AACR 2022 | Maximizing responses to anti-PD1 immunotherapy with 225Ac-J591 alpha therapy in mCRPC

Scott T. Tagawa, MD, MS, FACP, Weill Cornell Medical College, New York, NY, explains the rationale behind the novel combination of 225Ac-J591 alpha therapy, pembrolizumab, and androgen receptor signaling inhibition (ARSI) in chemotherapy-naive mCRPC. Prostate-specific membrane antigen (PSMA)-targeted alpha-emitters like 225Ac-J591 are high potency and have been shown to generate an immune response. Combination of ARSI may increase PSMA expression and as such radiosensitize tumors. ARSI resistance may lead to increased PD-L1 expression. It is thought that addition of 225Ac-J591 will lead to double-stranded DNA breaks, cell death, and subsequent release of neoantigens, and thus will increase the response to pembrolizumab plus ARSI resulting in a more durable effect. This combination therapy is currently being evaluated in a Phase I/II study (NCT04946370). This interview took place at the American Association for Cancer Research Annual Meeting 2022 in New Orleans, LA.