Research > Focus B > Work Packages B03
Summary
This project aims at evaluating and targeting immunosuppressive glioma cell-intrinsic and -extrinsic metabolic programs and microenvironmental immunomodulation to develop combinatorial targeted (immuno-) therapies for isocitrate dehydrogenase (IDH) mutant gliomas. The strategic aim is to utilize immunosuppressive IDH-associated metabolic vulnerabilities in pathophysiologically relevant preclinical glioma models for rationalizing combinatorial clinical trials. The visual abstract below shows the aims and planned tasks of the work package.
Task 1
Preclinical investigation of R-2-HG-associated transcriptomic, metabolic and proteomic immune cell signatures and their intratumoral heterogeneity
Steps / Workflow
- spatial resolution immunological tissue analyses combined with local R-2-HG levels
- Evaluation of R-2-HG-associated AHR-dependent immunosuppressive intratumoral programs
- Paired single immune and tumour cell analyses in infiltrative preclinical glioma
- reversibility of immunosuppressive programs by IDH1R132Hi
Task 2
Evaluate efficacy and dynamics of the inflammatory glioma microenvironment upon preclinical combinatorial therapeutic interventions for IDH1-mutant gliomas
Steps / Workflow
- antigen processing and presentation capacity of myeloids
- evaluation of IDH1R132Hi and T cell therapy in preclinical mutant IDH1 A2DR1 gliomas
- evaluation of AHRi and mutant IDH1-specific immunotherapy in preclinical gliomas
Task 3
Identify routes and evaluate potential druggable targets of R-2-HG transport in IDH1 mutant gliomas
Steps / Workflow
- verification of SLC13A3 as R-2-HG transporter in human gliomas
- CRISPR-Cas9 screen in patient-derived IDH1-mutant glioma tumour spheres
- pharmacological inhibitors of R-2-HG export in patient-derived IDH1 mutant glioma tumour spheres
- Effect of identified inhibitors on the microenvironment
Task 4
Evaluate mechanisms of natural immune surveillance of single in vivo-induced IDH1 mutated cells
Steps / Workflow
- evaluate existence of a natural immune surveillance of single IDH1-mutant astrocytes
- evaluate existence of a natural immune surveillance of single IDH1-mutant neural stem cells
- immunosurveillance by MHCII-restricted mutant IDH1-specific T cell receptors
Task 5
Generation of PBMC-humanized, patient-derived IDH1R132H-mutant brain tumour xenograft models from patients enrolled in the AMPLIFY-NEOVAC trial to study response and resistance mechanisms after combinatorial immunotherapy
Steps / Workflow
- establish NSG-SGM3 humanization protocols
- establish AMPLIFY-NEOVAC PDX
- evaluate combinatorial immunotherapy including IDH1-vaccine, mutant IDH1-specific T cell transfer, and checkpoint inhibition in combination with a mutant IDH1 inhibitor, respectively
PRINCIPLE INVESTIGATORS
PUSCH, STEFAN, DR. RER. NAT.
Post Doc
University Hospital Heidelberg, Institute of Pathology, Dep. of Neuropathology, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
BUNSE, LUKAS, DR. MED.
Post Doc
University Hospital Mannheim, Department of Neurology, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany