Translation

Why CAR T Therapies are Such a Headache with Kevin Parker

Episode Summary

Engineered T cells that hunt and kill blood cancers have recently obtained three landmark FDA approvals, forever changing the way we treat this disease. Even with its massive clinical success, these cells come with life-threatening neurotoxicities. But is neurotoxicity a set feature of using T cell therapies or is our engineering accidentally targeting the brain? Utilizing advances in bioinformatics and the huge sequencing datasets available to science, Kevin uncovers similarities between a cell type in our brain and the cancer we target with engineered cells. Finding this needle in a haystack, Kevin creates a link between how we engineer these cells and the neurotoxicities we see, discovering a potential root cause of the problem and generating a rule for how to engineer around it.

Episode Notes

Engineered T cells that hunt and kill blood cancers have recently obtained three landmark FDA approvals, forever changing the way we treat this disease. Even with its massive clinical success, these cells come with life-threatening neurotoxicities. But is neurotoxicity a set feature of using T cell therapies or is our engineering accidentally targeting the brain? Utilizing advances in bioinformatics and the huge sequencing datasets available to science, Kevin uncovers similarities between a cell type in our brain and the cancer we target with engineered cells. Finding this needle in a haystack, Kevin creates a link between how we engineer these cells and the neurotoxicities we see, discovering a potential root cause of the problem and generating a rule for how to engineer around it.

About the Author

• Kevin recently received his PhD from Stanford University in the labs of Professor Howard Chang and Professor Ansuman Satpathy. These labs specialize in uncovering the molecular mechanisms of disease using advanced sequencing modalities.
• Bridging both biology and computer science, Kevin’s background and expertise made him uniquely suited to hunt down the culprit of CAR T cell neurotoxicity.

Key Takeaways

• CAR T cells are excellent at killing blood cancers but are not without side-effects -- they can cause severe neurotoxicities.
• The receptor engineered into CAR T cells was thought to be specific to these blood cancers, ensuring the therapies don't attack healthy tissue.
• Kevin looked at publically available single cell sequencing data to find a small subset of brain cells hiding in plain sight that the CAR T cells could attack. 
• In mice, engineered “blood cancer specific” T cells attack the brain, demonstrating that neurotoxicity is an off-target effect of the therapy, not a byproduct.

Translation

• The finding points to the potential need for different engineered receptors to be used to target these blood cancers.
• As CAR T cells expand to other cancers and malignancies, this process can be run to ensure we engineer cells that minimize the opportunity for damage to healthy tissue.

First Author: Kevin Parker

Paper: 

Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies