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POS-ERC-Støtte til ERC søkere som oppnår god evaluering

Genetically engineered macrophages for immunotherapy of malignant brain tumors

Alternativ tittel: Engineered immune cells for immunotherapy of brain tumors

Tildelt: kr 0,50 mill.

Prosjektet handler om å utvikle en ny immunterapi for hjernekreft. I prosjektet skal det utføres eksperimenter for å forbedre neste ERC søknaden.

Despite dramatic progress in the use of immunotherapy to treat cancer, a method for adapting this treatment to patients with aggressive brain tumours remains elusive. Two barriers prevent progress: a) the blood brain barrier (BBB) which prevents the entrance of large molecules such as antibodies into the brain and; b) the highly immunosuppressive microenvironment of malignant brain tumours, which prevents T cell infiltration and makes the tumours immunologically “cold”. GEM will overcome both of these obstacles by developing a pioneering immunotherapeutic methodology based on the intratumoural adoptive transfer of genetically engineered macrophages derived from induced Pluripotent Stem (iPS) cells. We will focus on the most difficult-to-treat primary brain tumours: primary Central Nervous System (CNS) lymphoma (PCNSL) and glioblastoma (GBM). Our work with PCNSL will harness the first ever patient-derived cell culture and orthotopic animal models for PCNSL, established in the Miletic Lab. Using this cell line, we have recently demonstrated the hitherto undiscovered immunological vulnerability of PCNSL towards macrophages – a vulnerability which is completely unique compared to other brain cancers and which can, in this project, now be exploited to develop a successful treatment for aggressive brain cancers. The novelty of GEM is based on the adoptive transfer of iPS cell-derived macrophages that have been modified for specific gene deletion of a Phagocytosis Inhibitory Gene (PIG). Building upon this first treatment technology, we will employ genetic screening to identify novel molecular candidates that prevent macrophage phagocytosis of GBM/PCNSL. Promising candidates will be deleted on iPS cell-derived macrophages for adoptive transfer to GBM/PCNSL. The genetically engineered macrophages will phagocytose tumour cells and induce a proinflammatory (“hot”) tumour microenvironment which will, in turn, activate adaptive immunity for successful tumour eradication.

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POS-ERC-Støtte til ERC søkere som oppnår god evaluering

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