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cytotoxic t cell therapy

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
Yong Yu, Jason C H Tsang, Cui Wang, Simon Clare, Juexuan Wang, Xi Chen, Cordelia Brandt, Leanne Kane, Lia S Campos, Liming Lu, Gabrielle T Belz, Andrew N J McKenzie, Sarah A Teichmann, Gordon Dougan, Pentao Liu
Innate lymphoid cells (ILCs) functionally resemble T lymphocytes in cytotoxicity and cytokine production but lack antigen-specific receptors, and are important regulators in immune response and tissue homeostasis(1, 2). ILCs are generated from common lymphoid progenitors (CLPs), which are subsequently committed to innate lymphoid lineages in the α lymphoid progenitor (αLP), early innate lymphoid progenitor (EILP), common helper innate lymphoid progenitor (CHILP) and innate lymphoid cell progenitor (ILCP) compartments(3, 4, 5, 6, 7, 8)...
September 29, 2016: Nature
Sheldon Greer, Tieran Han, Cristina Dieguez, Nicola McLean, Rafael Saer, Isildinha Reis, Joe Levi, Victor E Marquez
Enzymatic activity from tumor and adjacent normal tissue of 200 patients involving deoxycytidine kinase (dCK), uridine/cytidine kinase (U/CK), cytidine deaminase (CD) and deoxycytidylate deaminase (dCMPD) was quantified. . Patients with brain (17), colon (24), and breast (30) tumors, 53, 67, and 73%, respectively, had an elevated T/N value (Specific Activity of tumor/ Specific Activity of normal tissue) involving dCK and dCMPD suggesting chemo therapy with 5-fluorodeoxycytidine (5-FdC) alone or in combination with thymidine plus deoxytetrahydrouridine, or with the radiosensitizer, 5-chlorodeoxycytidine (5-CldC) plus tetrahydrouridine (H4U)...
October 13, 2016: Anti-cancer Agents in Medicinal Chemistry
Daniel H Li, James B Whitmore, Wentian Guo, Yuan Ji
Recent trials of adoptive cell therapy (ACT), such as the chimeric antigen receptor T (CAR-T) cells therapy, have demonstrated promising therapeutic effects for cancer patients. A main issue in the product development is to decide appropriate dose of ACT. Traditional phase 1 trial designs for cytotoxic agents explicitly assume that toxicity increases monotonically with dose levels and implicitly assume the same for efficacy to justify dose escalation. ACT usually induces rapid responses, and the monotonic dose-response assumption is unlikely to hold due to its immunobiological activities...
October 14, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
A K S Salama, S J Moschos
BACKGROUND: Cancers escape immune surveillance via distinct mechanisms that involve central (negative selection within the thymus) or peripheral (lack of costimulation, receipt of death/anergic signals by tumor, immunoregulatory cell populations) immune tolerance. During the 1990s, moderate clinical benefit was seen using several cytokine therapies for a limited number of cancers. Over the past 20 years, extensive research has been performed to understand the role of various components of peripheral immune tolerance, with the co-inhibitory immune checkpoint molecules cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand (PD-L1) being the most well characterized at preclinical and clinical levels...
October 13, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
G L Uy, E J Duncavage, G S Chang, M A Jacoby, C A Miller, J Shao, S Heath, K Elliott, T Reinick, R S Fulton, C C Fronick, M O'Laughlin, L Ganel, C N Abboud, A F Cashen, J F DiPersio, R K Wilson, D C Link, J S Welch, T J Ley, T A Graubert, P Westervelt, M J Walter
Traditional response criteria in MDS and AML are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (i...
October 14, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Sara Alonso-Álvarez, Maria Belén Vidriales, Maria Dolores Caballero, Oscar Blanco, Noemí Puig, Alejandro Martin, Maria Jesús Peñarrubia, Esther Zato, Josefina Galende, Abelardo Bárez, Miguel Alcoceba, Alberto Orfão, Marcos González, Ramón García-Sanz
Prognostic factors in Hodgkin lymphoma (HL) still fail to accurately identify high-risk patients. Tumor microenvironment in HL is a current focus of research for risk definition but few studies have focused on infiltrating lymphocytes. Here, we analyzed the number of tumor infiltrating lymphocytes by flow cytometry in diagnostic biopsies from 96 HL homogeneously treated patients with ABVD with or without radiotherapy. Most lymph node cells were lymphocytes (90 ± 17), with a median T/B/NK distribution of 74%/26%/0...
