and thyroid antibody levels in patients on immune therapy who develop hypothyroidism to better understand its pathogenesis as well as examine the status of hypothyroidism in the long term...
January 10, 2017: Experimental and Clinical Endocrinology & Diabetes
https://www.readbyqxmd.com/read/28065783/mathematical-modeling-of-mutant-transferrin-crm107-molecular-conjugates-for-cancer-therapy
#11
Dennis J Yoon, Kevin Y Chen, André M Lopes, April A Pan, Joseph Shiloach, Anne B Mason, Daniel T Kamei
The transferrin (Tf) trafficking pathway is a promising mechanism for use in targeted cancer therapy due to the overexpression of transferrin receptors (TfRs) on cancerous cells. We have previously developed a mathematical model of the Tf/TfR trafficking pathway to improve the efficiency of Tf as a drug carrier. By using diphtheria toxin (DT) as a model toxin, we found that mutating the Tf protein to change its iron release rate improves cellular association and efficacy of the drug. Though this is an improvement upon using wild-type Tf as the targeting ligand, conjugated toxins like DT are unfortunately still highly cytotoxic at off-target sites...
January 6, 2017: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/28064019/the-random-co-polymer-glatiramer-acetate-rapidly-kills-primary-human-leukocytes-through-sialic-acid-dependent-cell-membrane-damage
#12
Stig Hill Christiansen, Xianwei Zhang, Kristian Juul-Madsen, Michael Lykke Hvam, Brian Stougaard Vad, Manja Annette Behrens, Ida Lysgaard Thygesen, Babak Jalilian, Jan Skov Pedersen, Kenneth A Howard, Daniel E Otzen, Thomas Vorup-Jensen
The formulation glatiramer acetate (GA) is widely used in therapy of multiple sclerosis. GA consists of random copolymers of four amino acids, in ratios that produce a predominantly positive charge and an amphipathic character. With the extraordinary complexity of the drug, several pharmacological modes-of-action were suggested, but so far none, which rationalizes the cationicity and amphipathicity as part of the mode-of-action. Here, we report that GA rapidly kills primary human T lymphocytes and, less actively, monocytes...
January 5, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28059852/immune-checkpoint-inhibitors-in-first-line-therapy-of-advanced-non-small-cell-lung-cancer
#13
Jordi Remon, Benjamin Besse
PURPOSE OF REVIEW: Evading immune destruction is a hallmark of cancer. The first therapeutic wave in immunotherapies comprised a series of monoclonal antibodies directed against the immune checkpoint molecules cytotoxic T-lymphocyte-associated protein 4, programmed death 1 (PD-1), and programmed death ligand-1 (PD-L1) revolutionizing the therapeutic landscape of advanced non-small cell lung cancer. They were validated initially as second-line treatment, becoming the new standard of care...
January 3, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28059091/identification-of-distinct-subgroups-of-ebv-positive-post-transplant-diffuse-large-b-cell-lymphoma
#14
Julie Morscio, Julio Finalet Ferreiro, Sara Vander Borght, Emilie Bittoun, Olivier Gheysens, Daan Dierickx, Gregor Verhoef, Iwona Wlodarska, Thomas Tousseyn
Post-transplantation lymphoproliferative disorder is an aggressive complication of transplantation, most frequently of diffuse large B-cell lymphoma morphology and associated with Epstein-Barr virus (EBV) infection/reactivation. In this study the microenvironment of EBV(+) (n=23) and EBV(-) (n=9) post-transplant non-germinal center B-cell diffuse large B-cell lymphoma was characterized. Of EBV(+) cases somatic hypermutation analysis, gene expression profiling, and extensive phenotyping were performed. Our results demonstrated variable cytotoxic T-cell infiltration and significantly increased CD163(+) M2 macrophage infiltration in EBV(+) compared with EBV(-) post-transplant diffuse large B-cell lymphoma...
January 6, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28058568/assessment-of-the-antimicrobial-antioxidant-and-cytotoxic-activities-of-the-wild-edible-mushroom-agaricus-lanipes-f-h-m%C3%A3-ller-jul-sch%C3%A3-ff-hlav%C3%A3-%C3%A4-ek
#15
Oğuzhan Kaygusuz, Meruyert Kaygusuz, Yavuz Dodurga, Mücahit Seçme, Emine Nur Herken, Kutret Gezer
The present investigation was undertaken to evaluate the antimicrobial and antioxidant activities of the wild edible mushroom Agaricus lanipes, and also to investigate its cytotoxicity and potential and possible apoptotic effect against the A549 lung cancer cell line in in vitro conditions. Total antioxidant capacity, total phenolic content, total oxidant status, total antioxidant status, lipid hydroperoxides, and total free -SH levels of A. lanipes were found to be 4.55 mg T/g, 14.6 mg GA equivalent/g, 3...
