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  • TCRs
  • These observations suggest that high TCR density compensates for the low affinity of individual TCRs for self-antigen. (aacrjournals.org)
  • Regarding shared (self) tumor antigens, it is unclear whether the human CD4+ T cell repertoire has been shaped by tolerance mechanisms and lacks highly functional TCRs suitable for therapy. (jci.org)
  • Here, TCRs against the tumor-associated antigen NY-ESO-1 were isolated either from human CD4+ T cells or from mice that express a diverse human TCR repertoire with HLA-DRA/DRB1*0401 restriction and are NY-ESO-1 negative. (jci.org)
  • NY-ESO-1-reactive TCRs from the mice showed superior recognition of tumor cells and higher functional activity compared with TCRs from humans. (jci.org)
  • These data suggest that MHC II-restricted TCRs against NY-ESO-1 from a nontolerant nonhuman host are of optimal affinity and that the combined use of MHC I- and II-restricted TCRs against NY-ESO-1 can make adoptive T cell therapy more effective. (jci.org)
  • D ) Human CD4 + T cells were transduced with NY-ESO-1-reactive TCRs isolated from CD4 + T cells shown in B and stained with DR4/NY-ESO-1 116 tetramer and for mouse TCRβ constant region (mTCRβ). (jci.org)
  • T cell receptor (TCR) gene transfer employing high affinity TCRs recognizing defined tumor-associated antigens can potentially circumvent these challenges. (washington.edu)
  • We hypothesized that in vitro engineering to increase TCR affinity would improve tumor cell recognition, although the potential for such high affinity TCRs to recognize normal tissues expressing low levels of WT1 would need to be assessed.To test this hypothesis, we characterized the murine and human T cell responses elicited to WT1RMFPNAPYL. (washington.edu)
  • The TCRs from these T cells are being used as templates for in vitro mutagenesis and selection of higher affinity TCRs by yeast display to determine the threshold required for efficient tumor recognition without targeting normal tissues. (washington.edu)
  • mice
  • NSG mice were transplanted with Raji-luciferase cells and were assigned to controls versus SIRPabody treatment. (aacrjournals.org)
  • However, antitumor treatment was accompanied by fatal autoimmune disease, i.e., autoimmune diabetes in transgenic mice expressing the tumor antigen also in pancreatic β islet cells or by severe arteritis, myocarditis, and eventually dilated cardiomyopathy when arterial smooth muscle cells and cardiomyocytes expressed the transgenic tumor antigen. (rupress.org)
  • B ) Mouse Spas-1 expression in normal versus tumor prostate: the level of Spas-1 expression was determined in a panel of normal prostates and primary TRAMP tumors from 21- and 27-week-old mice. (nih.gov)
  • In a mouse model of ovarian cancer, the CAR-NK cells inhibited tumor growth and prolonged survival of mice. (ca.gov)
  • B. Western blots displaying the expression of PyMT, mCherry and Ova from tumor cells and control T cells in PyMT ChOVA mice. (nih.gov)
  • E. 5×10 6 OT-I-UbGFP T cells or polyclonal Ub-GFP CD8 T cells were transferred to a PyMT ChOVA tumor bearing mice. (nih.gov)
  • F. Tumor-bearing PyMT ChOVA mice received 1×10 6 CD45.1 OT-I cells i.v., and were sacrificed at the specified day post-transfer. (nih.gov)
  • A. Tumor burden in individual PyMT ChOVA mice following adoptive transfer of 5×10 6 naïve OT-I cells (red lines, N=7) or untreated controls (black line, N=12). (nih.gov)
  • C. Cytotoxic activity of OT-I T cells isolated from the LNs (green), or tumor (red) of PyMTChOva mice 5 days after adoptive transfer, compared to in vitro activated control OT-I T cells (black line with triangles) or control OT-I lysis of unpulsed EL4s (black line with squares). (nih.gov)
  • Adoptive transfer of PLGA-NP-activated CD8 + T cells in tumor-bearing mice displayed good in vivo expansion capacity, potent Ag-specific cytotoxicity and IFN-γ cytokine production, resulting in curing mice with established tumors. (springer.com)
  • (c) T cells (1.0 × 10 6 ) described in ( a,b) were injected intravenously into NSG mice bearing green fluorescent protein/firefly-luciferase fusion protein (GFP/Luc) expressing CD19 + PSMA + PC3 human prostate tumors. (nih.gov)
  • (d) 1 × 10 6 CD19 + PSMA − , 1 × 10 6 CD19 − PSMA + and 1 × 10 6 CD19 + PSMA + PC3 cells were injected subcutaneously into the left flank, right flank and back, respectively, of NSG mice. (nih.gov)
  • iPS cells can be differentiated into progenitor T cells in vitro by stimulation with the Notch ligand Delta-like 1 (DL1) overexpressed on bone marrow stromal cells, with complete maturation occurring upon adoptive transfer into Rag1 -deficient mice. (aacrjournals.org)
