Chimeric antigen receptor (CAR) T cell therapy is a type of cancer immunotherapy that ‘trains’ a patient’s own immune system to eradicate their cancer. CAR T cell therapy has attained up to 80% complete remission rates in B-cell leukemia and lymphomas, but the broader use of CAR T cell therapy as a first-line treatment remains limited by life-threatening side effects primarily caused by the excessive release of inflammatory cytokines, known as cytokine release syndrome (CRS). The ability to maximise anti-tumour efficacy whilst minimising the risk of inflammatory toxicities is therefore integral to the continued improvement of CAR T cell therapies. We aimed to investigate the currently ill-defined relationship between CAR structure and potency, with the intention of leveraging these findings to predictably control CAR activity.
In collaboration with computational modelling experts, we have developed de novo designed transmembrane (TM) domain sequences capable of controlling the oligomeric state of receptors. We subsequently designed CD19 targeted CARs containing these novel TM sequences, termed ‘structurally programmed’ CARs (proCARs), and validated their effector function in comparison to an otherwise identical CD28TM containing clinical product, axicabtagene ciloleucel (Yescarta®). Using our panel of proCARs we have demonstrated that cytokine secretion in response to target antigen is significantly reduced by all proCARs in comparison to CARs possessing a conventional CD28 TM domain, and a positive linear correlation of proCAR oligomeric state with inflammatory cytokine secretion is evident. I will update on results of in vivo experiments directly testing the utility of these new designs in balancing safety and efficacy in B-ALL and MCL mouse models.
These findings present an opportunity to deliberately control the safety and potency of CAR T cell therapies by controlling for CAR oligomeric state through the TM domain. Furthermore, the absence of systematic optimisation of CAR TM sequences in the field, combined with the simple modularity of our TM designs, presents a compelling case for easy translation of our proCAR TMs into diverse clinical CAR-T cell designs.