<em>EphA2-Targeted CAR-NK Cell Therapy for Paediatric Sarcomas</em>  — ASN Events
  1. Schedule
  2. Poster Session One
  3. EphA2-Targeted CAR-NK Cell Therapy for Paediatric Sarcomas 

EphA2-Targeted CAR-NK Cell Therapy for Paediatric Sarcomas  (#155)

Pui Yeng Allie Lam 1 , Natacha Omer 1 2 , Joshua Wong 1 , Cui Tu 1 , Louisa Alim 1 , Gustavo Rossi 1 , Maria Victorova 3 , Hannah Tompkins 3 , Cheng Yu Lin 1 , Ahmed Mehdi 4 , Amos Choo 5 , Melissa Elliott 1 , Elaina Coleborn 1 , Jane Sun 1 , Tim Mercer 3 6 , Orazio Vittorio 7 , Lachlan Dobson 8 , Alex McLellan 8 , Andrew Brooks 1 , Zewen Kelvin Tuong 1 5 , Seth Cheetham 3 6 , Wayne Nicholls 2 5 , Fernando Guimaraes 1
  1. Frazer Institute, The University of Queensland, Woolloongabba, Queensland, Australia
  2. Oncology Services Group, Children's Health Queensland, Brisbane, Queensland, Australia
  3. Australian Institute for Bioengineering & Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia
  4. Queensland Cyber Infrastructure Foundation, Brisbane, Queensland, Australia
  5. Ian Frazer Centre for Children's Immunotherapy Research, Child Health Research Centre, The University of Queensland, St Lucia, Queensland, Australia
  6. BASE Facility, The University of Queensland, St Lucia, Queensland, Australia
  7. Children's Cancer Institute, The University of New South Wales, Sydney, New South Wales, Australia
  8. Department of Microbiology and Immunology, The University of Otago, Dunedin, Otago, New Zealand

Paediatric sarcomas, including rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma, have high rates of metastasis, recurrence, and treatment resistance, with a 5-year survival rate of ~20% for advanced disease. While chimeric antigen receptor (CAR)-T cell therapy has revolutionized haematological malignancies, its efficacy in solid tumours is limited due to poor tumour infiltration, immunosuppressive microenvironments, and off-target effects. In contrast, the adaptation of CAR technology in natural killer cells (CAR-NK) has demonstrated potential in both haematological and solid tumours, suggesting a promising therapeutic strategy for paediatric sarcomas.

This study developed and validated an ephrin type-A receptor-2 (EphA2)-targeted CAR-NK cell therapy for paediatric sarcomas. EphA2-specific CAR was introduced into NK cells via transient mRNA transfection, with >90% of NK cells expressing CAR protein 24 hours post-electroporation. EphA2-specific CAR also significantly enhanced cytotoxic activity of NK cells against rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma cell lines in vitro. We further assessed chemical modifications to mRNA delivered and demonstrated enhancement in stability of temporal EphA2-CAR expression in NK cells, leading to prolonged protein expression on the cell surface. Importantly, in vivo EphA2-CAR-NK cells tested in rhabdomyosarcoma and osteosarcoma mouse models demonstrated promising anti-cancer activity, thus strongly highlighting their potential as a therapy for these sarcomas.

In all, these findings aim to provide insights into optimising CAR-NK cell therapy for paediatric sarcomas by targeting an oncoprotein such as EphA2 and enhancing CAR stability and supports further clinical investigation to improve treatment outcomes in these aggressive malignancies.