Paul Beavis: Our New Approach to Enhance CAR T Cell Function in Solid Tumours
Paul Beavis, Group Leader at Peter MacCallum Cancer Centre, posted on X:
“Delighted to share our new approach to enhance CAR T cell function in solid tumours published today in Nature. In this work we identify a new strategy to generate armoured CAR T cells.
Armoured CAR T cells have shown great promise in preclinical settings and more recently with IL-15 armoured GPC3 CAR and IL-18 armoured CD19 CAR in the clinic. However, one challenge for armoured CAR T cells is toxicities arising from systemic expression of cytokines. To overcome this challenge, we employed CRISPR/HDR to place the armouring gene under the control of promoters that were active only when CAR T were at the tumour site.
We first identified a short list of candidate genes through rna-seq of CAR T cells isolated from the spleens and tumours of mice. From our shortlist of 27 genes we identified NR4A2 and RGS16 as two promoters of significant interest, which could support local expresssion of cytokines such as IL-12 and IL-2.
CAR T cells engineered to express these cytokines in this way elicited significantly enhanced therapeutic activity and importantly, we were able to demonstrate significantly improved safety relative to other armouring approaches. It is well known that IL-12 is highly potent when delivered safely and we observed that IL-12 secreting CAR T cells could simultaneously overcome immunosuppression, trafficking and had an ability to activate an endogenous immune response.
These are all key features of an effective CAR T cell therapy of solid tumours. Would like to thank all involved with the study particularly the talented PhD students who led the study Amanda Chen and Kah Min Yap, who made all of the CRISPR work in the lab possible and Phil Darcy who co-led the study.”
Title: Rewiring endogenous genes in CAR T cells for tumour-restricted payload delivery
Authors: Amanda X. Y. Chen, Kah Min Yap, Joelle S. Kim, Kevin Sek, Yu-Kuan Huang, Phoebe A. Dunbar, Volker Wiebking, Jesse D. Armitage, Isabelle Munoz, Kirsten L. Todd, Emily B. Derrick, Dat Nguyen, Junming Tong, Cheok Weng Chan, Thang X. Hoang, Katherine M. Audsley, Marit J. van Elsas, Jim Middelburg, Joel N. Lee, Maria N. de Menezes, Thomas J. Cole, Jasmine Li, Christina Scheffler, Andrew M. Scott, Paul A. Beavis
Read The Full Article at Nature.
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