T cells expressing chimeric antigen receptors (CAR T) are particularly promising for the treatment of refractory cancers. While Kymriah and Yescarta are FDA-approved for B-cell malignancies, safety and efficacy concerns remain across the cell therapy industry. Severe cytokine release syndrome triggered by T cell infusion is one of the urgent CAR T related downsides that needs to be addressed. A recent study led by researchers at Boston University reported the modularity and tunability of the innovative SUPRA CAR T cells (split, universal and programmable CARs).
- “Split” because instead of expressing CARs as fusion proteins where ligand binding and signaling domains coexist in one polypeptide (conventional CARs), SUPRAs rely on a two-component CAR system. The “zipCAR” fragment contains intracellular signaling domains connected via a transmembrane segment to an extracellular leucine zipper while the zipFv contains a ligand-binding scFv domain fused to a second leucine zipper. A functional CAR is reconstituted when zipFv proteins are added to engineered T cells that express zipCARs with matching leucine zippers.
- “Universal” because SUPRA CARs use a universal receptor for all interactions, allowing a large panel of antigens to be targeted without re-engineering the immune cells, a highly valuable asset in dealing with antigen escape.
- “Programmable” because this system allows for convenient redirection of target specificity and adjustment to T cell activity. The authors demonstrate the ability of the SUPRA CAR system to target multiple antigens with the same batch of T cells expressing the RR leucine zipper zipCAR and three zipFvs, all carrying the EE leucin zipper (RR cognate) but directed to different tumor antigens.
By using alternative leucine zippers in the zipFv fragment, a correlation between leucine zippers binding affinity and cellular activation regarding cancer cell killing efficiency and cytokine secretion was observed. The latter means that SUPRA CARs support user-defined T cell activation levels, a feature of special interest considering that conventional CARs often hyper-activate and show severe toxicities in clinical trials. For more controllable options, competitive zipFvs that bind to the first zipFv and neutralize it can be deployed to reduce CAR T cell activation.
Finally, the authors went further to demonstrate that SUPRA CARs allow for independent tuning of the activity of two different, engineered T cell subtypes (CD4+ and CD8+), a feature that could substantially improve the efficacy of CAR T cell therapy.
The article, titled “Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses” was featured by Cell.