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  • 1
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    Keywords: CANCER ; THERAPY ; CANCER-THERAPY ; THERAPIES ; USA ; cancer therapy
    Type of Publication: Patent
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  • 3
    Keywords: CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; BLOOD ; Germany ; human ; DISEASE ; ENZYMES ; GENOME ; RNA ; LINES ; RESPONSES ; INFECTION ; MECHANISM ; INDUCTION ; ANTIGEN ; ANTIGENS ; CELL-LINES ; CYCLE ; ASSOCIATION ; SIGNAL ; SUSCEPTIBILITY ; virus ; TRANSCRIPTION FACTORS ; OVARIAN-CANCER ; CELL-LINE ; LINE ; REPLICATION ; INTERFERON ; KINETICS ; sensitivity ; ADAPTIVE IMMUNITY ; DOUBLE-STRANDED-RNA ; BEHAVIOR ; FLUORESCENCE ; cell lines ; TUMOR CELLS ; INCREASED EXPRESSION ; RE ; INCREASE ; oncolytic virus ; ENZYME ; TUMOR-CELL ; antiviral ; ANTITUMOR VACCINATION ; antiviral proteins ; HUMAN CELL LINES ; interferon alpha ; paramyxovirus ; PROTEIN-KINASE PKR ; TRANSLATIONAL CONTROL ; virus infection
    Abstract: To investigate tumor-selective viral replication, we compared several tumorigenic human cell lines to nontumorigenic human cells from the blood for the sensitivity to become infected by a recombinant lentogenic strain of Newcastle Disease Virus (NDV) with incorporated transgene EGFP (NDFL-EGFP). Although fluorescence signals in nontumorigenic cells were only weak or missing completely, a massive and long-lasting transgene-expression was observed in all tumor cell lines. The majority of tumor cells (50-95%) could be infected, and viral replication was associated with an increase in the cell surface density of viral antigens. To clarify the underlying mechanism of the observed difference in virus susceptibility we examined the kinetics of interferon-induced antiviral enzymes because NDV is a strong type-I interferon inducer. This analysis revealed several defects of tumor cells in their antiviral defence responses: They showed no response to UV-inactivated NDV, whereas nontumorigenic cells reacted with induction of high-levels of the antiviral enzymes PKR and MxA. Upon coincubation with live NDV, tumor cells showed a delayed response in the increased expression of the antiviral enzymes in comparison with PBMC. In nontumorigenic cells the replication cycle of NDV stopped after the production of positive-strand RNA, while tumor cells continued in the replication cycle and copied viral genomes 10-50 hr after infection. These results can explain the tumor selective replication behavior of this interesting antineoplastic virus. (c) 2006 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16470838
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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; THERAPY ; VITRO ; DISEASE ; EXPOSURE ; SITE ; GENE ; PATIENT ; ACTIVATION ; IFN-GAMMA ; MARKER ; LYMPH-NODES ; T cell ; T cells ; T-CELL ; T-CELLS ; BONE-MARROW ; MEMORY ; STIMULATION ; virus ; ASSAY ; PARAMETERS ; HEAD ; VACCINE ; REPLICATION ; squamous cell carcinoma ; ELISPOT ; IMMUNOTHERAPY ; vaccination ; side effects ; IL-2 ; FUSION PROTEIN ; INTERLEUKIN-2 ; INCREASED EXPRESSION ; CELL CARCINOMA ; FEATURES ; ONCOLOGY ; RECOMBINANT ; NODES ; RE ; HNSCC ; NEWCASTLE-DISEASE-VIRUS ; Newcastle disease virus ; lymph nodes ; ANTITUMOR VACCINATION ; SQUAMOUS-CELL ; systemic ; DEGRANULATION ; cancer vaccination ; CYTOTOXIC ACTIVITY ; tumor therapy ; anti-tumor activity ; anti-tumor ; interleukin 2
    Abstract: A new recombinant (rec) Newcastle disease virus (NDV) with incorporated human interleukin 2 (IL-2) as foreign therapeutic gene [rec(IL-2)] will be described. The foreign gene in rec(IL-2) did not affect the main features of NDV replication nor its tumor selectivity. Biologically active IL-2 was produced in high amounts by tumor cells infected with rec(IL-2). Tumor vaccine cells infected by rec(IL-2) stimulated human T cells to exert anti-tumor activity in vitro in a tumor neutralization assay. These effects were significantly increased when compared to vaccine infected by rec(-) virus without IL-2 gene. After incubation with rec(IL-2) infected tumor cells, T cells showed increased expression of the activation marker CD69 and produced increased amounts of IFN gamma when compared to T cells co-incubated with rec(-) infected