New Investigator Symposium Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Novel EGFRvIII-specific murine CAR T cells completely eliminate glioblastoma tumours and provides scaffold for further genetic engineering (#66)

Rebecca C Abbott 1 2 , Daniel J Verdon 1 , Fiona M Gracey 3 , Hannah E Hughes-Parry 1 2 , Melinda Iliopoulos 1 , Kathy A Watson 1 , Matthias Mulazzani 1 , Kylie Luong 1 , Colleen D'Arcy 4 , Lucy C Sullivan 5 , Ben R Kiefel 3 , Ryan S Cross 1 , Misty R Jenkins 1 2 6
  1. Department of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  2. Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
  3. Myrio Therapeutics, Scoresby, Victoria, Australia
  4. Anatomical Pathology, Royal Children's Hospital, Parkville, Victoria, Australia
  5. Department of Microbiology and Immunology, Peter Doherty Institute, Parkville, Victoria, Australia
  6. Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia

Glioblastoma is a highly malignant brain tumour which accounts for approximately 60% of all adult brain cancer diagnosis and has a five-year survival rate of 5%1. New, tumour specific treatments for glioblastoma are critically required to enhance survival, whilst sparing healthy tissue. Chimeric Antigen Receptor (CAR) T cell therapy is a form of immunotherapy which provides a patient’s immune cells with a synthetic receptor, enabling recognition and lysis of malignant cells. We have developed a novel pipeline using a human Retained Display (ReD) antibody platform to screen for single chain binders (scFvs) to the glioblastoma tumour specific mutation; EGFRvIII. We identified a high affinity binder (designated GCT02) and designed a second-generation CAR2. We characterised the function of this CAR in vitro and in vivo orthotopic xenograft models of glioblastoma. The GCT02 CAR generally secreted lower quantities of evaluated cytokines, with comparable cytotoxic function to the industry benchmark EGFRvIII-CAR currently used in clinical trials. In vivo modelling demonstrated a single intravenously delivered dose of GCT02 CAR T cells was sufficient to eliminate implanted glioblastoma tumour cells two weeks post treatment, confirmed by pathological analysis2.

Appropriate target antigen selection is one major consideration for safe and effective CAR T cell therapy. Ideal target antigens are tumour specific, to preserve healthy tissue, however, the pool of such targets is very small. To increase the numbers of safely targetable antigens, logic gated genetic circuits have been previously developed to trigger the production of selected molecules within the tumour microenvironment, limiting systemic expression3,4. We are now investigating the incorporation of such synthetic circuitry in our CAR T cell systems. 

  1. Brain and Other Central Nervous System Cancers. Canberra: Australian Institute of Health and Welfare; 2017. Contract No.: CAN 106.
  2. Abbott RC, Verdon DJ, Gracey FM, Hughes-Parry HE, Iliopoulos M, Watson KA, et al. Novel high-affinity EGFRvIII-specific chimeric antigen receptor T cells effectively eliminate human glioblastoma. Clin Transl Immunology. 2021;10(5):e1283.
  3. Roybal Kole T, Rupp Levi J, Morsut L, Walker Whitney J, McNally Krista A, Park Jason S, et al. Precision Tumor Recognition by T Cells With Combinatorial Antigen-Sensing Circuits. Cell. 2016;164(4):770-9.
  4. Roybal KT, Williams JZ, Morsut L, Rupp LJ, Kolinko I, Choe JH, et al. Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors. Cell. 2016;167(2):419-32.e16.