Haematology Immunology Translational Research Achievements, Awards & Prizes

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Haematology Immunology Translational Research Achievements, Awards & Prizes - Research at Peter Mac

Recent Research Achievements

INVESTIGATION OF THE FUNCTIONAL STATUS OF GENE-MODIFIED T-CELLS FOR ADOPTIVE IMMUNOTHERAPY OF MULTIPLE MYELOMA.

This project examines the functional status of gene-modified T cells (redirected to attack tumour cells that express the Lewis Y antigen) prior to adoptive transfer. The ability of adoptively transferred T cells to induce a clinical regression is related to persistence (likely due to T cell memory) in the patient. We have demonstrated that the gene-modified T cells have a central or effector memory-like phenotype (Figure 1); furthermore, they respond to Lewis Y antigen on tumour cells by secreting IFN-γ, low levels of IL-2 and TNF, they proliferate rapidly and also kill the tumour target. Ongoing studies are exploring whether contact with LeY expressing tumour cells is required for full polarisation to memory or effector cells and the requirement for CD4 T cells in this process.

IMMUNOGENIC DEATH IN MULTIPLE MYELOMA.

This is an ongoing project examining whether novel therapies can induce both myeloma cell death and simultaneously promote an endogenous immune response to myeloma. Evidence to date indicates that tumour cells can display signature molecules on apoptotic bodies or release them from necrotic cells, these molecules incite dendritic cell (DC) maturation. DC maturation, following endocytosis of tumour cell apoptotic bodies, leads to display of tumour-derived peptides to antigen-specific T cell and induction of the endogenous response. We demonstrated that bortezomib (a proteasome inhibitor), and to a lesser extent Mapatumumab (anti-TRAIL-R1) treated myeloma cells form apoptotic bodies which are rapidly endocytosed by autologous immature DCs (iDCs). The iDCs mature over a 48 hour period displaying CD80/CD86/CD83 and upregulate MHC classII. Ongoing studies will examine the process of endocytosis by video microscopy and compare myeloma apopoptotic body uptake following treatment with different novel therapies. In addition, we will also examine whether the type of novel drug used to induce myeloma cell death has a downstream effect on the myeloma-specific T cell response.

NOVEL COMBINATION THERAPY TARGETING TRAIL RECEPTOR AND PROTEOSOME INHIBITOR TO INDUCE SYNERGISTIC CELL DEATH IN MULTIPLE MYELOMA.

This in vitro project investigated the efficacy of Mapatumumab (Mapa) combined with low dose bortezomib (BTZ) to induce human myeloma cell death. BTZ has a number of deleterious effects on DC biology, including inhibiting activation and maturation as well as antigen presentation. We have established that we can kill human myeloma cells using Mapa plus low dose velcade. Importantly, we also showed that DC function is retained in these conditions, in particular the ability to endocytose apoptotic myeloma cells and respond to toll-like receptor signaling. Ongoing studies will explore whether DCs can process myeloma versus pathogen protein to peptides and incite an antigen-specific T cell response.