WEHI PhD Completion Seminar hosted by Professor Misty Jenkins

Krishneel Prasad
PhD Student – Jenkins Laboratory, Brain Cancer Centre – Cancer division, WEHI

Genetically Engineering Safer T Cell Therapies for Brain Cancer 

L3C Seminar Room

Join via TEAMS

Including Q&A session

Glioblastoma is a severe brain cancer where 5-year survival rates have remained at 5% for decades. Chimeric Antigen Receptor (CAR) T cell therapies are emerging as promising treatment options, with recent clinical trial results beginning to report cases of tumour regression and improved survival. However, treatment related toxicities and cytokine release syndrome still require careful management.  

The Jenkins Laboratory has applied cell surface proteomics on primary brain tumour tissue and has uncovered many novel targets for CAR T cell therapy development, including the heat shock protein HSP90B1. HSP90B1 is normally localised to the Endoplasmic Reticulum and increases in expression within stressed and proliferative cells. Although small molecule drugs have failed to safely target intracellular HSP90B1, cell surface mis-localisation in cancer may improve tumour-specificity when targeted using cell therapies. Our HSP90B1 CAR T cells displayed pan-cancer activity in vitro, and remarkably, have demonstrated potent in vivo tumour protection against glioblastoma and colon cancer models.  

Further addressing safety, Versatile Proteolysis CAR (VIPER) T cells utilise split CAR designs that can be inhibited using an FDA approved anti-viral agent, grazoprevir. We designed a panel of solid-tumour targeting VIPER T cells and confirmed in vitro pan-cancer cytotoxicity, grazoprevir mediated inhibition and tunable function when targeting HSP90B1, CD276 and HER2. Future work serves to validate in vivo grazoprevir mediated inhibition using models where VIPER T cells have demonstrated strong, anti-tumour activity. 

Next-generation T cell therapies are increasingly potent, whether through multi-antigen targeting or armouring, but are necessary to tackle solid tumours. These studies identify an under-explored antigen class for targeting cancer and establishes VIPERs as a platform for engineering drug regulatable cell therapies.  

All welcome!