Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
  • 2
  • 3
    Keywords: COLORECTAL-CANCER ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; HEMATOPOIETIC STEM-CELLS ; ACUTE MYELOID-LEUKEMIA ; RESIDUAL DISEASE ; SINGLE-CHAIN ANTIBODY ; INTERNATIONAL EXPERT PANEL ; GEMTUZUMAB OZOGAMICIN ; B-LINEAGE ; EXPRESSION LEVELS
    Abstract: Antibody-based immunotherapy represents a promising strategy to target and eliminate chemoresistant leukemic cells. Here, we evaluated the CD33/CD3-bispecific T cell engaging (BiTE) antibody (AMG 330) for its suitability as a therapeutic agent in acute myeloid leukemia (AML). We first assessed CD33 expression levels by flow cytometry and found expression in 〉99% of patient samples (n = 621). CD33 was highest expressed in AMLs with NPM1 mutations (P 〈 .001) and lower in AMLs with complex karyotypes and t(8;21) translocations (P 〈 .001). Furthermore, leukemic stem cells within the CD34(+)/CD38(-) compartment displayed CD33 at higher levels than healthy donor stem cells (P = .047). In MS-5 feeder cell-based long-term cultures that supported the growth of primary AML blasts for up to 36 days, AMG 330 efficiently recruited and expanded residual CD3(+)/CD45RA(-)/CCR7(+) memory T cells within the patient sample. Even at low effector to target ratios, the recruited T cells lysed autologous blasts completely in the majority of samples and substantially in the remaining samples in a time-dependent manner. This study provides the first correlation of CD33 expression levels with AML genotype in a comprehensive analysis of adult patients. Targeting CD33 ex vivo using AMG 330 in primary AML samples led to T cell recruitment and expansion and remarkable antibody-mediated cytotoxicity, suggesting efficient therapeutic potential in vivo.
    Type of Publication: Journal article published
    PubMed ID: 24300852
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    Abstract: Bispecific T-cell engagers (BiTEs) are very effective in recruiting and activating T cells. We tested the cytotoxicity of the CD33/CD3 BiTE antibody construct AMG 330 on primary acute myeloid leukemia (AML) cells ex vivo and characterized parameters contributing to antileukemic cytolytic activity. The E:T ratio and the CD33 expression level significantly influenced lysis kinetics in long-term cultures of primary AML cells (n=38). AMG 330 induced T-cell-mediated proinflammatory conditions, favoring the upregulation of immune checkpoints on target and effector cells. Although not constitutively expressed at the time of primary diagnosis (n=123), PD-L1 was strongly upregulated on primary AML cells upon AMG 330 addition to ex vivo cultures (n=27, P〈0.0001). This phenomenon was cytokine-driven as the sole addition of interferon (IFN)-gamma and tumor necrosis factor-alpha also induced expression. Through blockade of the PD-1/PD-L1 interaction, AMG 330-mediated lysis (n=9, P=0.03), T-cell proliferation (n=9, P=0.01) and IFN-gamma secretion (n=8, P=0.008) were significantly enhanced. The combinatorial approach was most beneficial in settings of protracted AML cell lysis. Taken together, we have characterized a critical resistance mechanism employed by primary AML cells under AMG 330-mediated proinflammatory conditions. Our results support the evaluation of checkpoint molecules in upcoming clinical trials with AMG 330 to enhance BiTE antibody construct-mediated cytotoxicity.
    Type of Publication: Journal article published
    PubMed ID: 26239198
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; DNA ; BONE-MARROW ; COMPARATIVE GENOMIC HYBRIDIZATION ; TUMOR-SUPPRESSOR GENE ; MUTATIONS ; DUCTAL CARCINOMA ; CARCINOMA IN-SITU ; HETEROGENEITY ; MICROMETASTATIC CELLS
    Abstract: According to the present view, metastasis marks the end in a sequence of genomic changes underlying the progression of an epithelial cell to a lethal cancer. Here, we aimed to find out at what stage of tumor development transformed cells leave the primary tumor and whether a defined genotype corresponds to metastatic disease. To this end, we isolated single disseminated cancer cells from bone marrow of breast cancer patients and performed single-cell comparative genomic hybridization. We analyzed disseminated tumor cells from patients after curative resection of the primary tumor (stage MO), as presumptive progenitors of manifest metastasis, and from patients with manifest metastasis (stage M1). Their genomic data were compared with those from microdissected areas of matched primary tumors. Disseminated cells from MO-stage patients displayed significantly fewer chromosomal aberrations than primary tumors or cells from M1-stage patients (P 〈 0.008 and P 〈 0.0001, respectively), and their aberrations appeared to be randomly generated. In contrast, primary tumors and M1 cells harbored different and characteristic chromosomal imbalances. Moreover, applying machine-learning methods for the classification of the genotypes, we could correctly identify the presence or absence of metastatic disease in a patient on the basis of a single-cell genome. We suggest that in breast cancer, tumor cells may disseminate in a far less progressed genomic state than previously thought, and that they acquire genomic aberrations typical of metastatic cells thereafter. Thus, our data challenge the widely held view that the precursors of metastasis are derived from the most advanced clone within the primary tumor
