Castration-Resistant Prostate Cancer (CRPC), Metastatic Castration-Resistant Prostate Cancer Patients, Prostate Neoplasms
Conditions
Brief summary
This phase I study tests a personalized cancer vaccine (Neo-DC) for men with advanced prostate cancer (metastatic castration-resistant prostate cancer, or mCRPC) that has continued to grow despite standard hormone therapies and other treatments. The vaccine is custom-made for each participant using their own immune cells (dendritic cells) mixed with specific tumor markers (neoantigens) unique to their cancer. These neoantigens are identified through genetic sequencing of the patient's tumor. The goal is to help the body's immune system recognize and attack the cancer cells specifically. The study will enroll approximately 9 to 18 men and will test three different dose levels to find the safest amount. Participants will receive the vaccine as an injection under the skin every two weeks for a total of 4 doses over an 8-week treatment period. The main purpose is to evaluate the safety of this vaccine, determine the maximum tolerated dose, and identify any serious side effects. Researchers will also look at whether the vaccine helps lower PSA levels (a blood marker for prostate cancer), slows cancer growth, and stimulates an immune response against the tumor. Participants will be monitored closely during treatment and followed for several months afterward to assess long-term safety and effects.
Detailed description
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.
Interventions
BIOLOGICALAutologous Neoantigen-Pulsed Dendritic Cell Vaccine
Personalized autologous dendritic cell vaccine manufactured from patient-derived peripheral blood mononuclear cells (PBMCs). Dendritic cells are differentiated ex vivo using GM-CSF and IL-4, loaded with patient-specific synthetic neoantigen peptides (identified via NGS sequencing of tumor tissue), and matured using TNF-α, IFN-γ, and PGE2. The vaccine is administered subcutaneously at 1-3 sites (axillary or inguinal lymph node regions) every 2 weeks for a total of 4 doses. Each injection site receives 0.3 mL cell suspension. Three sequential dose cohorts: 5×10⁶ cells (low), 1×10⁷ cells (medium), and 1.5×10⁷ cells (high) per dose.
Sponsors
Changhai Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and Severity of Treatment-Emergent Adverse Events (TEAEs) | From first dose through 60 days after the last dose (up to approximately 3 months) | Number of participants experiencing treatment-emergent adverse events (TEAEs), including specifically Grade ≥3 TEAEs, serious adverse events (SAEs), and immune-related adverse events. The severity of all adverse events will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. |
| Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | From first dose through 60 days after the last dose (up to approximately 3 months) | Determination of the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of the autologous neoantigen-pulsed dendritic cell vaccine (YS247). The MTD and RP2D will be determined based on the assessment of Dose-Limiting Toxicities (DLTs) observed during the dose-escalation phase. |
| Incidence of Dose-Limiting Toxicities (DLTs) | From first dose through 60 days after the last dose (up to approximately 3 months) | Number of participants experiencing Dose-Limiting Toxicities (DLTs) during the first 4 weeks (following 2 doses) of treatment. This is evaluated per the 3+3 dose-escalation design to assess the safety and tolerability of the autologous neoantigen-pulsed dendritic cell vaccine (YS247) in mCRPC patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | From date of first response to disease progression or death (up to approximately 24 months) | Time from first documented evidence of CR or PR (per RECIST v1.1) until disease progression or death in participants who achieve objective response. For PSA responses, time from first documented ≥50% PSA decline until PSA progression (≥25% increase and ≥2 ng/mL above nadir) per PCWG3. |
| Neoantigen-Specific T-cell Immune Response | Baseline and Week 8 (up to 2 months from first dose) | Frequency of peripheral blood neoantigen-specific T cells measured by IFN-γ ELISPOT assay at baseline and Week 8 (end of treatment). Assessment of induction of cellular immunity and vaccine-specific immune response magnitude. |
| Tumor-Infiltrating Lymphocyte (TIL) Density | Baseline and Week 8 (up to 2 months from first dose) | Quantitative assessment of tumor-infiltrating lymphocyte density by immunohistochemistry (IHC) in tumor tissue samples (baseline biopsy and optional Week 8 biopsy if available) to evaluate treatment-induced changes in tumor immune microenvironment. |
| Overall Survival (OS) | From first dose until death or end of study (up to approximately 36 months) | Time from first dose of YS247 to death from any cause. Survival status will be monitored through telephone follow-up or medical record review every month during the follow-up period. |
| Progression-Free Survival (PFS) | From first dose until disease progression, death, or end of study (up to approximately 24 months) | Time from first dose of YS247 to radiographic disease progression (per RECIST v1.1 for soft tissue lesions and PCWG3 criteria for bone lesions) or death from any cause, whichever occurs first. Radiographic assessments include CT/MRI of chest/abdomen/pelvis and bone scan (or PSMA-PET/CT) performed at baseline, Week 8, and every 6-8 weeks thereafter until progression. |
| Prostate-Specific Antigen (PSA) Response Rate (PSA50) | From baseline through end of study (up to approximately 24 months) | Percentage of participants achieving confirmed PSA50 response (≥50% decline from baseline PSA level), confirmed by a second measurement at least 3 weeks later per PCWG3 criteria. PSA will be measured every 4 weeks during the treatment period and monthly during follow-up. |
| Objective Response Rate (ORR) | From baseline through end of study (up to approximately 24 months) | Percentage of participants achieving best overall response of complete response (CR) or partial response (PR) per RECIST v1.1 criteria based on measurable soft tissue metastases (lymph nodes or visceral lesions). Bone lesions will be assessed per PCWG3 criteria (stable disease or response in bone lesions will be reported separately). |
| Disease Control Rate (DCR) | From baseline through end of study (up to approximately 24 months) | Percentage of participants achieving CR, PR, or stable disease (SD) persisting for at least 6 weeks per RECIST v1.1 (soft tissue) and PCWG3 (bone) criteria. Includes assessment of measurable soft tissue lesions and evaluable bone metastases. |
Countries
China
Outcome results
None listed