An engineered IL-2 partial agonist promotes CD8+ T cell stemness and anti-tumor efficacy

Adoptive cell transfer of antigen specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in a subset of patients. To achieve effective responses, both the number of transferred T cells and their cell differentiation state are critical determinants. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and IL-2, but this can also lead to T cell differentiation into effector T cells and result in lower therapeutic efficacy, whereas maintenance of a more stem-like state prior to adoptive transfer is beneficial. Here, we show that H9T, an engineered IL-2 partial agonist, promoted T-cell expansion without driving terminal differentiation. H9T exhibited altered signaling and mediated distinctive downstream transcriptional, epigenetic, and metabolic programs. H9T sustained expression of transcription factor TCF-1 (T cell transcription factor 1) and promoted mitochondrial fitness, facilitating the maintenance of a stem cell-like state. Accordingly, TCR transgenic and CAR-modified CD8+ T cells expanded with H9T displayed robust anti-tumor activity in vivo in established models of melanoma and acute lymphoblastic leukemia. Thus, tempering cytokine signaling with H9T provides a novel strategy for enhancing therapeutic efficacy by limiting exhaustion while preserving stemness.