Cellular immune therapy as a basis for multi-modality cancer therapy

Mattarollo, Stephen Robert (2007). Cellular immune therapy as a basis for multi-modality cancer therapy PhD Thesis, School of Medicine, University of Queensland.

       
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Author Mattarollo, Stephen Robert
Thesis Title Cellular immune therapy as a basis for multi-modality cancer therapy
School, Centre or Institute School of Medicine
Institution University of Queensland
Publication date 2007
Thesis type PhD Thesis
Abstract/Summary Treatment of cancer remains largely ineffective despite ongoing efforts to improve therapy modalities. Conventional treatments such as chemotherapy and radiation have proven to be effective in some cases, however the unstable genome of transformed cells leads to mutations and generation of new sub-clones that are able to escape therapeutic control. Overcoming tumour resistance requires the development of alternative or additional modalities of treatment that optimally would possess greater selectivity for tumour targets, provide alternative cytotoxic mechanisms and have non-cross reactive toxicities with current treatments. Cellular immunotherapy is an attractive alternative to conventional treatments. Harnessing the patients’ own immune cell defence system to recognize and kill tumour cells reduces the risk of toxicity associated with administering chemotherapy or radiation and has the potential to be highly specific towards malignant tissue. In many clinical situations there is evidence that combination therapy, utilising two or more modalities of treatment simultaneously, is superior to single agent therapy. Combining drugs or agents on the basis of differing mechanisms of action has the theoretical capacity to increase anti-tumour cytotoxicity with minimal increases in systemic or tissue toxicity. Also, there are reduced chances of resistance emerging when a number of modalities are used. The research undertaken for this dissertation aimed to determine the potential therapeutic benefits of combining cell based immune therapy with chemotherapy agents and the bisphosphonate, zoledronate, for improvements in therapy of solid malignancies. Human immune effector cells, VH24/VO11 NKT cells and VB9VD2 T cells, possess potent cytotoxic anti-tumour activities against a range of tumour cell types without the requirement for MHC-restriction. These effector cell populations were assessed for their direct cytotoxic capacity against solid tumour-derived targets in combination with anti-tumour agents. Mechanistic interactions between effector cells, chemotherapy and zoledronate were investigated and a human in vivo trafficking study of adoptively transferred VB9VD2 T cells was performed to predict the clinical feasibility of this multi-modality approach. Results demonstrate high levels of VB9VD2 T cell and NKT cell cytotoxicity against tumour cell lines in combination treatment with chemotherapeutic agents. Pretreatment with low concentrations of chemotherapy sensitized tumour cells to rapid killing by these effector cells and levels of cytotoxicity approached 90%. Zoledronate pre-treatment of tumour cells induced potent lytic responses by VB9VD2 T cells and also enhanced chemotherapy-induced sensitization resulting in almost 100% cell death of tumour targets in some cases. Mechanisms of cytotoxicity involved a range of pathways, including perforin, TRAIL and FasL, some of which were instigated by the effects of chemotherapy or zoledronate exposure. In vivo migration studies of intravenously administered VB9VD2 T cells show for the first time preferential movement of these cells to large organs and small tumour deposits, but the inability to infiltrate large tumour masses. In conclusion, the administration of NKT cells or VB9VD2 T cells at suitable intervals after chemotherapy and/or zoledronate in a cell based multi-modality therapy approach, may substantially increase anti-tumour activities in a range of solid tumour malignancies and improve patient outcomes. The anticipated benefits of this research are combinations of cancer therapies that are not only more effective than those currently available, but also reduce toxicity associated with conventional treatments.

 
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Created: Fri, 21 Nov 2008, 17:06:27 EST