YS247 (Neoantigen-Pulsed DC Vaccine) for Metastatic Prostate Cancer

This is a phase I, single-center, open-label, dose-escalation study evaluating the safety, tolerability, and preliminary efficacy of an autologous neoantigen-pulsed dendritic cell vaccine (Neo-DC, also known as YS247) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Study Design:

The study employs a traditional "3+3" dose-escalation methodology with three sequential dose cohorts: 5×10⁶, 1×10⁷, and 1.5×10⁷ cells per injection. A sentinel dosing approach will be used within each cohort, where the first participant is observed for 4 weeks before subsequent participants are enrolled at that dose level.

Intervention:

The investigational product is an autologous cellular immunotherapy manufactured from patient-derived peripheral blood mononuclear cells (PBMCs) obtained via leukapheresis. Dendritic cells are differentiated ex vivo, loaded with personalized neoantigens identified through next-generation sequencing (NGS) of tumor tissue (fresh biopsy or archival specimen), and matured using cytokine activation (GM-CSF, IL-4, TNF-α, IFN-γ, PGE2). The final product is administered as a subcutaneous injection (0.3 mL per site, 1-3 sites per dose) in the axillary or inguinal regions every 2 weeks for 4 doses (total 8-week treatment period).

Study Population:

Approximately 9-18 adult male participants (≥18 years) with histologically confirmed metastatic prostate adenocarcinoma will be enrolled. Eligibility requires documented disease progression following at least one novel endocrine therapy (e.g., abiraterone or enzalutamide), ECOG performance status 0-1, and adequate organ function (hematologic, hepatic, renal, cardiac). Participants must provide tumor tissue for neoantigen screening and HLA typing during the screening period (up to 90 days before first dose).

Endpoints:

Primary: Incidence of dose-limiting toxicities (DLTs) during the first 4 weeks (following 2 doses), frequency of grade ≥3 treatment-emergent adverse events (TEAEs per CTCAE v5.0), and determination of the maximum tolerated dose (MTD).

Secondary: PSA response rate (PSA50, defined as ≥50% decline from baseline), median progression-free survival (PFS) assessed by RECIST 1.1 and PCWG3 criteria, objective tumor response rate, and disease control rate.

Exploratory: Immunogenicity assessed by peripheral blood neoantigen-specific T-cell frequency (IFN-γ ELISPOT), changes in tumor-infiltrating lymphocyte density (IHC), and biomarker analysis of the tumor microenvironment.

Assessments:

Safety monitoring includes clinical laboratory tests (hematology, chemistry, PSA, testosterone), physical examinations, vital signs, and adverse event collection throughout the study. Efficacy evaluations include serial PSA measurements every 4 weeks and radiographic imaging (CT/MRI, bone scan, PSMA-PET/CT) at baseline, week 8, and every 6-8 weeks thereafter until progression. Immune response assessments will be conducted at baseline and week 8 (end of treatment).

Follow-up:

Participants will undergo safety follow-up at 60±7 days after the last dose. Long-term efficacy follow-up includes monthly visits for the first 6 months post-treatment, then every 2 months until disease progression, initiation of new anticancer therapy, loss to follow-up, or death. Survival status will be monitored via telephone follow-up monthly thereafter.

Statistical Considerations:

The sample size of 9-18 participants is based on the 3+3 dose-escalation design with 3 dose levels (3-6 participants per cohort). Safety and efficacy analyses will be performed on the safety analysis set and full analysis set, respectively, using descriptive statistics. Time-to-event endpoints (PFS, OS) will be estimated using Kaplan-Meier methods.

Inclusion criteria

• Male, age ≥18 years, with life expectancy ≥6 months.
• Histologically confirmed prostate adenocarcinoma with documented metastatic disease (bone, lymph nodes, or visceral organs) by recent whole-body MRI, bone scintigraphy (ECT), or PSMA-PET/CT.
• Confirmed metastatic castration-resistant prostate cancer (mCRPC) with documented disease progression after ≥1 line of novel endocrine therapy (e.g., abiraterone or enzalutamide).
• ECOG performance status 0-1.
• Availability of tumor tissue (fresh biopsy or archival specimen) for neoantigen screening.
• Willingness to undergo long-term follow-up.
• Provision of signed informed consent form by participant or legally authorized representative prior to study procedures.
• Willingness to undergo prostate biopsy if required for tissue acquisition. Adequate organ function as defined by laboratory values at screening: Absolute neutrophil count (ANC) >1.5×10⁹/L; Platelet count >100×10⁹/L; Hemoglobin >90 g/L; Total bilirubin, ALT, and AST within normal laboratory limits; Serum creatinine <133 μmol/L (or <1.5 mg/dL); INR <1.3 (or <3.0 if on warfarin or other anticoagulants); Albumin >30 g/L; Left ventricular ejection fraction (LVEF) ≥45% Negative for HIV, HBV (HBV DNA ≤500 IU/mL acceptable), and HCV (HCV RNA negative); No clinically significant ECG abnormalities.

Exclusion criteria

• History of other malignancies within the past 5 years (except non-melanoma skin cancer or carcinoma in situ with documented disease-free survival >5 years).
• Symptomatic central nervous system metastases.
• Uncontrolled active or persistent infection requiring systemic therapy.
• Systemic corticosteroid therapy within 4 weeks prior to enrollment (equivalent to >20 mg/day prednisone).
• Prior immunomodulatory therapy within 3 months, including but not limited to IL-2, CTLA-4 inhibitors, PD-1/PD-L1 inhibitors, CD40 agonists, or CD137 agonists (except adjuvant IFN-α for high-risk melanoma).
• Prior investigational prostate cancer-targeted vaccine therapy or cellular therapy within 3 months.
• Receipt of other investigational products within 2 months prior to enrollment.
• Known, confirmed, or suspected autoimmune disease or immunosuppressive condition.
• History of severe allergic reaction to any prior vaccination (for infectious disease prevention).
• Major cardiovascular events within 6 months prior to first dose, including acute coronary syndrome, aortic dissection, or stroke; or presence of severe cardiovascular disease requiring clinical intervention.
• Active autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus).
• Receipt of live vaccines within 4 weeks prior to first study treatment or planned during the study period.
• Uncontrolled hypertension (despite optimal medical management).
• Substance abuse or any psychological condition that, in the investigator's judgment, may interfere with study participation or results.
• Investigator's assessment of insufficient compliance or presence of other severe systemic diseases that would make the participant unsuitable for the study.
• High tumor burden as assessed by imaging, deemed unsuitable by the investigator.