Engineered IL-2 for improved treatment of bladder cancer 3420

Abstract Description Bladder cancer (BC) is immunogenic but incompletely immunotherapy responsive. Interleukin-2 (IL-2) is limited by Treg activation, toxicity, and short half-life. A CD122-directed IL-2 (IL-2c, IL-2 bound by CD25 binding site-occluding ab) overcomes these issues in BC models. We developed two IL-2/anti-IL-2 antibody fusion proteins: F10 IC, a CD25-occluding ab (F10) fused to native IL-2, aimed at promoting effector T cell (Teff) responses, and F10 H9T, (H9T engineered IL-2 from the Garcia lab) fused to F10 ab designed to enhance memory T cell (Tmem). In vivo studies in MB49 orthotopic BC show F10 IC activates anti-tumor Teff and NK cells. F10 H9T biases to central memory T cells (CD44+CD62L+) and induces tissue-resident memory T cells (Trm), potentially boosting local immunity. Sequential treatment with Teff-biased F10 IC followed by Tmem-biased F10 H9T increased cytotoxic lymphocyte activity vs. either alone, suggesting clinical promise for tumor control, but overall efficacy was similar. Anti-PD1 antibody immune check point blockade (ICB) plus these engineered IL2 proteins prevented tumor recurrence and inhibited lung metastasis. Thus far, F10 H9T in all treatment cycles is superior to sequencing F10 IC with F10 H9T in ongoing work. Our findings outline a strategy for next-generation IL2-based therapies, providing insights into rational treatment combinations. Combining Teff and Tmem-biased IL2 molecules could be more effective than either alone, especially combined with ICB. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)