Viral hemagglutinin augments peptide‐specific cytotoxic T cell responses

Ertel, C; Millar, Neil S.; Emmerson, Peter T.; Schirrmacher, Volker; Hoegen, Paul von

doi:10.1002/eji.1830231032

Cited by 55 publications

(43 citation statements)

References 26 publications

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“…10,11 In a murine tumor model, immunization with ATV-NDV did not change the specificity of the T-cell-mediated antitumor response, 12 although it did selectively increase the frequency of tumor-specific CTL precursors 12 and potentiate tumor-specific CTL activity via the induction of type I interferons (IFNs) 16 and via the HN molecule. 15,17 There was no nonspecific mitogenic or adjuvant effect of NDV. 17 Virus potentiation of tumor vaccine T-cell stimulatory capacity required cell surface binding but not infection.…”

Section: Strategy Of Tumor Cell Modificationmentioning

confidence: 98%

“…The mean percentage of specific 51 Cr release was calculated from triplicates as described previously. 15 …”

Section: Cytotoxicity Testmentioning

confidence: 99%

“…It consists of two steps: Tumor cells are first infected according to a previously standardized protocol 13,15,18 with a low dose of NDV to generate NDV-infected ATV-NDV or TuN. This leads to the introduction of the viral HN molecule into the tumor cell plasma membrane.…”

Section: Strategy Of Tumor Cell Modificationmentioning

confidence: 99%

“…13,14 The mechanism of the immunopotentiating effect of this virus was analyzed in detail. [15][16][17] Since 1988, a comparable ATV-NDV was developed for clinical application. 18,19 To obtain a high-quality product with potential clinical efficacy, a number of procedures were developed: mechanical dissection and enzymatic digestion to obtain single cells from freshly operated tumors, removal of debris by Percoll centrifugation, and removal of tumor-infiltrating leukocytes by immunomagnetic beads.…”

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confidence: 99%

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An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules

Haas

Herold‐Mende

Gerhards³

et al. 1999

Cancer Gene Ther

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A new, generally applicable procedure is described for the introduction of defined costimulatory molecules into human cancer cells to increase their T-cell stimulatory capacity. The procedure involves infection with Newcastle disease virus to mediate the cell surface binding of costimulatory molecules (e.g., specially designed bispecific antibodies (bsAb)). The modification is independent of tumor cell proliferation and laborious recombinant gene technology and can be applied directly to freshly isolated and ␥-irradiated patient-derived tumor cells as an autologous cancer vaccine. Following the infection of tumor cells with a nonvirulent strain of Newcastle disease virus, the cells are washed and then further modified by coincubation with bsAbs, which attach with one arm to the viral hemagglutinin-neuraminidase (HN) molecule on the infected tumor cells. The second specificity of one bsAb (bs HN ϫ CD28) is directed against CD28 to augment antitumor T-cell responses by selectively channeling positive costimulatory signals via the CD28 pathway. A second bsAb (bs HN ϫ CD3) was produced to deliver T-cell receptor-mediated signals either alone (bsCD3 vaccine) or in combination with anti-CD28 (bsCD3 vaccine plus bsCD28 vaccine). In human T-cell stimulation studies in vitro, the bsCD28 vaccine caused an up-regulation of early (CD69) and late (CD25) T-cell activation markers on CD4 and CD8 T lymphocytes from either normal healthy donors or cancer patients (autologous system) and induced tumor cytostasis in nonmodified bystander tumor cells. In addition, in combination with the bsCD3 vaccine, augmented antitumor cytotoxicity and T-cell proliferative responses were observed. This tumor vaccine modification procedure is highly specific, quick, economic, and has a broad range of clinical applications. T here is now much evidence that an antigen (Ag)-specific, T-cell-mediated immune response requires, apart from the Ag, additional costimulatory signals. 1,2 These signals are normally provided by professional Ag-presenting cells (APCs) such as dendritic cells, macrophages, and activated B lymphocytes but not, for instance, by carcinoma cells, which represent the majority of human tumors and are derived from the non-APCtype cells that form the epithelial layers. In the absence of costimulation, encounters with a tumor-associated Ag (TAA) can lead to T-cell inactivation or death rather than to proliferation and differentiation into effector cells. Modern gene therapy strategies, therefore, aim at transforming carcinoma cells into professional APCs by transfecting genes that code for T-cell costimulatory molecules, such as CD80 (B7-1), 2,3 CD86 (B7-2), and/or cytokines. 4,5 In support of this concept, some nonimmunogenic transplantable tumor cells were shown to become immunogenic after CD80, CD86, and/or cytokine gene transfection, and mice that rejected such transfectants developed systemic protective immunity against the nontransfected tumor. [2][3][4][5][6] B7 transfection, however, often does not suffice to transfer immunogen...

