Poster Presentation 31st Lorne Cancer Conference 2019

Designing Novel Effective EGFRvIII CAR T cells for Glioblastoma (#111)

Rebecca C Abbott 1 , Fiona Gracey 2 , Ben Kiefel 2 , Bradley McColl 2 , Lucy C Sullivan 3 , Ryan S Cross 1 , Misty R Jenkins 1 4
  1. Department of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  2. Myrio Therapeutics, Scoresby, Victoria, Australia
  3. Department of Microbiology and Immunology, Peter Doherty Institute, Parkville, Victoria, Australia
  4. Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia

Glioblastoma (GBM) is an aggressive and malignant form of glioma, with a dismal 5% five-year overall survival rate1. The treatment for glioblastoma has largely remained unchanged for over a decade, with the last advance being the addition of a chemotherapeutic agent to a patient’s treatment regimen alongside radiotherapy2. Immunotherapy provides a new therapeutic option to enhance cancer survival rates. One such therapy is Chimeric Antigen Receptor (CAR) T cell therapy, which involves genetically modifying a patient's own T-cells to express a synthetic receptor, designed to specifically bind to a tumour expressed mutation. Once bound, the T-cell kills the malignant cell. This therapy has been incredibly successful in treating haematological cancers3. One challenge for CAR T cell therapy is identifying a tumour specific target, to minimise on target/off tumour side effects. EGFRvIII is a tumour specific mutation of EGFR, caused by the deletion of exons 2-7 from the extracellular domain of EGFR. EGFRvIII mutations occur in a subset of GBM, as well as breast and ovarian cancer4.

 

We have identified two EGFRvIII-specific short chain variable fragments (scFv) using phage display screening and cloned these into a second generation CAR construct. The recombinant scFv were confirmed to have high and specific affinity to EGFRvIII using Surface plasmon resonance (SPR). We have successfully generated EGFRvIII-specific CART cells and provide data to demonstrate both specificity of the scFvs to the EGFRvIII mutation, and cytotoxic function against EGFRvIII-expressing targets.  

 

  1. Brain and Other Central Nervous System Cancers. In.Canberra: Australian Institute of Health and Welfare; 2017: 80.
  2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, Belanger K, Brandes AA, Marosi C, Bogdahn Uet al. (2005) Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. New England Journal of Medicine. 352(10):987-996.
  3. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD et al. (2018) Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. New England Journal of Medicine. 378(5):439-448.
  4. Moscatello DK, Holgado-Madruga M, Godwin AK, Ramirez G, Gunn G, Zoltick PW, Biegel JA, Hayes RL, Wong AJ. (1995) Frequent Expression of a Mutant Epidermal Growth Factor Receptor in Multiple Human Tumors. Cancer Research. 55(23):5536-5539.