Neoadjuvant Fc-enhanced anti-CTLA-4 targets Tregs to augment androgen deprivation in high-risk prostate cancer: A...

Despite high rates of post-surgical recurrence in men with high-risk localized prostate cancer (PCa), there is currently no role for neoadjuvant therapy. Tumor infiltrating regulatory T cells (TI-Tregs) limit the antitumor effects of presurgical androgen deprivation therapy (ADT). We present a neoadjuvant clinical trial testing whether an afucosylated anti-CTLA-4 antibody (BMS-986218) with ADT is safe, feasible, and reduces TI-Treg frequencies. This single-center, two-arm, open-label study randomizes 24 men with high-risk localized PCa to ADT with or without BMS-986218 prior to radical prostatectomy. Treatment is well tolerated and feasible. Mechanistic studies reveal reductions in TI-Treg frequencies correlate with CD16a/FCGR3A on tumor macrophages, dendritic cell (DC) modulation, and augmented T cell priming following BMS-986218 treatment. Depth of Treg inhibition and increased DC frequencies are associated with improved clinical outcomes. Overall, this study supports the feasibility and biological activity of neoadjuvant ADT + Fc-enhanced anti-CTLA-4 in high-risk PCa. Trial is registered at clinicaltrials.gov (NCT04301414).