  • In this study, we adoptively transferred into mice iPS cells that were transduced with Ag-specific TCR genes. (aacrjournals.org)
  • Tumor burden was determined by BLI for BV173 ( n = 5 mice) ( A ), SET2 ( n = 5 mice) ( B ), and AML14 ( n = 4 mice) ( C ) once a week throughout the experiment, and the BLI data are summarized below the images. (jci.org)
  • D ) Mice from the AML14 experiment were sacrificed on day 29, and bone marrow was harvested to determine tumor burden by flow cytometry for GFP + HLA-A2 + AML14 cells. (jci.org)
  • Because Pr20M-treated mice presumably had Pr20M already bound on tumor cells, staining was performed by an additional Pr20 stain on all samples followed by a secondary PE-conjugated anti-human Ab ( n = 4 mice per group). (jci.org)
  • Mice immunized with this peptide generate a diverse T cell response, recruiting T cells of multiple TCR Vbeta families and encompassing an avidity range of three logs. (washington.edu)
  • However, in a proportion of treated mice, initial tumor regressions were followed by recurrences. (aacrjournals.org)
  • Therapy was further enhanced by targeting an additional tumor antigen with the VSV-antigen + ACT combination strategy, leading to sustained response in 100% of mice. (aacrjournals.org)
  • cytotoxicity
  • One such virus is PVSRIPO, an engineered hybrid of poliovirus and rhinovirus that cannot attack neurons but retains cytotoxicity in neoplastic cells, including glioma. (sciencemag.org)
  • B ) The tumor specificity of the T cell line was determined by cytotoxicity using a standard JAM assay. (nih.gov)
  • Adverse events, survival, and cytotoxicity against autologous tumor and tumor-associated antigens were measured. (aacrjournals.org)
  • Six of 10 patients demonstrated robust systemic cytotoxicity as demonstrated by IFN-γ expression by peripheral blood mononuclear cells in response to tumor lysate after vaccination. (aacrjournals.org)
  • Furthermore, γδ T cells exhibited markedly enhanced cytotoxicity against the Ag-pulsed tumor cells as compared with untreated tumor cells. (jimmunol.org)
  • Survey of a number of human tumor cell lines of different origins revealed that the majority of them became susceptible for γδ T cell-mediated cytotoxicity following the Ag pulsing except for breast cancer lines so far examined, while normal PHA blast cells remained resistant. (jimmunol.org)
  • Survey of a number of human solid tumor lines of distinct origins indicated that the majority of them could be "sensitized" effectively for the γδ T cell-mediated, but not for nonspecific lymphokine-activated killer (LAK) 3 -mediated, cytotoxicity by pulsing with nonpeptide Ags, except for breast cancer cell lines so far tested. (jimmunol.org)
  • An afucosylated Fc form (Pr20M) directed antibody-dependent cellular cytotoxicity against PRAME+HLA-A2+ leukemia cells and was therapeutically effective against mouse xenograft models of human leukemia. (jci.org)
  • The cells do not show cytotoxicity against cell lines or primary cells that are not both HLA-A*02:01- positive and WT1 positive. (bloodjournal.org)
  • clinically
  • This lack of autoimmunity may be due to the fact that only low CTL activities present for a relatively short time were sufficient to control and clear these early and small tumors without or before causing clinically apparent autoimmune disease. (rupress.org)
  • In contrast, clinically established tumors seem to require a strong and sustained CTL response to guarantee complete remission of more sizeable tumors ( 21 ). (rupress.org)
  • Solid Tumor
  • CAR-T cell therapy has achieved gratifying breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. (springermedizin.de)
  • flow cytometry
  • D. Flow cytometry of tumor-draining lymph nodes 48 hours after 1×10 6 CFSE labeled CD45.1 OT-I T cells were transferred to either a PyMT tumor-bearing mouse or a PyMT ChOVA tumor-bearing mouse. (nih.gov)
  • 5 days post-transfer tumor draining lymph nodes and tumors were removed and analyzed by flow cytometry. (nih.gov)
  • The OVA-expressing E.G7 lymphoma cell line (E.G7-OVA) was purchased from American Type Culture Collection and was authenticated by flow cytometry before use. (aacrjournals.org)
  • induce
  • Indeed, efficient tumor control in human patients may be associated with autoimmune phenomena, e.g., antimelanoma immunity that sometimes correlates with vitiligo ( 8 ), certain gynecological tumors that appear to induce paraneoplastic cerebellar degeneration ( 9 ), or Wegener's granulomatosis, which is often associated with renal cell carcinoma ( 10 ). (rupress.org)
  • Protein antigen (Ag)-based immunotherapies have the advantage to induce T cells with a potentially broad repertoire of specificities. (springer.com)
  • Remarkably, NuMA overexpression, a frequent event in tumors, is sufficient to induce expression of ACRBP. (aacrjournals.org)
