Immune-Checkpoint Blockade Enhances²²⁵Ac-PSMA617 Efficacy in a Mouse Model of Prostate Cancer

Abstract

Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (RNT) may increase tumor immunogenicity. We aimed at exploiting this effect by combining RNT with immunotherapy in a mouse model of prostate cancer (PC). <b>Methods:</b> C57BL/6-mice bearing syngeneic RM1-PGLS tumors were treated with ²²⁵Ac-PSMA617, an anti-PD-1 antibody, or both. Therapeutic efficacy was assessed by tumor volume measurements (CT), time to progression (TTP), and survival. <b>Results:</b> PSMA RNT or anti-PD-1 alone tended to prolong TTP (isotype control, 25 d; anti-PD-1, 33.5 d [<i>P</i> = 0.0153]; RNT, 30 d [<i>P</i> = 0.1038]) and survival (control, 28 d; anti-PD-1, 37 d [<i>P</i> = 0.0098]; RNT, 32 d [<i>P</i> = 0.1018]). Combining PSMA RNT and anti-PD-1 significantly improved disease control compared with either monotherapy. TTP was extended to 47.5 d (<i>P</i> ≤ 0.0199 vs. monotherapies), and survival to 51.5 d (<i>P</i> ≤ 0.0251 vs. monotherapies). <b>Conclusion:</b> PSMA RNT and PD-1 blockade synergistically improve therapeutic outcomes in our PC model, supporting the evaluation of RNT and immunotherapy combinations for PC patients.