Immunotherapy with mannan-MUC1 and IL-12 in MUC1 transgenic mice

Lees, Catherine; Apostolopoulos, Vasso; Acres, Bruce; Ramshaw, Ian A.; Ramsay, Alistair J.; Ong, Chin.-Swee; McKenzie, Ian F. C.

doi:10.1016/s0264-410x(00)00065-7

Cited by 32 publications

(15 citation statements)

References 12 publications

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“…Many efforts that have been made in recent years to improve the cellular immune response against MUC1 protein include: (1) conjugation of MUC1 peptides with Keyhole Limpet Hemocyanin (KLH) or mannan, 53,54 (2) coexpression of MUC1 with costimulation molecule B7.1 (CD80) in tumor cells to provide costimulatory signals to the immune system, 55 (3) fusion MUC1 positive tumor cells with antigen presenting cells (APC) or pulsing the dendritic cells with MUC1 peptide [56][57][58] and (4) combined application of Th1 cytokines with MUC1. 59 Different clinical trials have been carried out using MUC1 mucin peptide-based vaccines.…”

Section: Advancement Of Immunotherapeutic Applications With Muc1mentioning

confidence: 99%

MUC1: A target molecule for cancer therapy

Singh

Bandyopadhyay²

2007

Cancer Biology & Therapy

151

142

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Section: Advancement Of Immunotherapeutic Applications With Muc1mentioning

confidence: 99%

MUC1: A target molecule for cancer therapy

Singh

Bandyopadhyay²

2007

Cancer Biology & Therapy

151

142

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“…Strategies during the last years to improve the cellular immune responses against MUC1 protein include: (i) conjugation of MUC1 peptides with KLH or mannan Gilewski et al, 2000), (ii) coexpression of MUC1 with CD80 (B7.1) in tumour cells to provide costimulatory signals to the immune system (Smith et al, 1999), (iii) fusing MUC1-positive tumour cells with antigenpresenting cells or pulsing dendritic cells with MUC1-derived peptides (Brossart et al, 2000;Gong et al, 2000), (iv) application of MUC1 together with Th1 cytokines ; Carr-Brendel Lees et al, 2000;Mukherjee et al, 2003), and (v) use of a BCG-MUC1-IL2 fusion protein (He et al, 2002). The latter fusion protein consists of the BCG antigen signal sequence, the MUC1 VNTR core peptide, and IL2.…”

Section: Discussionmentioning

confidence: 99%

An anti-MUC1-antibody–interleukin-2 fusion protein that activates resting NK cells to lysis of MUC1-positive tumour cells

et al. 2003

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MUC1 mucin is aberrantly glycosylated and overexpressed in a number of epithelial malignancies and is therefore a promising tumour-associated antigen for target-directed immunotherapy of a panel of malignant diseases. In MUC1-positive tumours, MHC class I expession is frequently downregulated and MUC1-specific cytotoxic T cells (CTLs) are either not available or in a state of anergy allowing tumour growth without limitation by CTL control. To activate lymphocytes and natural killer (NK) cells, we here generated an anti-MUC1-scFv-IL2 fusion protein (C595scFv-Fc-IL2) that contains the C595 single-chain antibody for MUC1 binding, the human IgG1 CH2CH3 domain for protein dimerisation, and interleukin-2 (IL2) for activation of immunological effector cells. The fusion protein binds to MUC1-derived peptides and to MUC1-positive tumour cells with the same specificity as does the C595 monoclonal antibody. Bound to MUC1, the C595scFv-Fc-IL2 fusion protein stimulates proliferation of human activated lymphocytes in vitro. Upon binding to MUC1-positive MCF7 breast carcinoma cells, moreover, the fusion protein activates resting NK cells to tumour cell lysis. These properties make the C595scFv-Fc-IL2 fusion protein a suitable candidate for the immunotherapy of MUC1-positive tumours.

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“…A MUC1-GST fusion protein containing 5 variable number of tandem repeat (VNTR) regions from the extracellular protein core of MUC1 [14] was produced in a bacterial expression system (pGEX-3X) and conjugated to oxidised mannan to form MFP as described previously [15][16][17][18][19][20][21][22][23]. BALB/c mice aged 6-10 weeks were given three intraperitoneal immunisations (on days 0, 7 and 14) with either MFP (containing 5μg of MUC1 fusion protein) or a control pH 9.0 phosphate buffer.…”

Section: Mice and Immunisationsmentioning

confidence: 99%

“…Prior to challenge, the tumour cells were cultured with 20 ng/ml vaccinia virus-IFNγ supernatant (UV inactivated) [22,23,25,26] for 72 h to increase cell surface MHC class I expression. Tumour growth was measured every 2-3 days for 2 weeks using electronic callipers.…”

Section: Tumour Modelmentioning

confidence: 99%

MUC1 immunotherapy against a metastatic mammary adenocarcinoma model: Importance of IFN-gamma

Lees¹,

Smorodinsky

Horn

et al. 2016

Prilozi

Self Cite

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Immunotherapy using mucin 1 (MUC1) linked to oxidised mannan (MFP) was investigated in an aggressive MUC1 + metastatic tumour, DA3-MUC1 because, unlike many MUC1 + tumour models, DA3-MUC1 is not spontaneously rejected in mice making it an alternative model for immunotherapy studies. Further, DA3-MUC1 cells are resistant to lysis by anti-MUC1 cytotoxic T cells (CTLs). The inability of DA3-MUC1 tumours to be rejected in naïve mice as well as vaccination to MUC1 was attributed to a deficiency of expression of MHC class I molecules on the tumour cell surface. In vitro and in vivo analysis of subcutaneous tumours and lung metastases demonstrated that DA3-MUC1 tumour cells have a low expression (< 6%) of MHC class I which can be upregulated (> 90%) following culturing with IFN-γ. Results from flow cytometry analysis and immunoperoxidase staining indicated that the in vitro up-regulation of MHC class I could be maintained for up to seven days in vivo, without affecting the expression levels of MUC1 antigen. Interestingly, MUC1-specific CTL that lyse DA3-MUC1 targets in vitro were induced in MFP immunised mice but failed to protect mice from a DA3-MUC1 tumour challenge. These results highlight the importance of MHC class I molecules in the induction of anti-tumour immunity and the MFP immune response.

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Immunotherapy with mannan-MUC1 and IL-12 in MUC1 transgenic mice

Cited by 32 publications

References 12 publications

MUC1: A target molecule for cancer therapy

MUC1: A target molecule for cancer therapy

An anti-MUC1-antibody–interleukin-2 fusion protein that activates resting NK cells to lysis of MUC1-positive tumour cells

MUC1 immunotherapy against a metastatic mammary adenocarcinoma model: Importance of IFN-gamma

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