    Type of Publication: Journal article published
    PubMed ID: 12808139
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    Keywords: brain ; CELLS ; INVASION ; tumor ; TUMOR-CELLS ; DISEASE ; liver ; PROTEIN ; SAMPLES ; TUMORS ; TIME ; PATIENT ; MESSENGER-RNA ; prognosis ; ANTIGEN ; ANTIGENS ; SKIN ; bone marrow ; BONE-MARROW ; BREAST-CANCER ; antibodies ; LYMPHOMA ; METASTASIS ; metastases ; MELANOMA ; MONOCLONAL- ANTIBODY ; PROGNOSTIC-SIGNIFICANCE ; MALIGNANT-MELANOMA ; melanoma cells ; PERIPHERAL-BLOOD ; GASTRIC-CANCER ; relapse ; OCULAR MELANOMA ; SERUM LEVELS ; ANTIBODIES NKI-BETEB ; HMB-45 ; micrometastasis ; MICROMETASTATIC CARCINOMA-CELLS
    Abstract: We report on a case of a 70-year-old woman with an ocular melanoma, which was diagnosed and treated 14 years ago. The patient was referred to the hospital with a suspected lymphoma. Cytological examination of bone marrow proved a marked infiltration with melanoma cells. Because detection of isolated tumor cells in the bone marrow of patients with various types of tumors was shown to be of prognostic significance and since current tumor-staging techniques are unable to detect single disseminated tumor cells or small aggregates of tumor cells, which might be the seed for subsequent metastatic relapse, we therefore evaluated the feasibility of immunocytochemical screening of bone marrow aspirates of 36 melanoma patients in different clinical stages using three monoclonal antibodies against melanoma-associated antigens in comparison with 43 non- melanoma control patients. Two of these antibodies (HMB45 and NKI-beteb) are directed against the melanoma antigen gp100/pmel17, whereas the third one (TA99) recognizes gp75/Tyrosinase-related protein I (TRP-1). None of the patients demonstrated a makroskopic bone marrow infiltration as was present in our patient with metastatic ocular melanoma. Seven (20.6%) of the 34 eligible melanoma patients presented with cells in the bone marrow positive for one or more of the above- mentioned melanosomal markers. Four of the positive patients were clinically free of tumors by the time of puncture, whereas the remaining 3 patients showed overt metastases in the subcutaneous fat (2 patients) and the brain (I patient). On the other hand, 20 (66%) of the 29 patients with negative bone marrow findings also presented with clinical advanced disease with overt metastasis in the skin, lymph node, spleen, liver, lung, bone and brain. In conclusion, immunocytochemical screening of bone marrow samples is a feasible procedure that allows the detection of micrometastatic tumor cells in a subset of melanoma patients. Massive invasion of bone marrow with melanoma cells is a rare event even in far-advanced metastatic stages and no clear correlation between tumor load and bone marrow infiltration could be established
    Type of Publication: Journal article published
    PubMed ID: 12702145
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    ISSN: 1432-119X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Early dissemination of malignant cells is the main cause for metastatic relapse in patients with solid tumours. By use of monoclonal antibodies (mAbs) specific for cytokeratins, disseminated individual epithelial tumour cells can now be identified in mesenchymal organs such as bone marrow. Further to characterize such cells in patients with prostate cancer, an immunocytochemical procedure was developed for simultaneous labelling of cytokeratin component no. 18 (CK18) and prostate specific antigen (PSA). In a first step, cells were incubated with mAb ER-PR8 against PSA and secondary gold-conjugated goat anti-mouse antibodies. In a second step, biotinylated mAb CK2 to CK18 was applied as primary antibody and subsequently incubated with complexes of streptavidin-conjugated alkaline phosphatase, which were developed with the Newfuchsin substrate. The binding of gold-labelled antibodies was visualized by silver enhancement. The sensitivity and specificity of the technique was demonstrated on cryostat sections of hyperplastic prostatic tissue, and cytological preparations of LNCaP prostatic tumour cells. Double staining was restricted to cells derived from the secretory epithelium of the prostate. Cross-reactivity between both detection systems was excluded by several controls, including the use of unrelated antibodies of the same isotype and the staining of CK18+/PSA− HT29 colon carcinoma cells. CK18+ cells co-expressing PSA were found in bone marrow aspirates from 5 out of 13 patients with carcinomas of the prostate, a finding that is consistent with the relative fraction of double-positive LNCaP cells. The specificity of CK18 for epithelial tumour cells in bone marrow was supported by negative staining of 12 control aspirates from patients with benign prostatic hypertrophy. In conclusion, the approach presented appears to be a reliable method to phenotype individual prostatic carcinoma cells.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    ISSN: 1433-0385
