Serial killing of tumor cells by cytotoxic T cells redirected with a CD19-/CD3-bispecific single-chain antibody construct

2005 ◽  
Vol 115 (1) ◽  
pp. 98-104 ◽  
Author(s):  
Patrick Hoffmann ◽  
Robert Hofmeister ◽  
Klaus Brischwein ◽  
Christian Brandl ◽  
Sandrine Crommer ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Cytotoxic T Cells ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Serial Killing

scholarly journals Construction of Anti-CD20 Single-Chain Antibody-CD28-CD137-TCRζ Recombinant Genetic Modified T Cells and its Treatment Effect on B Cell Lymphoma

2015 ◽  
Vol 21 ◽  
pp. 2110-2115 ◽  
Author(s):  
Fei Chen ◽  
Chuming Fan ◽  
Xuezhong Gu ◽  
Haixi Zhang ◽  
Qian Liu ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Treatment Effect ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Anti Cd20

scholarly journals Participation of the H-2 antigens of tumor cells in their lysis by syngeneic T cells.

1976 ◽  
Vol 143 (3) ◽  
pp. 601-614 ◽  
Author(s):  
J W Schrader ◽  
G M Edelman
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Target Cell ◽  
Cytotoxic T Cells ◽  
Hybrid Origin ◽  
Target Cells ◽  
Cytotoxic Lymphocytes ◽  
Effector Cells

Cytotoxic T lymphocytes were generated in vitro against H-2 compatible or syngeneic tumor cells. In vitro cytotoxic activity was inhibited by specific anti-H2 sera, suggesting that H-2 antigens are involved in cell lysis. Two observations directly demonstrated the participation of the H-2 antigens on the tumor cells in their lysis by H-2-compatible T cells. First, coating of the H-2 antigens on the target tumor cell reduced the number of cells lysed on subsequent exposure to cytotoxic T cells. Second, when cytotoxic T cells were activated against an H-2 compatible tumor and assayed against an H-2-incompatible tumor, anti-H-2 serum that could bind to the target cell, but not to the cytotoxic lymphocyte, inhibited lysis. H-2 antigens were also shown to be present on the cytotoxic lymphocytes. Specific antisera reacting with these H-2 antigens, but not those of the target cell, failed to inhibit lysis when small numbers of effector cells were assayed against H-2-incompatible target cells or when effector cells of F1-hybrid origin and bearing two H-2 haplotypes were assayed against a tumor cell of one of the parental strains. These findings suggest that it is the H-2 antigens on the tumor cell and not those on the cytotoxic lymphocytes that are important in cell-mediated lysis of H-2-compatible tumor cells.

scholarly journals Granzyme B-expressing peripheral T-cell lymphomas: neoplastic equivalents of activated cytotoxic T cells with preference for mucosa- associated lymphoid tissue localization

Blood ◽  
1994 ◽  
Vol 84 (11) ◽  
pp. 3785-3791 ◽  
Author(s):  
PC de Bruin ◽  
JA Kummer ◽  
P van der Valk ◽  
P van Heerde ◽  
PM Kluin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Lymphoid Tissue ◽  
Cytotoxic T Cells ◽  
Granzyme B ◽  
Clinical Behavior ◽  
T Cell Lymphomas ◽  
Hodgkin's Lymphomas ◽  
Peripheral T Cell Lymphomas

T-cell non-Hodgkin's lymphomas can be considered the neoplastic equivalents of immunologically functional, site-restricted T lymphocytes. Little is known about the occurrence and clinical behavior of T-cell lymphomas that are the neoplastic equivalents of different functional T-cell subsets. Here, we investigated the prevalence, preferential site, immunophenotype, and clinical behavior of the neoplastic equivalents of activated cytotoxic T cells (CTLs) in a group of 140 nodal and extranodal T-cell lymphomas. Activated CTLs were shown immunohistochemically with a monoclonal antibody against granzyme B, a major constituent of the cytotoxic granules of activated T cells. Granzyme B-positive T-cell lymphomas were mainly found in mucosa- associated lymphoid tissue (MALT; nose, 63% of the cases; gastrointestinal tract, 46%; and lung, 33%). Granzyme B-positive cases with primary localization in MALT were more often associated with angioinvasion (P = .005), necrosis (P = .002), and histologic characteristics of celiac disease in adjacent mucosa not involved with lymphoma. Eosinophilia was more often observed in granzyme B-negative cases (P = .03). Most cases belonged to the pleomorphic medium- and large-cell group of the Kiel classification. CD30 expression was more often found in granzyme B-positive lymphomas of MALT (P = .04), whereas CD56 expression was exclusively found in nasal granzyme B-positive lymphomas. Immunophenotypically, most of the cases should be considered as neoplastic equivalents of activated CTLs based on the presence of T- cell markers on tumor cells. In two cases of nasal lymphoma, tumor cells probably were the neoplastic counterparts of natural killer cells. The prognosis of the granzyme B-positive gastrointestinal T-cell lymphomas was poor but did not differ from granzyme B-negative gastrointestinal T-cell lymphomas. This indicates that, in peripheral T- cell lymphomas, site of origin is more important as a prognostic parameter than derivation of activated CTLs.

scholarly journals New insights in the biology of Hodgkin lymphoma

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 328-334 ◽  
Author(s):  
Ralf Küppers
Keyword(s):  
T Cells ◽  
B Cells ◽  
Signaling Pathways ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Cytotoxic T Cells ◽  
Cell Gene Expression ◽  
Expression Program ◽  
Multiple Signaling ◽  
Cell Gene

Abstract The Hodgkin and Reed/Sternberg (HRS) tumor cells of classical Hodgkin lymphoma (HL) and the lymphocyte-predominant tumor cells of nodular lymphocyte–predominant HL are both derived from germinal center B cells. HRS cells, however, have largely lost their B-cell gene-expression program and coexpress genes typical of various types of hematopoietic cells. Multiple signaling pathways show a deregulated activity in HRS cells. The genetic lesions involved in the pathogenesis of HL are only partly known, but numerous members and regulators of the NF-κB and JAK/STAT signaling pathways are affected, suggesting an important role for these pathways in HL pathogenesis. Some genetic lesions involve epigenetic regulators, and there is emerging evidence that HRS cells have undergone extensive epigenetic alterations compared with normal B cells. HRS and lymphocyte-predominant cells are usually rare in the lymphoma tissue, and interactions with other cells in the microenvironment are likely critical for HL pathophysiology. T cells represent a main population of infiltrating cells, and it appears that HRS cells both inhibit cytotoxic T cells efficiently and also receive survival signals from Th cells in direct contact with them.

Antigen-dependent costimulation to improve T-cell therapy for cancer.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 151-151
Author(s):  
Christopher C. DeRenzo ◽  
Phuong Nguyen ◽  
Stephen Gottschalk
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Tumor Antigens ◽  
Single Chain ◽  
Antitumor Effects ◽  
T Cell Therapy ◽  
Potential Strategy

151 Background: T-cell therapy for cancer faces several challenges, including limited T-cell expansion at tumor sites, and lack of unique tumor antigens that are not expressed in normal tissues. To overcome the first obstacle, we developed Engager (ENG) T cells, which secrete bispecific molecules consisting of single chain variable fragments specific for CD3 and a tumor antigen. ENG T cells have the unique ability to redirect bystander T cells to tumors, amplifying antitumor effects. Costimulatory chimeric antigen receptors (CoCARs) are one potential strategy to restrict full T-cell activation to tumor sites that express a unique "antigen address." The goal of this project was now to generate T cells that express engager molecules and CoCARs (ENG/CoCAR T cells), which recognize distinct tumor antigens, and evaluate their effector function. Methods: We focused on two tumor antigens, EphA2 and HER2, which are expressed in a broad range of solid tumors. RD114-pseudotyped retroviral particles encoding an EphA2-ENG or a HER2-CoCAR were used to transduce CD3/CD28-activated human T cells. Transduced T cells were cocultured with EphA2+/HER2- or EphA2+/HER2+ tumor cells. Results: Both EphA2-ENG and EphA2-ENG/HER2-CoCAR T cells were activated by EphA2+ targets, as judged by IFNγ secretion. EphA2-ENG T cells secreted little IL-2 and died after one stimulation with EphA2+/HER2- or EphA2+/HER2+ tumor cells. In contrast, EphA2-ENG/HER2-CoCAR T cells secreted high levels of IL-2 and proliferated when stimulated with EphA2+/HER2+ cells. Little IL-2 secretion and no proliferation was observed after stimulation of the same T cells with EphA2+/HER2- cells, indicating these T cells are only fully activated in the presence of both target antigens. Upon repeated stimulation with EphA2+/HER2+ tumor cells, EphA2-ENG/HER2-CoCAR T cells continued to secrete IL-2 and proliferate without the addition of external cytokines for at least 10 weeks. Conclusions: EphA2-ENG/HER2-CoCAR T cells demonstrated robust dual antigen dependent IL-2 secretion, and continued proliferation upon repeat stimulation with EphA2+/HER2+ cells. Thus, providing antigen-specific costimulation is a potential strategy to improve the safety and efficacy of T-cell therapy for cancer.

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