Moving the needle of CAR-T beyond oncology 

DNA research molecule

CAR-T Therapies have revolutionised the field of personalised medicine, especially in oncology. DDW’s Megan Thomas speaks with Dr Blythe Sather, Vice President and Head of Research at Tune Therapeutics, about how genetic tuning will transform the reach for CAR-T therapies, the different diseases that can benefit, and the disruptive technology making this happen.  

MT: What is genetic tuning?

BS: Genetic tuning, also called epigenetic editing, actively manipulates the epigenetic machinery to influence gene transcription. Orchestrating the naturally occurring conductors of gene expression can shift the functional state of cells and alter gene expression.

The epigenome is a system of reversible marks that regulate how the DNA is read, translated, and used. While DNA encodes the fundamental building blocks of life, the epigenome controls which blocks are accessible for use. The epigenetic system can selectively package regions of the DNA away, making them inaccessible and, therefore, less active. Epigenetic editing can also make regions of the genome more accessible, thereby upregulating the region’s expression. 

MT: What is the current state of CAR T therapies in terms of challenges and opportunities?  

BS: CAR T-cell therapy revolutionised oncology. But creating consistent high-performing CARs still poses a challenge, particularly for treating solid tumours. For both allogeneic and autologous treatments, CAR manufacturing can be labour-intensive and highly variable. This leads to long wait times and inconsistent therapeutic performance. To address this issue, standardising practices across development and manufacturing pipelines can help reduce the variability and improve the overall efficiency of the process. Additionally, modification to enhance function and persistence of these remarkable products will be critical to improving their overall success rates.

MT: How will genetic tuning improve CAR T therapies? 

BS: The flexible mechanism of genetic tuning naturally lends itself to enhanced CAR therapies. Because epigenetic editing does not cut the underlying DNA, it allows for altering multiple gene expression pathways without generating a series of double-stranded DNA breaks, which can be dangerous. Genetic tuning can impart a wide range of transcriptional changes, from complete silencing to enhanced expression and every range in between. The duration of the transcriptional change is also flexible, and epigenetic changes can be enduring or transient based on the desired outcome. 

These factors can be harnessed to improve CAR T-cell engineering. T-cells use epigenetic programs to regulate their maturation. Using epigenetic editing, we can nudge differentiating T-cells toward specific and beneficial identities with greater effector functions, prevent or reverse their exhaustion, and preprogram them with enhanced cytokine activity.

MT: Where is the most promise for CAR T therapies in the future? 

BS: There are several avenues for CAR T-cells beyond their current applications. The first is more success in the oncology clinical in the solid tumour space. We are rapidly learning more about the tumour microenvironment and improving our ability to design optimal T-cells through tools like epigenetic editing. 

Beyond the oncology clinic, I anticipate CAR T-cells will be extremely useful in the autoimmunity space, where we can engineer CARs to target autoimmune cells. Indeed, there is already strong clinical data suggesting that this is the case. Another exciting application is using CAR T-cells to clear out senescent or fibrotic cells. 

MT: Where is the innovation in this field? 

BS: The field of genetic tuning is full of innovation and potential. I can’t imagine leaving because I enjoy working in such a dynamic field. 

With new tools to modulate gene expression in precise and specific ways, we are in a renaissance of genetic medicine. Not only can we use genetic tuning to enhance CAR T-cells, but we can also alter the epigenome to control cell differentiation patterns. For example, using genetic tuning, we can control iPSC development and pre-programme cells for success in regenerative medicine. It’s an exciting and vibrant time to be in this field! 

MT: What disruptive technologies can push this field to its full potential?  

BS: Epigenomics lies on top of the DNA—it touches every aspect of our genetic experience. Modifying the epigenome is a powerful yet precise technology. Genetic tuning has the precision to transform far-reaching areas of medicine from rare to common diseases and free up clinical bandwidth from our overtaxed system. 


Dr Blythe Sather is VP and Head of Research at Tune Therapeutics. Prior to Tune, Sather was Senior Director of T Cell Engineering at Lyell Immunopharma, and an Associate Director of Research at Juno Therapeutics. She also led the research collaboration with Editas Medicine. She has a PhD in Immunology from the University of Washington, and did postdoctoral work at Seattle Children’s Research Institute. 

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