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

Abstract

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.

Fig. 1

Strategies for AML-immune activation. a Immune evasion by AML. In the absence of co-stimulation, T cells develop anergy towards AML. This is augmented by the secretion of immunosuppressive factors, which further inhibits immune responses against AML. b Genetically modified AML cells for immune activation. B7.1 (CD80) and IL-2 gene transduction provides the essential co-stimulatory signal and IL-2 for induction of anti-leukaemia immunological responses

Fig. 2

Third generation self-inactivating lentiviral vector. a Backbone encoding B7.1 (CD80) and IL-2 cDNAs in a monocistronic expression cassette driven by a myeloid efficient promoter derived from spleen focus forming virus (SFFV). The IL-2/B7.1 fusion protein is separated by a recognition sequence for the endoprotease–furin, which cleaves to generate the biologically active constituents of soluble IL-2 and transmembrane B7.1. b Magnetic concentration following conjugation with paramagnetic microparticles (PMP). Titres presented as cfu/ml following infection and selection of infected leukaemic K562 cells in a soft agar cloning assay. VSV or A control unconcentrated, V or A biotin unconjugated control titre, V or A biotin conc PMP mediated concentrated samples (methodology described by Chan et al. [49])