Neoadjuvant Fc-Enhanced Anti-CTLA-4 Targets Tregs to Augment Androgen Deprivation in High-Risk Prostate Cancer: A Randomized Phase I Trial - Beyond the Abstract
In prior studies, we showed that androgen deprivation therapy (ADT) can rapidly promote immune cell infiltration in localized prostate cancer. However, this immune infiltrate is complex and includes tumor-infiltrating regulatory T cells (TI-Tregs), which are suppressive lymphocytes that actively blunt the antitumor effects of ADT. TI-Tregs express CTLA-4, but standard anti-CTLA-4 antibodies like ipilimumab have shown only modest activity in prostate cancer, in part because they do not efficiently deplete TI-Tregs via antibody-dependent cellular cytotoxicity (ADCC). Therefore, a next-generation anti-CTLA-4 antibody (BMS-986218) was engineered specifically to overcome this via afucosylation of the Fc region, which dramatically increases binding affinity to FcγRIIIa (CD16a) on innate immune effector cells, enhancing Treg depletion within the tumor.
To test this treatment in patients, we conducted a single-center, randomized, open-label phase I trial (the neoREDP study) of neoadjuvant ADT alone or ADT plus BMS-986218 prior to radical prostatectomy. 24 men were enrolled. We collected fresh tumor specimens at the time of surgery to perform comprehensive correlative analyses using single-cell and high-dimensional proteomic assays, which provided a detailed understanding of the treated tumor microenvironment.
The combination was well tolerated and feasible. BMS-986218 significantly reduced TI-Treg frequencies, and the depth of this depletion was mechanistically linked to CD16a/FCGR3A expression on tumor-associated macrophages, supporting the hypothesis that Fc-enhanced CTLA-4 antibodies facilitate ADCC in patients. We also observed significant dendritic cell (DC) modulation, augmented T cell priming, and a remodeled tumor microenvironment. Importantly, tumors with lower Treg and higher DC frequencies following treatment had improved clinical outcomes, establishing these immune parameters as candidate biomarkers of response.
These findings suggest that the immunological composition of the tumor at the time of treatment, particularly the balance of Tregs and DCs, shapes clinical outcome, and that this balance is modifiable. This study also provides proof-of-concept that combination immuno-hormonal therapy in the neoadjuvant setting is both biologically active and clinically feasible in high-risk prostate cancer, warranting future studies to optimize this approach.
Written by: Matthew Dallos, MD, Assistant Attending, Solid Tumor Genito-Urinary Service, Memorial Sloan Kettering Cancer Center, New York, NY
Read the Abstract