January 5, 2017: Cytotechnology
https://www.readbyqxmd.com/read/28056337/marked-enteropathy-in-an-accelerated-macaque-model-of-aids
#16
Joshua D Croteau, Elizabeth L Engle, Suzanne E Queen, Erin N Shirk, M Christine Zink
Enteropathy in HIV infection is not eliminated with combination antiretroviral therapy and is possibly linked to microbial translocation. We used a rapidly progressing SIV/pigtailed macaque model of HIV to examine enteropathy and microbial translocation. Histologic evidence of intestinal disease was observed in only half of infected macaques during late-stage infection (LSI). Combination antiretroviral therapy initiated during acute infection prevented intestinal disease. In the ileum and colon, enteropathy was associated with increased caspase-3 staining, decreased CD3(+) T cells, and increased SIV-infected cells...
January 2, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28056202/trastuzumab-emtansine-with-or-without-pertuzumab-versus-trastuzumab-plus-taxane-for-human-epidermal-growth-factor-receptor-2-positive-advanced-breast-cancer-primary-results-from-the-phase-iii-marianne-study
#17
Edith A Perez, Carlos Barrios, Wolfgang Eiermann, Masakazu Toi, Young-Hyuck Im, Pierfranco Conte, Miguel Martin, Tadeusz Pienkowski, Xavier Pivot, Howard Burris, Jennifer A Petersen, Sven Stanzel, Alexander Strasak, Monika Patre, Paul Ellis
Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) -targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study...
January 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28056055/hdac-and-proteasome-inhibitors-synergize-to-activate-pro-apoptotic-factors-in-synovial-sarcoma
#18
Aimée N Laporte, Jared J Barrott, Ren Jie Yao, Neal M Poulin, Bertha A Brodin, Kevin B Jones, T Michael Underhill, Torsten O Nielsen
Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting its driving SS18-SSX fusion oncoprotein are currently available. Patients remain at high risk for early and late metastasis. A high-throughput drug screen consisting of over 900 tool compounds and epigenetic modifiers, representing over 100 drug classes, was undertaken in a panel of synovial sarcoma cell lines to uncover novel sensitizing agents and targetable pathways. Top scoring drug categories were found to be HDAC inhibitors and proteasomal targeting agents...
2017: PloS One
https://www.readbyqxmd.com/read/28055304/synergistic-effect-of-cytokine-induced-killer-cell-with-valproate-inhibits-growth-of-hepatocellular-carcinoma-cell-in-a-mouse-model
#19
Dong Hyeon Lee, Joon Yeul Nam, Young Chang, Hyeki Cho, Seong Hee Kang, Young Youn Cho, EunJu Cho, Jeong-Hoon Lee, Su Jong Yu, Yoon Jun Kim, Jung-Hwan Yoon
OBJECTIVE: Long-term prognosis of hepatocellular carcinoma (HCC) remains poor owing to the lack of treatment options for advanced HCC. Cytokine-induced killer (CIK) cells are ex vivo expanded T lymphocytes expressing both NK- and T-cell markers. CIK cell therapy alone is insufficient for treating advanced HCC. Thus, this study aimed to determine whether treatment with CIK cells combined with valproic acid (VPA) could provide a synergistic effect to inhibit tumor growth in a mouse model of HCC...
January 5, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28049640/cml-patients-with-deep-molecular-responses-to-tki-have-restored-immune-effectors-decreased-pd-1-and-immune-suppressors
#20
Amy Hughes, Jade Clarson, Carine Tang, Ljiljana Vidovic, Deborah L White, Timothy P Hughes, Agnes S M Yong
Immunological control may contribute to achievement of deep molecular response in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitor (TKI) therapy and may promote treatment free remission (TFR). We investigated effector and suppressor immune responses in CML patients at diagnosis (n=21), on TKI (imatinib, nilotinib, dasatinib) prior to achieving major molecular response (pre-MMR, BCR-ABL1 >0.1%, n=8), MMR (BCR-ABL1 ≤0.1%, n=20), molecular response(4.5) (MR(4.5), BCR-ABL1 ≤0.0032%, n=16) and sustained TFR (BCR-ABL1 undetectable following cessation of TKI therapy, n=13)...
January 3, 2017: Blood
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