tumor cells. CD8 T cells incubated with rec(IL-2) infected tumor cells showed upregulation of perform, cell surface exposure of the degranulation marker CD107a and increased anti-tumor cytotoxic activity. Purified T cells from lymph nodes of head and neck squamous cell carcinoma (HNSCC) patients could be stimulated to secrete IFN gamma in an ELISPOT assay upon 40 h of stimulation with rec(IL-2) infected autologous tumor cells [ATV-rec(IL-2)] but not upon stimulation with rec(IL-2) infected allogeneic U937 tumor cells. This suggests direct activation of patient derived tumor antigen-specific memory T cells by ATV-rec(IL-2). In conclusion, the already inherent immunostimulatory properties of NDV could be further augmented by the introduction of the therapeutic gene IL-2. Active specific immunization of patients with ATV-rec(IL-2) should provide the microenvironment at the vaccination site with IL-2 and avoid side effects as seen after systemic IL-2 application
    Type of Publication: Journal article published
    PubMed ID: 18813797
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  • 5
    Keywords: CANCER ; CELLS ; SURVIVAL ; tumor ; CELL ; Germany ; THERAPY ; PATIENT ; T cells ; MUTATION ; MUTATIONS ; IMMUNOTHERAPY ; review ; THERAPIES ; cancer vaccine ; COOPERATIVE-ONCOLOGY-GROUP ; MODIFIED TUMOR-CELLS ; PROGRESSION-FREE SURVIVAL ; therapeutic ; antigen specific ; autologous ; CELL-LUNG-CANCER ; ACTIVE SPECIFIC IMMUNOTHERAPY ; allogenic ; ANTIIDIOTYPIC MONOCLONAL-ANTIBODY ; HIGH-DOSE INTERFERON-ALPHA-2B ; MELANOMA PEPTIDE VACCINE ; METASTATIC COLORECTAL-CANCER ; PHASE-II-TRIAL ; REFRACTORY PROSTATE-CANCER ; whole cell
    Abstract: This review elucidates state-of-the-art clinical studies on active specific immunotherapy with tumor vaccines. It refers solely to randomized studies and has a special focus on patient's survival, the most important parameter for any therapy. Of special interest, from a tumor immunological point of view, is a comparison between the results obtained with allogeneic tumor cell-derived vaccines and those obtained with autologous tumor cell-derived vaccines. Overall, autologous vaccines have given better results than allogeneic vaccines. Random mutations in cancer generate unique antigens in each individual case. The superiority of autologous vaccines suggests that unique tumor-associated antigens are particularly important in generating responsive T cells for a therapeutic effect
    Type of Publication: Journal article published
    PubMed ID: 19093773
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  • 6
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; DISEASE ; PROTEIN ; PROTEINS ; TUMOR-NECROSIS-FACTOR ; ACTIVATION ; LIGAND ; RESPONSES ; INFECTION ; MECHANISM ; mechanisms ; BINDING ; RECOGNITION ; ACID ; antibodies ; antibody ; PARTICLES ; TARGET ; virus ; NECROSIS-FACTOR-ALPHA ; MELANOMA ; LIGANDS ; NATURAL-KILLER-CELLS ; NK cells ; NKG2D ; SIALIC-ACID ; INTERFERON ; melanoma cells ; RECEPTORS ; CYTOTOXICITY ; APOPTOSIS-INDUCING LIGAND ; GAMMA ; MELANOMA-CELLS ; HEPARAN-SULFATE ; Newcastle disease virus ; USA ; macrophage ; ANTITUMOR VACCINATION ; NECROSIS ; paramyxovirus ; virology ; MODIFIED TUMOR-CELLS ; CYTOTOXICITY RECEPTORS ; NATURAL-KILLER-CELL ; NKG2D ligands ; PARTICLE ; CYTOMEGALOVIRUS UL16 GLYCOPROTEIN ; INFECTED CELLS ; INTRACELLULAR RETENTION ; KILLER-CELL ; natural killer cell
    Abstract: The avian paramyxovirus Newcastle disease virus (NDV) selectively replicates in tumor cells and is known to stimulate T-cell-, macrophage-, and NK cell-mediated responses. The mechanisms of NK cell activation by NDV are poorly understood so far. We studied the expression of ligand structures for activating NK cell receptors on NDV-infected tumor cells. Upon infection with the nonlytic NDV strain Ulster and the lytic strain MTH-68/H, human carcinoma and melanoma cells showed enhanced expression of ligands for the natural cytotoxicity receptors NKp44 and NKp46, but not NKp30. Ligands for the activating receptor NKG2D were partially downregulated. Soluble NKp44-Fc and NKp46-Fc, but not NKp30-Fc, chimeric proteins bound specifically to NDV-infected tumor cells and to NDV particle-coated plates. Hemagglutinin-neuraminidase (HN) of the virus serves as a ligand structure for NKp44 and