October 12, 2016: Leukemia & Lymphoma
Sana Saif Ur Rehman, Suresh S Ramalingam
Advanced stage nonsmall cell lung cancer had been treated mainly with platinum-based doublet chemotherapy, and other cytotoxic agents that offered significant survival advantage over best supportive care, until recently. Modest improvements were achieved with the addition of antibodies targeting the vascular endothelial growth factor, and the introduction of maintenance chemotherapy. Improvements in our knowledge of lung cancer biology have shifted the current treatment paradigm from being based on histology to one based on molecular biomarkers...
October 2016: Seminars in Respiratory and Critical Care Medicine
Anuradha Basavaraju
Toxoplasma gondii is an obligate intracellular protozoan parasite presenting as a zoonotic infection distributed worldwide. In HIV-positive individuals, it causes severe opportunistic infections, which is of major public health concern as it results in physical and psychological disabilities. In healthy immunocompetent individuals, it causes asymptomatic chronic persistent infections, but in immunosuppressed patients, there is reactivation of the parasite if the CD4 counts fall below 200 cells/μl. The seroprevalence rates are variable in different geographic areas...
July 2016: Tropical Parasitology
Rahul Sampath, Nathan W Cummins, Andrew D Badley
HIV cure is now the focus of intense research after Timothy Ray Brown (the Berlin patient) set the precedent of being the first and only person cured. A major barrier to achieving this goal on a meaningful scale is an elimination of the latent reservoir, which is thought to comprise CD4-positive cells that harbor integrated, replication-competent HIV provirus. These cells do not express viral proteins, are indistinguishable from uninfected CD4 cells, and are thought to be responsible for HIV viral rebound-that occurs within weeks of combination anti retroviral therapy (cART) interruption...
2016: Journal of Cell Death
David W Nauen
Anti-N-methyl-d-aspartate-type glutamate receptor autoimmune encephalitis can arise in the setting of ovarian teratoma and often responds to resection. When it occurs in the absence of tumor, failure to respond to treatment may be more likely, and affected patients often require intensive care. To further understand the mechanisms and potential management, we present findings from an autopsy conducted on a young woman who died of refractory autoimmune encephalitis of this type. Rituximab was administered 70 days before death, and both 37 and 14 days before death, CD19(+) lymphocytes were only 0...
September 22, 2016: Journal of Critical Care
Baochang Qi, Tiecheng Yu, Chengxue Wang, Tiejun Wang, Jihang Yao, Xiaomeng Zhang, Pengfei Deng, Yongning Xia, Wolfgang G Junger, Dahui Sun
BACKGROUND: Osteosarcoma is the most prevalent primary malignant bone tumor, but treatment is difficult and prognosis remains poor. Recently, large-dose chemotherapy has been shown to improve outcome but this approach can cause many side effects. Minimizing the dose of chemotherapeutic drugs and optimizing their curative effects is a current goal in the management of osteosarcoma patients. METHODS: In our study, trypan blue dye exclusion assay was performed to investigate the optimal conditions for the sensitization of osteosarcoma U2OS cells...
October 3, 2016: Journal of Experimental & Clinical Cancer Research: CR
Xianfeng Zha, Ling Xu, Shaohua Chen, Lijian Yang, Yikai Zhang, Yuhong Lu, Zhi Yu, Bo Li, Xiuli Wu, Wenjie Zheng, Yangqiu Li
Adoptive immunotherapy with antigen-specific T cells can be effective for treating melanoma and chronic myeloid leukemia (CML). However, to obtain sufficient antigen-specific T cells for treatment, the T cells have to be cultured for several weeks in vitro, but in vitro T cell expansion is difficult to control. Alternatively, the transfer of T cell receptors (TCRs) with defined antigen specificity into recipient T cells may be a simple solution for generating antigen-specific T cells. The objective of this study was to identify CML-associated, antigen-specific TCR genes and generate CML-associated, antigen-specific T cells with T cell receptor (TCR) gene transfer...
October 4, 2016: Oncotarget
Yukiyoshi Hirayama, Min Gi, Shotaro Yamano, Hirokazu Tachibana, Takahiro Okuno, Satoshi Tamada, Tatsuya Nakatani, Hideki Wanibuchi
Immunotherapy based on blockade of the programmed death-1 (PD-1)/programmed death-ligand 1(PD-L1) axis has shown promising clinical activity for renal cell carcinoma (RCC) patients; however, the most effective use of these agents in combination with conventional targeted therapy remains to be resolved. Here we evaluated the therapeutic efficacy of the combination of the mTOR inhibitor everolimus (EVE) and anti-PD-L1 using an immunocompetent mouse model of RCC. We first assessed the in vitro effect of EVE on PD-L1 expression in the human 786-O and mouse RENCA RCC cell lines and found that EVE up-regulated PD-L1 expression in these RCC cell lines...
October 6, 2016: Cancer Science
Markus V Heppt, Cecilia Dietrich, Saskia A Graf, Thomas Ruzicka, Julia K Tietze, Carola Berking
Melanoma is a common type of skin cancer with a high propensity to metastasize. Tyrosine kinase inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway and immune checkpoint blockade have recently revolutionized the management of unresectable and metastatic disease. However, acquired resistance and primary non-response to therapy require novel treatment strategies and combinations. The purpose of this review is to provide a brief and up-to-date overview on the clinical management and current trial landscape in melanoma...
2016: Oncology Research and Treatment
Osamu Imataki, Makiko Uemura
BACKGROUND: The recent study described a better outcome in acute promyelocytic leukemia patients treated with all-trans retinoic acid and arsenic oxide compared to those treated with all-trans retinoic acid combined with conventional chemotherapy. The pivotal study indicated that favorable-risk acute promyelocytic leukemia patients can be cured without any cytotoxic chemotherapy. Even high-risk patients are treatable with cytotoxic agents. Acute promyelocytic leukemia does not develop only by the dedifferentiation caused by PML-RARA...
2016: BMC Clinical Pathology
Eileen E Parkes, Steven M Walker, Laura E Taggart, Nuala McCabe, Laura A Knight, Richard Wilkinson, Karen D McCloskey, Niamh E Buckley, Kienan I Savage, Manuel Salto-Tellez, Stephen McQuaid, Mary T Harte, Paul B Mullan, D Paul Harkin, Richard D Kennedy
BACKGROUND: Previously we identified a DNA damage response-deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance. METHODS: We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype...
January 2017: Journal of the National Cancer Institute
Cara C Schafer, Yong Wang, Kenneth P Hough, Anandi Sawant, Stefan C Grant, Victor J Thannickal, Jaroslaw Zmijewski, Selvarangan Ponnazhagan, Jessy S Deshane
Indoleamine 2,3-dioxygenase (IDO) has been implicated in immune evasion by tumors. Upregulation of this tryptophan (Trp)-catabolizing enzyme, in tumor cells and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME), leads to Trp depletion that impairs cytotoxic T cell responses and survival; however, exact mechanisms remain incompletely understood. We previously reported that a combination therapy of gemcitabine and a superoxide dismutase mimetic promotes anti-tumor immunity in a mouse model of lung cancer by inhibiting MDSCs, enhancing polyfunctional response of CD8+ memory T cells, and extending survival...
September 26, 2016: Oncotarget
S Jemimah Naine, C Subathra Devi, V Mohanasrinivasan, C George Priya Doss
Despite clinical advances in antimicrobial and anticancer therapy, there is an urge for the search of new bioactive compounds. In the present study, previously isolated Streptomyces sp. VITJS4 strain (NCIM No. 5574) (ACC No: JQ234978.1) crude extract tested for antibacterial activity showed a broad spectrum at the concentration of 20 mg/mL against pathogens. The antioxidant potential tested at 0.5 mg/mL concentration exhibited reducing power activity with a maximum of 90 % inhibition. The anticancer property by MTT assay on HeLa and HepG2 cells showed cytotoxic effect with IC50 of 50 µg/mL each...
October 1, 2016: Interdisciplinary Sciences, Computational Life Sciences
Nikolaos Papadantonakis, Anjali S Advani
This is an exciting time in the treatment of acute lymphoblastic leukemia (ALL) given the advances in the relapsed/refractory setting. The development of antibody treatments (including antibody drug conjugates with toxins) offers a different treatment approach compared with conventional chemotherapy regimens. Moreover, the use of bispecific T-cell-engager antibodies (BiTEs) such as blinatumomab harness the cytotoxic activity of T cells against CD19-positive lymphoblasts. Another strategy involves the use of chimeric antigen receptor (CAR) T cells...
October 2016: Therapeutic Advances in Hematology
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