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Section: Strategy Of Tumor Cell Modificationmentioning

confidence: 98%

“…The mean percentage of specific 51 Cr release was calculated from triplicates as described previously. 15 …”

Section: Cytotoxicity Testmentioning

confidence: 99%

Section: Strategy Of Tumor Cell Modificationmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules

Haas

Herold‐Mende

Gerhards³

et al. 1999

Cancer Gene Ther

Self Cite

View full text Add to dashboard Cite

show abstract

“…25 Immunostimulatory properties of the hemagglutininneuraminidase (HN) of the Newcastle disease virus (NDV) have been demonstrated in vitro. 26,27 Mouse fibroblasts transfected with HN or infected with NDV have been shown to stimulate specific T-cell proliferation with greater efficacy than untreated fibroblasts. 26 A major effect of NDV infection is the induction of IFN-a/b secretion, which can be mediated either through TLRs or by RIG-I-dependent signaling.…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-mediated gene transfer of pathogen-associated molecular patterns for cancer immunotherapy

et al. 2008

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The delivery of stimulatory signals to dendritic cells (DCs) in the tumor microenvironment could be an effective means to break tumorinduced tolerance. The work presented here evaluates the immunostimulatory properties of pathogen-associated molecular patterns (PAMPs), microbial molecules which bind Toll-like receptors and deliver activating signals to immune cells, when expressed in tumor cells using adenoviral (Ad) vectors. In vitro, transduction of A549 tumor cells with Ad vectors expressing either flagellin from Listeria monocytogenes or P40 protein from Klebsiella pneumoniae induced the maturation of human monocyte-derived DCs in co-cultures. In mixed lymphocyte reactions (MLRs), Ad-flagellin and Ad-P40 transduction of tumor cells stimulated lymphocyte proliferation and the secretion of IFN-g. In vivo, these vectors were used either as stand-alone immunoadjuvants injected intratumorally or as vaccine adjuvants combined with a tumor antigen-expressing vector. When Ad-PAMPs were administered intratumorally to mice bearing subcutaneous syngeneic B16F0-CAR (cocksackie-adenovirus receptor) melanomas, tumor progression was transiently inhibited by Ad-P40. In a therapeutic vaccine setting, the combination of Ad-MUC1 and Ad-PAMP vectors injected subcutaneously delayed the growth of implanted RenCa-MUC1 tumors and improved tumor rejection when compared with vaccination with Ad-MUC1 alone. These results suggest that Ad-PAMPs could be effective immunoadjuvants for cancer immunotherapy.

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Effective anti‐metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with newcastle disease virus (NDV)

Plaksin

Porgador

Vadai

et al. 1994

Intl Journal of Cancer

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The therapeutic efficacy of active immunization with B16-F10.9 melanoma cells transfected with syngeneic major histocompatibility complex (MHC) class-I genes, modified by infection with Newcastle Disease virus (NDV) or modified by both treatments, was compared. B16-F10.9 tumor-bearing mice were treated at various stages of tumor growth and metastasis with irradiated, modified tumor-cell vaccines. Irradiated tumor cells and H-2Db transfectants did not stimulate anti-tumor immunity while H-2Kb transfectants and NDV-modified F10.9 cells showing low and high expression of MHC class-I genes efficiently prevented metastasis of small established tumors. NDV-modified parental-cell vaccines functioned optimally and improved overall survival by about 60%, also at early stages of metastasis establishment. A synergistic effect of H-2Kb expression and virus modification on rejection of micrometastases was observed in mice bearing advanced tumors. Postoperative vaccination of mice carrying multiple metastases with NDV-modified vaccines caused significant, but incomplete, reduction of metastatic tumor load. The therapeutic effect of NDV-modified tumor vaccines was dependent on multiple immune mechanisms. Depletion of CD8, CD4 or NK cells by in vivo treatment with monoclonal antibodies reversed the immunotherapeutic effects of the vaccine. Thus, tumor xenogenization and gene modification may act synergistically to vaccinate against advanced tumors, while single modalities can effectively vaccinate against metastasis at early stages of tumor growth.

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Viral hemagglutinin augments peptide‐specific cytotoxic T cell responses

Cited by 55 publications

References 26 publications

An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules

An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules

Adenovirus-mediated gene transfer of pathogen-associated molecular patterns for cancer immunotherapy

Effective anti‐metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with newcastle disease virus (NDV)

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