NKp46, as indicated by the blockade of binding to NDV-infected cells and viral particles in the presence of anti-HN antibodies and by binding to cells transfected with HN cDNA. Consistent with the recognition of sialic acid moieties by the viral lectin HN, the binding of NKp44-Fc and NKp46-Fc was lost after desialylation. NKp44- and NKp46-CD3 zeta lacZ-inducible reporter cells were activated by NDV-infected cells. NDV-infected tumor cells stimulated NK cells to produce increased amounts of the effector lymphokines gamma interferon and tumor necrosis factor alpha. Primary NK cells and the NK line NK-92 lysed NDV-infected tumor cells with enhanced efficiency, an effect that was eliminated by the treatment of target cells with the neuraminidase inhibitor Neu5Ac2en. These results suggest that direct activation of NK cells contributes to the antitumor effects of NDV
    Type of Publication: Journal article published
    PubMed ID: 19515783
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  • 7
    Keywords: CD8(+) T-CELLS ; innate immunity ; NATURAL-KILLER-CELLS ; NK cells ; PROGNOSTIC-SIGNIFICANCE ; I INTERFERON ; INTERFERON-ALPHA ; VIRAL-INFECTION ; IFN-alpha ; Newcastle disease virus ; SUPPRESSOR-CELLS ; anti-tumor ; FUNCTIONAL-SIGNIFICANCE ; Hemagglutinin-Neuraminidase
    Abstract: A plasmid encoding the Hemagglutinin-Neuraminidase (HN) protein of Newcastle Disease Virus (pHN) was tested for its capacity to stimulate innate anti-tumor activity in tumor-bearing mice. We observed that application of the pHN plasmid at the ear pinna site (i.e.) of mice induces higher levels of systemic interferon-alpha and reduced tumor growth in the prophylactic mammary carcinoma DA3 tumor model in comparison to application of a control plasmid not encoding the HN protein. Analysis of the tumor microenvironment revealed a significant increase in NK cell infiltration and decrease in infiltration of CD11b(+)Gr-1(high) myeloid cells bearing the myeloid-derived suppressor cell (MDSC) phenotype after vaccination with the pHN DNA compared to a control DNA. Finally, innate immunity and partially type I IFN responses were proved important for the reduction of s.c. RMA-S tumor growth after pHN vaccination, as shown with the use of RAG2(-/-) and RAG2(-/-)IFNAR1(-/-) mice. These data demonstrate that triggering innate immunity by pHN application at the ear pinna of mice modulates the immune cell compartment in the tumor microenvironment and reduces tumor growth. This highlights thus the potential adjuvant activity of the HN gene in tumor therapy.
    Type of Publication: Journal article published
    PubMed ID: 21172381
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  • 8
    Keywords: CANCER ; CELLS ; IN-VITRO ; IN-VIVO ; ACTIVATION ; RESPONSES ; INFECTION ; DENDRITIC CELLS ; BINDING ; antibody ; COLORECTAL-CANCER ; GROWTH-FACTOR-BETA ; TOLL-LIKE RECEPTORS ; NEWCASTLE-DISEASE-VIRUS ; IMMUNE-SYSTEM ; METASTATIC SPREAD ; POSTOPERATIVE IMMUNOTHERAPY ; DANGER SIGNALS
    Abstract: New approaches of therapeutic cancer vaccination are needed to improve the antitumor activity of T cells from cancer patients. We studied over the last years the activation of human T cells for tumor attack. To this end, we combined the personalized therapeutic tumor vaccine ATV-NDV-which is obtained by isolation, short in vitro culture, irradiation, and infection of patient's tumor cells by Newcastle Disease Virus (NDV)-with bispecific antibodies (bsAbs) binding to this vaccine and introducing anti-CD3 (signal 1) and anti-CD28 (signal 2) antibody activities. This vaccine called ATV-NDV/bsAb showed the unique ability to reactivate a preexisting potentially anergized antitumor memory T cell repertoire. But it also activated naive T cells to have antitumor properties in vitro and in vivo. This innovative concept of direct activation of cancer patients' T cells via cognate and noncognate interactions provides potential for inducing strong antitumor activities aiming at overriding T cell anergy and tumor immune escape mechanisms
    Type of Publication: Journal article published
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  • 9
