CD8 T-cell exhaustion linked with CAR T-cell failure can be mitigated by a non-alpha IL2 receptor agonist.

Chimeric antigen receptor T-cell (CART19) therapy represents a breakthrough for relapsed or refractory large B-cell lymphoma (rrLBCL). However, suboptimal CART19 activity can lead to therapeutic failure and dismal outcomes. Through single cell RNA-sequencing of tumors at the time of progression from CART19, we show that a subset of tumor contain clonally expanded and proliferating populations of CART19 cells that acquire transcriptional features of dysfunction, suggestive of ongoing tumor cell engagement and chronic stimulation. Using an in vitro system to model this process, we show that iterative rechallenge of CART19 cells with target cells drives failure of tumor control associated with acquired transcriptomic features of T-cell dysfunction and reduced IL2 signaling. Pegenzileukin, a non-alpha IL2-receptor agonist, prevented CART19 dysfunction, improving T-cell expansion and tumor control in vitro. To test this concept in vivo, we developed a cell line model from a post-CART19 progression tumor that reproduces the response and failure kinetics observed in the originating patient. In vivo CART19 alone led to transient response followed by progression and secondary central nervous system relapse in this model, while the addition of pegenzileukin to CART19 led to the complete eradication of tumors. This provides mechanism-informed pre-clinical rationale for the use of non-alpha IL2 receptor agonists in combating T-cell exhaustion, a critical mechanism of CART19 failure.