  • aAPCs induce numerical expansion of TILs that is statistically similar to an established rapid expansion method at a 100-fold lower feeder cell to TIL ratio, and greater than those achievable using anti-CD3/CD28 activation beads or extended IL-2 culture. (biomedcentral.com)
  • effector
  • T cells were cultured at varied effector to target cell ratios (E:T) with TRAMP-C2 or MC38 EL4 target cells. (nih.gov)
  • a ) T cells were incubated at indicated effector:target ratios with 51 Cr-loaded target cells expressing CD19 and/or PSMA, and target cell lysis (chromium release) was measured. (nih.gov)
  • peripheral
  • This study documents that antitumor treatment with DCs may cause severe autoimmune disease when the tumor antigens are not tumor-specific but are also expressed in peripheral nonlymphoid organs. (rupress.org)
  • Our aim was to demonstrate the ability of a CCR4 antagonist (a small chemical molecule identified in silico) when combined with vaccines to break peripheral tolerance controlled by Tregs, a prerequisite for the induction of CD8 + T cells against self Ags. (bloodjournal.org)
  • Peripheral blood mononuclear cells were differentiated into phenotypically and functionally confirmed DCs. (aacrjournals.org)
  • We therefore examined the ability of tumor lysate-pulsed DCs to activate peripheral tumor-reactive CTL activity and CD8+ T-cell infiltration into tumors in situ in recurrent malignant glioma patients. (aacrjournals.org)
  • heterogeneous
  • Germ cell tumors are a heterogeneous group of neoplasms derived from residual primordial tissue. (jimmunol.org)
  • Renal cell carcinoma (RCC) is a heterogeneous group of kidney cancers with clear cell RCC (ccRCC) as the major subgroup. (uzh.ch)
  • relevant tumor
  • For example, tumor cell lines used in animal studies are often transfected with surrogate rejection Ag ( 7 , 8 , 9 ), which would not necessarily reflect expression or tissue distribution of an endogenously derived, relevant tumor Ag. (jimmunol.org)
  • macrophages
  • 3 A number of immunohistochemical studies have demonstrated that the immune cell infiltrate of many germ cell tumors includes substantial yet variable numbers of T cells, macrophages, and B cells ( 3 , 4 , 5 ). (jimmunol.org)
  • We generated a fluorescent mouse model of spontaneous immunoevasive breast cancer and identified a subset of myeloid cells with significant similarity to dendritic cells and macrophages that constitutively ingest tumor-derived proteins and present processed tumor antigens to reactive T cells. (nih.gov)
  • syngeneic tumor
  • In a syngeneic tumor model, mocetinostat decreased intratumoral T-regulatory cells (Tregs) and potentially myeloid-derived suppressor cell (MDSC) populations and increased intratumoral CD8+ populations. (springermedizin.de)
  • protein
  • Sera from three of eight vaccinated men contained new antibodies recognizing polypeptides of 26, 31, and 150 kDa in protein extracts from prostate cells. (aacrjournals.org)
  • The interaction of CD47 with signal regulatory protein alpha (SIRPα), a protein on phagocytic cells, transmits a "don't eat me" signal that negatively regulates phagocytosis. (aacrjournals.org)
  • We used adenoviral expression of Macrophage Inflammatory Protein 1α (MIP 1α) to recruit DCs into hTert-Ad infected tumors and Ad-Flt3L to expand DCs within the tumor nodules during virotherapy. (jimmunol.org)
  • Genetic engineering of immune cells called T cells, allows the T cells to recognize and kill tumor cells that have the specific protein on their cell surface. (ca.gov)
  • In the present study, we have applied poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) which strongly improve protein Ag presentation by dendritic cells (DC) in the absence of additional Toll-like receptor ligands or targeting devices. (springer.com)
  • In a direct comparison with soluble protein Ag, we show that DC presentation of protein encapsulated in plain PLGA-NP results in efficient activation of CD4 + and CD8 + T cells as reflected by high numbers of activated CD69 + and CD25 + , interferon (IFN)-γ and interleukin (IL)-2-producing T cells. (springer.com)
  • We conclude that delivery of protein Ag through encapsulation in plain PLGA-NP is a very efficient and simple procedure to stimulate potent anti-tumor T cells. (springer.com)
  • iPS-MEF-Ng-20D-17 cell generated from male C57BL/6 mouse embryonic fibroblasts by introducing the 4 factors (Oct3/4, Sox2, Klf4, and c-Myc) is carrying Nanog promoter-driven green fluorescent protein (GFP)/internal ribosome entry site (IRES)/puromycin-resistant gene ( 11 ). (aacrjournals.org)
  • Cytomegalovirus and tumor stress surveillance by binding of a human γδ T cell antigen receptor to endothelial protein C receptor. (nih.gov)
  • Here we found that the TCR of a human V(γ)4V(δ)5 clone directly bound endothelial protein C receptor (EPCR), which allowed γδ T cells to recognize both endothelial cells targeted by cytomegalovirus and epithelial tumors. (nih.gov)
  • We have designed and engineered the first CAR T cell against a human intracellular protein, WT1. (bloodjournal.org)
  • patients
  • Such treatment is associated with encouraging long-term survival rates, and results are superior in patients treated with DCV loaded with antigen from such cells. (springer.com)
  • Dillman RO, Beutel LD, Barth NM, de Leon C, O'Connor AA, DePriest C, Nayak SK (2002) Irradiated cells from autologous tumor cell lines as patient-specific vaccine therapy in 125 patients with metastatic cancer: induction of delayed-type hypersensitivity to autologous tumor is associated with improved survival. (springer.com)
  • High-risk patients will first receive one cycle of chemotherapy with a regimen called DT PACE, after which the white blood cells will be collected. (knowcancer.com)
  • Fourteen patients were thrice vaccinated 2 weeks apart with autologous DCs pulsed with tumor lysate. (aacrjournals.org)
  • A significant CD8+ T-cell infiltrate was noted intratumorally in three of six patients who underwent reoperation. (aacrjournals.org)
  • This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous tumor lysate-pulsed DC vaccine for patients with malignant glioma. (aacrjournals.org)
  • The overwhelming majority of patients with malignant glioma, composed of GBM and anaplastic astrocytoma (AA), experience increasingly rapid tumor recurrence after surgical resection or other treatment and eventually succumb to such events. (aacrjournals.org)
  • The generation of such lines is particularly difficult in recurrent patients, whose tumors have been exposed to radiation. (aacrjournals.org)
  • Despite extensive experimental and clinical efforts, the treatment of patients with advanced metastatic disease of solid tumors is frequently ineffective. (jimmunol.org)
  • Cyclin D1-specific CD8+ T cells secreted TNF-α, IFN-γ, and interleukin-2 (IL-2), and degranulated, indicating the presence of polyfunctional tumor-specific CD8+ T cells in the blood of these patients with ccRCC. (uzh.ch)
  • In addition, researchers have produced iPS cells that are safe for transplantation into patients ( 5, 6 ). (aacrjournals.org)
  • Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL. (springermedizin.de)
  • neoplastic cells
  • Cytopathogenic infection of neoplastic cells releases the proteome and exposes pathogen- and damage-associated molecular patterns. (sciencemag.org)
  • These limitations reinforce the need for the development of safer and more effective strategies that better target neoplastic cells while sparing normal host cells. (jimmunol.org)
  • blockade
  • In addition, Tim-3-Tim-3L blockade enhanced cytokine production and proliferation of NY-ESO-1-specific CD8 + T cells upon prolonged antigen stimulation and acted in synergy with PD-1-PD-L1 blockade. (rupress.org)
  • ovarian cancer
  • Dillman RO, Nayak SK, Brown JV, Mahdavi K, Beutel LD (1999) The feasibility of using short-term cultures of ovarian cancer cells for use as autologous tumor cell vaccines as adjuvant treatment of advanced ovarian cancer. (springer.com)
  • In an ovarian cancer xenograft model, NK-CAR-iPSC-NK cells significantly inhibited tumor growth and prolonged survival compared with PB-NK cells, iPSC-NK cells, or T-CAR-iPSC-NK cells. (ca.gov)
  • Here, we find that ACRBP is both necessary and sufficient for paclitaxel resistance in ovarian cancer cell lines and ovarian tumor explants. (aacrjournals.org)
  • They are cytotoxic in standard 51 Cr assays against a range of cancer cell lines, including the megakaryoblastic cell line SET2, the acute myeloid leukemia (AML) cell line AML14, the multiple myeloma cell line KARPAS, and the ovarian cancer line, OVCAR3, as compared to CAR T cells against an irrelevant antigen. (bloodjournal.org)
  • Selective
  • Selective tumor binding was tested using CFSE-labeled human primary CLL cells in the presence of 20-fold excess of human RBCs. (aacrjournals.org)
  • The requirement for more selective cancer therapies, along with the molecular identification of tumor-specific Ags (TSA) 2 and tumor-associated Ags, has led to the development of immune-based strategies for the treatment of metastatic disease, which are being tested in both animal models and clinical trials ( 1 , 2 , 3 , 4 , 5 ). (jimmunol.org)
  • Mocetinostat is a spectrum-selective inhibitor of class I/IV histone deacetylases (HDACs), a family of proteins implicated in epigenetic silencing of immune regulatory genes in tumor and immune cells. (springermedizin.de)