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  • 1
    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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  • 2
    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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  • 3
    Keywords: CANCER ; CELLS ; tumor ; TUMOR-CELLS ; BLOOD ; carcinoma ; CELL ; COMBINATION ; Germany ; human ; DISEASE ; MOLECULES ; PATIENT ; ACTIVATION ; INFECTION ; MECHANISM ; INDUCTION ; CD8(+) T-CELLS ; mechanisms ; T cell ; T cell activation ; T cells ; T-CELL ; T-CELLS ; BINDING ; MOLECULE ; ANTITUMOR-ACTIVITY ; BREAST ; RECOGNITION ; antibodies ; antibody ; TARGET ; virus ; CARCINOMA CELLS ; LYMPHOCYTES ; CARCINOMA-CELLS ; BREAST-CARCINOMA ; VACCINE ; CANCER-PATIENTS ; INTERFERON ; NEWCASTLE-DISEASE VIRUS ; CANCER PATIENTS ; TUMOR CELLS ; EFFECTOR ; HUMAN BREAST ; bispecific antibody ; T-cell response ; tumor vaccine ; APOPTOSIS-INDUCING LIGAND ; MONONUCLEAR-CELLS ; ONCOLOGY ; RE ; COSTIMULATION ; NEWCASTLE-DISEASE-VIRUS ; carcinoma cell ; TUMOR-CELL ; bispecific ; Newcastle disease virus ; VIROTHERAPY ; breast carcinoma ; CD3 and CD28 cross-linking ; ANTITUMOR ; ANTITUMOR ACTIVITIES ; bispecific single-chain antibodies ; CONTACT ; tumor neutralization assay
    Abstract: We recently reported on newly designed virus-targeted bispecific CD3- and CD28-binding molecules for human T-cell activation. When bound via one arm to a human virus-modified tumor cell vaccine, these reagents caused a polyclonal T-cell response and overcame the potential various T-cell evasion mechanisms of tumor cells. In our current study, we demonstrated the induction of strong antitumor activity in human lymphocytes upon coincubation with a virus-modified tumor vaccine containing anti-CD3 and anti-CD28 bispecific antibodies. Blood mononuclear cells or purified T cells that were coincubated with such a tumor vaccine for 3 days were able to destroy monolayers of human breast carcinoma and other carcinoma cells. Serial transfer to new tumor cell monolayers revealed antitumor cytotoxic activity in such effector cells that lasted for about 10 days. Nontumor target cells appeared to be much less sensitive to the activated effector cells. Although the bispecific molecules alone did not activate effector cells, their binding to virus-infected tumor cells was important and. more effective than their binding to free virus. Antitumor activity of the activated effector cells was mediated through soluble factors as well as through direct cell contact of effector cells with the nontargeted bystander tumor cells. Since the virus-modified tumor vaccine is well tolerated and already exhibits a certain effectiveness in cancer patients, the combination with new bispecific molecules has the potential to introduce additional antitumor effects. The reagents can also be combined with Newcastle Disease Virus (NDV)-based oncolytic virotherapy. (c) 2005 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16108015
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