    Keywords: CANCER ; CELLS ; IN-VITRO ; proliferation ; tumor ; TUMOR-CELLS ; CELL-PROLIFERATION ; Germany ; human ; DISEASE ; ADHESION MOLECULES ; MOLECULES ; RELEASE ; PATIENT ; ACTIVATION ; RESPONSES ; ANTIGEN ; T-CELL ; T-CELLS ; MOLECULE ; cytokines ; IMMUNE-RESPONSES ; antibodies ; antibody ; virus ; UP-REGULATION ; MONOCLONAL-ANTIBODIES ; VACCINE ; SAFETY ; IMMUNE-RESPONSE ; INTERFERON ; INTERFERON-ALPHA ; NEWCASTLE-DISEASE VIRUS ; CANCER PATIENTS ; chemokine ; EFFECTOR ; IMMUNOLOGICAL SYNAPSE ; bispecific antibody ; CYTOTOXICITY ; tumor vaccine ; RE ; NEWCASTLE-DISEASE-VIRUS ; SINGLE-CHAIN ANTIBODY ; bispecific ; Newcastle disease virus ; CD28 COSTIMULATION ; bispecific single chain antibody ; CD3 and CD28 cross-linking
    Abstract: The aim was to develop T cell costimulatory molecules that are broadly applicable to augment anti-tumor immune responses upon application of a virus-modified tumor vaccine to cancer patients. We generated recombinant bispecific single-chain antibodies with one specificity directed against the CD3 or the CD28 antigen on human T cells and the other against the viral target molecule hemagglutinin-neuraminidase (HN) of Newcastle Disease Virus (NDV). By re-directing unstimulated primary human T cells against HN-expressing NDV-infected tumor cells, the bispecific molecule bsHN-CD3 cross-linked effector and target cells and rapidly induced cytotoxicity at nanomolar concentrations. The bsHN-CD28 molecule exerted T cell co-stimulatory function. Maximal T cell activation was achieved with tumor cells infected by NDV and modified with both new stimulatory molecules. This was revealed by T cell proliferation, upregulation of CD69 and CD25 and by release of cytokines, interferons and chemokines. The new molecules combine high-effectivity with specificity and safety. (c) 2004 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15752830
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  • 10
    Keywords: RECEPTOR ; CANCER ; CELLS ; IN-VITRO ; tumor ; carcinoma ; CELL ; COMBINATION ; Germany ; human ; IN-VIVO ; VITRO ; DISEASE ; PROTEIN ; PROTEINS ; MOLECULES ; MICE ; GENE-TRANSFER ; PATIENT ; ACTIVATION ; INFECTION ; INDUCTION ; ANTIGEN ; T cell ; T cells ; T-CELL ; T-CELLS ; MOLECULE ; BREAST ; virus ; ASSAY ; IMMUNODEFICIENT MICE ; FUSION ; EFFICIENT ; FUSION PROTEINS ; VACCINE ; ELISPOT ; IMMUNOTHERAPY ; FUSION PROTEIN ; AGENT ; ONCOLOGY ; REGRESSION ; RE ; COSTIMULATION ; T-CELL-ACTIVATION ; NEWCASTLE-DISEASE-VIRUS ; Newcastle disease virus ; CD28 COSTIMULATION ; ANTITUMOR VACCINATION ; SHORT-TERM ; viral ; cancer vaccination ; immunocytokine ; IMMUNOGENE THERAPY
    Abstract: T cell costimulation has great therapeutic potential if it can be optimized and controlled. To achieve this, we engineered T cell-activating fusion proteins and immunocytokines that specifically attach to viral antigens of a virus-infected tumor vaccine. We employed the avian Newcastle Disease Virus because this agent is highly efficient for human tumor cell infection, and leads to introduction of viral hemagglutinin-neuraminidase (HN) molecules at the tumor cell surface. Here, we demonstrated the strong potentiation of the T cell stimulatory activity of such a vaccine upon attachment of bispecific or trispecific fusion proteins which bind with one arm to viral HN molecules of the vaccine, and with the other arm either to CD3 (signal 1), to CD28 (costimulatory signal 2a), or to interleukin-2 receptor (costimulatory signal 2b) on T cells. A vaccine with a combination of all three signals triggered the strongest activation of naive human T cells, thereby inducing the most durable bystander antitumor activity in vitro. Adoptive transfer of such polyclonally activated cells into immunodeficient mice bearing human breast carcinoma caused tumor regression. Furthermore, tumor-reactive memory T cells from draining lymph nodes of carcinoma patients could be efficiently reactivated in a short-term ELISpot assay using an autologous tumor vaccine with optimized signals 1 and 2, but not with a similarly modified vaccine from an unrelated tumor cell line. Our data describe new bioactive molecules which in combination with an established virus-modified tumor vaccine greatly augments the antitumor activity of T cells from healthy donors and cancer patients
    Type of Publication: Journal article published
    PubMed ID: 18360705
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