Background Due to the immunological characteristics of metastatic castration-resistant prostate cancer (mCRPC), various attempts to target a single immune mechanism have not been effective. The effective immunotherapy for mCRPC requires overcoming the following three challenges: (i) the absence of tumor-specific T cells, (ii) an immunosuppressive tumor microenvironment, and (iii) impaired T cell immunity. This study aims to evaluate the safety and tolerability of the combination of the prostate cancer therapeutic DNA vaccine BG-210 (which targets PAP, PSA, and PSMA), long-acting IL-7 (GX-I7), and pembrolizumab, while also assessing whether effective immunotherapy for prostate cancer can be achieved by addressing these three issues.

Methods The trial is conducted in mCRPC patients (who have progressed after at least one prior systemic therapy), using BG-210 and GX-I7 dual combination therapy (Cohort 1) or triple combination therapy with pembrolizumab (Cohort 2). The primary trial endpoints assess the safety and tolerability. Secondary endpoints include evaluating preliminary anti-tumor activity (by Prostate Cancer Working Group 3 criteria) and determining the systemic induction or expansion of vaccine antigen-specific T cells. Vaccine-induced immune responses are analyzed ex vivo using an interferon-γ enzyme-linked immune absorbent spot (ELISpot) assay and following short-term in vitro stimulation.

Results Four patients received BG-210 in combination with GX-I7, and another four patients received the triple combination of BG-210, GX-I7, and pembrolizumab. Safety (n=4) and efficacy (n=3) were assessed in each cohort. The most common related adverse events (AEs) were injection site reactions, such as edema and pruritus. Five serious AEs were reported in three patients, but none were related to the study drugs. ELISpot data showed vaccine-induced immune responses in 4 out of 6 evaluable patients. Two of three BG-210 tumor-associated antigens (PAP and PSMA) were found to be notably immunogenic. Remarkably, two patients (one on 2^nd-line therapy and one on 3^rd-line therapy) exhibited vaccine-induced immune responses, accompanied by a >90% decline in prostate-specific antigen (PSA) levels, returning to normal ranges.

Conclusions These data suggest that BG-210 in combination with GX-I7 dual therapy or with pembrolizumab triple therapy has an acceptable safety profile. Additionally, BG-210 induces meaningful immune and PSA responses in mCRPC patients.