Activated CMRF-56 Immunoselected Cells: A Potential Anti-Myeloma Vaccine

Jennifer Hsu (2009). Activated CMRF-56 Immunoselected Cells: A Potential Anti-Myeloma Vaccine PhD Thesis, School of Medicine, The University of Queensland.

       
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Author Jennifer Hsu
Thesis Title Activated CMRF-56 Immunoselected Cells: A Potential Anti-Myeloma Vaccine
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2009-03
Thesis type PhD Thesis
Supervisor Prof Derek Hart
Dr Frank Vari
Total pages 264
Total colour pages 9
Total black and white pages 255
Subjects 11 Medical and Health Sciences
Abstract/Summary The Mater Medical Research Institute proposes to undertake a Phase I clinical trial using CMRF-56 immunoselected blood dendritic cells (BDC) loaded with control and myeloma-associated tumour peptide antigens for the treatment of multiple myeloma (MM) patients with minimal residual disease. This thesis describes some of the fundamental pre-clinical in vitro experiments undertaken in preparation for this trial so as to maximise the potential of this vaccine to induce myeloma-specific immune responses. These experiments involved determining the parameters for optimal activation of the CMRF-56 immunoselected cell preparation and exploring the potential of novel myeloma peptide antigens to induce anti-myeloma cytotoxic T lymphocyte (CTL) responses. CMRF-56 immunoselected cell preparations, containing predominately myeloid BDC, monocytes and B cells, were prepared from both healthy donors and myeloma patients. Activation of this preparation with granulocyte macrophage colony stimulating factor (GM-CSF) was found to increase co-stimulatory molecule expression by and survival of BDC, improve peptide- and lysate-specific CTL induction, and, in combination with prostaglandin E2 (PGE2), improve chemokine-specific migration of BDC. Following optimisation of in vitro CTL generation protocols, GM-CSF activated CMRF-56 immunoselected cells were examined for their ability to induce myeloma-specific immunity. Using lysate from myeloma cell line U266 as an antigen source, a polyclonal T cell pool was generated within which peptide specific CTL recognising myeloma antigens Muc1, HM1.24/BST2, DKK-1 and CT-7/MAGE-C1 could be identified. Furthermore, GM-CSF activated CMRF-56 immunoselected cells pulsed with HLA-A*201 restricted peptides derived from Muc1, HM1.24/BST2 and CT-7/MAGE-C1 could induce CTL capable of lysing both peptide- and myeloma cell line targets in both healthy donors and myeloma patients. These results provide the first evidence of immunogenic HLA-A*201 restricted epitopes of novel myeloma antigen CT-7/MAGE-C1. The data collected in this study supports the application of GM-CSF activated CMRF-56 immunoselected cells loaded with defined myeloma peptide antigens for the therapeutic vaccination of MM patients with minimal residual disease.
Keyword Dendritic Cell
Immunotherapy
Cytotoxic T Cell
Multiple Myeloma
tumour antigen
Additional Notes Colour pages: 69, 104, 124, 132, 133, 141, 189, 206, 217 Landscape pages: 68, 69, 98, 102, 106, 137, 185, 196, 198, 200, 201, 203, 204, 206

 
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