    Keywords: Key words: Carcinomas ; Minimal residual cancer ; Immunocytochemistry ; Polymerase chain reaction ; Bone marrow ; Blood ; Lymph nodes. ; Schlüsselwörter: Carcinome ; minimale residuale Krebserkrankung ; Immuncytochemie ; Polymerasekettenreaktion ; Knochenmark ; Blut ; Lymphknoten.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung. Während das Auftreten und die Häufigkeit von Lokalrezidiven bei der R0-Resektion solider Tumoren weitgehend in der Hand des Operateurs liegt, sind Fernrezidive nach derzeitigem Kenntnisstand auf die bereits prä- oder perioperativ erfolgte, systemische Disseminierung von Tumorzellen zurückzuführen. Das Vorliegen von einzelnen, disseminierten Tumorzellen – z. B. im Knochenmark als Indikatororgan – ist im Rahmen eines erweiterten Tumorstagings durch sensitive immuncytochemische und molekulare Methoden nachweisbar und wird zunehmend als klinisch relevanter Prognosefaktor angesehen. Im Gegensatz zu soliden Metastasen stellen isolierte mikrometastatische Tumorzellen aufgrund ihrer Zugänglichkeit für Makromoleküle und immunkompetente Effektorzellen geeignete Ziele für intravenös appplizierte Therapeutica dar. Der überwiegend nicht mitotisch aktive Zustand (G0-Phase) dieser Tumorzellen könnte eine Ursache für das Versagen einer adjuvanten Chemotherapie sein. Daher rücken adjuvante Therapiestrategien, die auch gegen ruhende Zellen wirksam sind, zunehmend in den Mittelpunkt des Interesses. Diese therapeutische Rationale ist mit dem Antikörper 17–1A bei Patienten mit colorectalem Carcinom im Stadium UICC III nach R0-Resektion randomisiert untersucht und bestätigt worden. Die Antikörpertherapie zeichnet sich dadurch aus, daß Antikörper sich im Gegensatz zur Chemotherapie auch gegen mitotisch nicht aktive Tumorzellen („dormant cells“) richten und zudem unabhängig von möglichen Chemotherapieresistenzen wirken. Als eine gegen den Zustand der minimalen residualen Krebserkrankung gerichtete Therapie wäre der adjuvante Einsatz von Antikörpern zukünftig auch als Kombinationsbehandlung mit der Chemotherapie parallel oder sequentiell sinnvoll. Ziel dieser Übersicht ist es, den momentanen Stand der Forschung auf dem Gebiet der Diagnostik und Therapie der minimalen residualen Krebserkrankung zu erläutern.
    Notes: Summary. The incidence of local relapse after complete (R0) resection of solid tumors is largely determined by the skill of the surgeon, whereas metastatic relapse in distant organs is caused by pre- or perioperative systemic dissemination of tumor cells. The presence of individual disseminated tumor cells – e. g., in bone marrow as indicator organ – can be detected by sensitive immunocytochemical and molecular methods and is increasingly considered as a clinically relevant prognostic indicator. In contrast to solid metastases, isolated micrometastatic tumor cells are appropriate targets for intravenously applied anti-cancer therapeutics because they are easily accessible to macromolecules and immunologic effector cells. The majority of these tumor cells appear to be nonproliferating (i. e., in the G0 phase of the cell cycle), which may explain the failure of adjuvant chemotherapy. Adjuvant therapeutic strategies aimed at quiescent tumor cells are therefore of increasing interest. This therapeutic rationale has been tested and confirmed in a randomized clinical trial using antibody 17–1A in patients with non-metastatic colorectal carcinoma (UICC stage III). The antibody therapy kills also quiescent tumor cells (“dormant cells”) and is independent from a potential chemotherapy resistance of the tumor cells. As treatment for minimal residual cancer, the clinical use of antibody therapy could be envisaged in conjunction with chemotherapy, applied either in parallel or sequentially. The aim of this review is to present and discuss the current state of research in the field of diagnosis and therapy of minimal residual cancer.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    ISSN: 1432-0584
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Lysosomes were prepared according toCohn andHirsch from peritoneal exudate cells of rabbits. In the isolated subcellular fraction, lysosomes were characterized biochemically, histochemically, and by polarisation microscopy. They show positive polarisation crosses in unstained air-fixed preparations and appear in a reddish-yellow colour of birefringence after supravital staining with toluidine-blue. From the presented data it is concluded, that these lysosomes consist of superimposed spherical glycolipoprotein membranes or respectively of glycoprotein membranes with orderly interposed lipidmolecules.
    Notes: Zusammenfassung Lysosomen aus peritonealen Leukozyten von Kaninchen wurden nachCobn undHirsch isoliert und biochemisch, histochemisch und im Polarisationsmikroskop untersucht. Die Partikel zeigen in ungefärbten, luftgetrockneten Präparaten ein positives Polarisationskreuz und eine gelbrötliche Polarisationsfarbe nach Toluidinblau-Färbung. Aus diesen Beobachtungen wird geschlossen, daß diese Lysosomen aus übereinandergelagerten Glykolipoproteinmembranen aufgebaut sind, oder aber aus Glykoproteinmembranen zwischen denen Lipide eingelagert sind.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    ISSN: 1432-0584
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...