Newcastle disease virus infection induces B7-1/B7-2-independent T-cell costimulatory activity in human melanoma cells

Termeer, Christian; Schirrmacher, Volker; Bröcker, Eva‐Bettina; Becker, Jürgen C.

doi:10.1038/sj.cgt.7700109

Cited by 62 publications

(59 citation statements)

References 34 publications

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“…However, it was demonstrated that HN molecules when expressed at the surface of NDV-infected tumor vaccine induce a B7-1/B7-2-independent costimulation effect leading to induction of CD28RC in T lymphocytes (23,47). These observations differ from the present results obtained with naive T-cells in so far as Termeer et al (47) and Ertel et al (23) used, in their studies, memory T cells.…”

Section: Discussioncontrasting

confidence: 83%

Transcriptome analysis and cytokine profiling of naive T cells stimulated by a tumor vaccine via CD3 and CD25

Fournier

Aigner²,

Schirrmacher³

2010

Int J Oncol

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Abstract. T-cell receptor engagement by peptide/MHC complexes constitutes the main signal for the activation of naive T cells, but for a productive generation and maintenance of effector cells, full activation requires additional signals driven by costimulatory molecules present on activated antigenpresenting cells. Herein we describe T cell costimulation via CD25, the interleukin (IL)-2 receptor, during priming of naive T cells with a tumor vaccine. To this end, we produced, purified and characterized the fusion protein bsHN-IL2 which contains the IL-2 cytokine and an antibody scFv fragment directed towards the Hemagglutinin-Neuraminidase (HN) protein of Newcastle Disease Virus (NDV). Tumor vaccine cells were modified by infection with this virus which allows the attachment of the immunocytokine bsHN-IL2. In the presence of CD3-mediated signal 1, the vaccine/bsHN-IL2 provided via CD25 a strong bystander antitumor effect in vitro leading to tumor growth inhibition, even stronger than the vaccine/bsHN-CD28 which provides costimulation via CD28. Transcriptome analysis of naive T cells which were stimulated with the vaccine/bsHN-IL2 showed, similarly to the vaccine/ bsHN-CD28, upregulation of 71 genes belonging to different signalling pathways, including PLC-Á1, Grb-2, Vav-1 and PDE-4A. Analysis of the supernatants of activated T cells with ligand-bound tumor vaccine showed that the vaccine/ bsHN-IL2, in contrast to the vaccine/bsHN-CD28, did not lead to the production of additional IL-2. We report here the first transcriptome analysis of IL-2 receptor mediated costimulatory signals. The findings provide new insights into mechanisms of function of IL-2 during T cell priming.

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Section: Discussioncontrasting

confidence: 83%

Transcriptome analysis and cytokine profiling of naive T cells stimulated by a tumor vaccine via CD3 and CD25

Fournier

Aigner²,

Schirrmacher³

2010

Int J Oncol

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“…It also possibly prevents activation-induced cell death (AICD) or unresponsiveness. 9 The IFN-a detected in our stimulation cultures 10 appears to be of particular significance because type I interferons were recently shown to function like ''danger signals'' for DCs, causing their activation and promoting cross-priming of CD8 T cells. 31 For many of these reasons, the polyclonal T-cell response to the modified tumor vaccine appears to be unusually effective.…”

Section: Discussionmentioning

confidence: 92%

“…[1][2][3][4][5] These Phase I/II studies included primary operated breast carcinoma, 1 glioblastoma 3 and squamous cell carcinoma of the head and neck (HNSCC). 4 Infection of tumor cells with Newcastle Disease Virus (NDV) was shown to introduce into the tumor cells danger signals 6 by way of double-stranded RNA 7,8 and T-cell costimulatory activity 9 via the viral cell surface-expressed hemagglutinin-neuraminidase (HN) protein. 10 NDV can infect tumor cells efficiently, leading to high levels of HN expression on proliferating and nonproliferating cells because it replicates in the cytoplasm and does not integrate into the DNA.…”

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confidence: 99%

A tumor vaccine containing anti‐CD3 and anti‐CD28 bispecific antibodies triggers strong and durable antitumor activity in human lymphocytes

Haas

Lulei

Fournier

et al. 2005

Intl Journal of Cancer

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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. © 2005 Wiley‐Liss, Inc.

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“…In the past, we have been working with lentogenic strains such as Ulster and LaSota to infect patient derived tumor cells ex vivo for production of the immunogenic virus modified autologous tumor vaccine, ATV-NDV. We studied the immunological effects of this tumor-cell modification (28)(29)(30)(31) In the present study, we investigated systemic tumor targeting of NDV and used for this purpose either a recombinant mesogenic strain derived from LaSota (NDFL) or the native velogenic strain Italien. Both strains have a furin cleavage site in their F protein which allows its activation in a proteolytic environment such as the tumor microenvironment (25,36).…”

Section: Discussionmentioning

confidence: 99%

In vivo efficacy of systemic tumor targeting of a viral RNA vector with oncolytic properties using a bispecific adapter protein

Bian

Wilden²,

Fournier³

et al. 2006

Int J Oncol

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Abstract. The aim of the study was: i) to specifically target tumor tissue by Newcastle disease virus (NDV) with oncolytic properties, ii) to improve the delivery system for systemic application of NDV via a bispecific adapter protein and iii) to investigate anti-tumor activity and side-effects. We selected two oncolytic virus strains, one native and the other recombinant, which showed multicyclic replication patterns in tumor cells. In order to reduce normal cell binding, they were modified by preincubation with a recombinant bispecific protein which blocks the viral native cell binding site and introduces a new binding site for a tumor-associated target (in this study, the interleukin-2-receptor, IL-2R). After intravenous transfer to mice, uptake of modified NDV in liver, spleen, kidney and lung was greatly reduced in comparison to unmodified NDV as determined by RRT-PCR of viral M gene copies. In IL-2R + tumor bearing mice, the same assay revealed a high replication efficiency of the modified virus in the tumor tissue. Tumor therapy experiments showed that the side-effects induced by systemic application were greatly reduced by the adapter protein and that the anti-tumor effects were mostly undiminished. The demonstration of significant systemic anti-tumor activity of this viral vector suggests potential for augmentation by inclusion of one or more therapeutic genes.

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Newcastle disease virus infection induces B7-1/B7-2-independent T-cell costimulatory activity in human melanoma cells

Cited by 62 publications

References 34 publications

Transcriptome analysis and cytokine profiling of naive T cells stimulated by a tumor vaccine via CD3 and CD25

Transcriptome analysis and cytokine profiling of naive T cells stimulated by a tumor vaccine via CD3 and CD25

A tumor vaccine containing anti‐CD3 and anti‐CD28 bispecific antibodies triggers strong and durable antitumor activity in human lymphocytes

In vivo efficacy of systemic tumor targeting of a viral RNA vector with oncolytic properties using a bispecific adapter protein

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