Metabolic engineering of CD70CAR T cells to enhance immunotherapy targeting DIPG
Malignant brain tumors are the most common cause of cancer-related death in children. The current standard of care treatment is often associated with lifelong cognitive and motor deficits and is almost inevitably followed by disease recurrence. Therapiesthat specifically and efficiently target tumor cells and minimize toxicity to normal cells are thus critical to the next generation of interventionsthat promise improved clinical outcomesfor children affected by these deadly diseases. The potential of immunotherapy in central nervoussystem (CNS) malignancies has previously been thought to be futile given the immune privileged and immunosuppressive nature of the intracranial environment. Our group and others have demonstrated that the immune system is capable of surveying the CNS and mount an immunological response that can be therapeutically exploited to treat brain cancer. Several immunotherapeutic approaches have been advanced for the treatment of brain tumors and are currently under evaluation in clinical trials. We established a new CAR T cell platform based on the targeting of CD70, a member of the tumor necrosisfactor superfamily,shown to contribute to brain tumor progression including pediatric glioma. Despite significant therapeutic efficacy, our studiesrevealed limitations of this approach characterized by a lack of complete and long-lasting response.
Project Goal:
Capitalizing on our current knowledge of tumor metabolism and how metabolic pathways affect immune response, this project proposesto test an innovative therapeutic modality based on reprograming the metabolic qualities of anti-tumor immune cellsto enhance immunotherapy for childhood cancer. Our overarching hypothesisisthat manipulating the metabolic fitness of chimeric antigen receptor (CAR) modified T cells can ameliorate their tumoricidal activity. The following points will be addressed: 1) can glucose transporters overexpression in CAR T cells overcome tumor-imposed glucose restriction and 2) can metabolically engineered CAR T cells engender a complete response and long-lasting anti-tumor immunity. The main innovation of this project isthe integration of fundamental concepts of tumor and immune metabolism in the design of CAR T cell therapy. The major impact of our study isthat successfully completed it will confirm that immunometabolism represents a viable and critical target for the development of new cancer therapiesto treat pediatric cancers, especially brain tumors
