An immune edited tumour versus a tumour edited immune system: Prospects for immune therapy of acute myeloid leukaemia.

Cell based therapies for acute myeloid leukaemia (AML) have made significant progress in the last decade benefiting the prognosis and survival of patients with this aggressive form of leukaemia. Due to advances in haematopoietic stem cell transplantation (HSCT) and particularly the advent of reduced intensity conditioning (RIC), the scope of transplantation has now extended to those patients previously ineligible due to age and health restrictions and has been associated with a decrease in transplant related mortality. The apparent graft versus leukaemia (GvL) effect observed following HSCT demonstrates the potential of the immune system to target and eradicate AML cells. Building on previously published pre-clinical studies by ourselves and others, we are now initiating a Phase I clinical study in which lentiviral vectors are used to genetically modify AML cells to express B7.1 (CD80) and IL-2. By combining allogeneic HSCT with immunisation, using the autologous AML cells expressing B7.1 and IL-2, we hope to stimulate immune eradication of residual AML cells in poor prognosis patients that have achieved donor chimerism. In this report we describe the background to cell therapy based approaches for AML, and discuss difficulties associated with the deployment of a chronically stimulated, hence exhausted/depleted immune system to eradicate tumour cells that have already escaped immune surveillance.

IL-2/B7.1 (CD80) fusagene transduction of AML blasts by a self-inactivating lentiviral vector stimulates T cell responses in vitro: a strategy to generate whole cell vaccines for AML.

Combined expression of costimulatory factors and proinflammatory cytokines stimulate effective immune-mediated tumor rejection in a variety of murine tumor models. Specifically, syngeneic tumor cells genetically modified to express B7.1 (CD80) have been shown to induce rejection of previously established murine solid tumors, and transduction with IL-2 can further increase survival. However, poor rates of gene transfer and inefficient expression of multiple transgenes encoded by single vectors have hampered the development of such autologous tumor cell vaccines for clinical trials in acute myeloid leukemia (AML) patients. Here we describe the development of a self-inactivating lentiviral vector encoding B7.1 and IL-2 as a single fusion protein postsynthetically cleaved to generate biologically active membrane-anchored B7.1 and secreted IL-2. This enables the efficient transduction of both established and primary AML blasts, resulting in expression of the transgenes in up to 98% of the cells following a single round of infection at an m.o.i. of 10. The combined expression of IL-2 and B7.1 in AML blasts enables increased stimulation of both allogeneic and autologous T cells. The stimulated lymphocytes secrete greater levels of Th1 cytokines and show evidence of specificity, as indicated by their increased proliferation in the presence of autologous AML compared to remission bone marrow cells.