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Updated: Nov 11, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Phase I study of a multitargeted recombinant Ad5 PSA/MUC-1/brachyury-based immunotherapy vaccine in patients with
Marijo Bilusic1, Sheri McMahon2, Ravi A Madan2
1Genitourinary Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA marijo.bilusic@nih.gov.
Background:
Antitumor vaccines targeting tumor-associated antigens (TAAs) can generate antitumor immune response. A novel vaccine platform using adenovirus 5 (Ad5) vectors [E1-, E2b-] targeting three TAAs-prostate-specific antigen (PSA), brachyury, and MUC-1-has been developed. Both brachyury and the C-terminus of MUC-1 are overexpressed in metastatic castration-resistant prostate cancer (mCRPC) and have been shown to play an important role in resistance to chemotherapy, epithelial-mesenchymal transition, and metastasis. The transgenes for PSA, brachyury, and MUC-1 all contain epitope modifications for the expression of CD8+ T-cell enhancer agonist epitopes. We report here the first-in-human trial of this vaccine platform.
Methods:
Patients with mCRPC were given concurrently three vaccines targeting PSA, brachyury, and MUC-1 at 5×1011 viral particles (VP) each, subcutaneously every 3 weeks for a maximum of three doses (dose de-escalation cohort), followed by a booster vaccine every 8 weeks for 1 year (dose-expansion cohort only). The primary objective was to determine the safety and the recommended phase II dose. Immune assays and clinical responses were evaluated.
Results:
Eighteen patients with mCRPC were enrolled between July 2018 and September 2019 and received at least one vaccination. Median PSA was 25.58 ng/mL (range, 0.65-1006 ng/mL). The vaccine was tolerable and safe, and no grade >3 treatment-related adverse events or dose-limiting toxicities (DLTs) were observed. One patient had a partial response, while five patients had confirmed PSA decline and five had stable disease for >6 months. Median progression-free survival was 22 weeks (95% CI: 19.1 to 34). Seventeen (100%) of 17 patients mounted T-cell responses to at least one TAA, whereras 8 (47%) of 17 patients mounted immune responses to all three TAAs. Multifunctional T-cell responses to PSA, MUC-1, and brachyury were also detected after vaccination in the majority of the patients.
Conclusions:
Ad5 PSA/MUC-1/brachyury vaccine is well tolerated. The primary end points were met and there were no DLTs. The recommended phase II dose is 5×1011 VP. The vaccine demonstrated clinical activity, including one partial response and confirmed PSA responses in five patients. Three patients with prolonged PSA responses received palliative radiation therapy. Further research is needed to evaluate the clinical benefit and immunogenicity of this vaccine in combination with other immuno-oncology agents and/or palliative radiation therapy.
Trial Registration Number:
NCT03481816.
Insights
This study shows a new prostate cancer vaccine is safe and well-tolerated in patients with metastatic castration-resistant prostate cancer (mCRPC). The vaccine generated T-cell responses and demonstrated some clinical activity, warranting further investigation.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) is associated with overexpression of tumor-associated antigens (TAAs) like prostate-specific antigen (PSA), brachyury, and MUC-1.
- These TAAs play roles in chemotherapy resistance, epithelial-mesenchymal transition, and metastasis.
- A novel adenovirus 5 (Ad5) vector vaccine platform was developed targeting these three TAAs with modified epitopes to enhance CD8+ T-cell responses.
Purpose of the Study:
- To evaluate the safety and determine the recommended phase II dose of a novel Ad5-vectored vaccine targeting PSA, brachyury, and MUC-1 in patients with mCRPC.
- To assess the immunogenicity and preliminary clinical activity of this multi-TAA vaccine platform.
Main Methods:
- A first-in-human trial involving patients with mCRPC.
- Vaccination involved three Ad5 vectors (PSA, brachyury, MUC-1) at 5×10^11 viral particles (VP) each, administered subcutaneously every 3 weeks for up to three doses.
- Dose de-escalation and dose-expansion cohorts were included, with booster vaccinations and monitoring of safety, immune responses, and clinical outcomes.
Main Results:
- The Ad5 PSA/MUC-1/brachyury vaccine was well-tolerated and safe, with no grade >3 treatment-related adverse events or dose-limiting toxicities (DLTs).
- Seventeen out of 17 evaluable patients mounted T-cell responses to at least one TAA, and 8 out of 17 responded to all three TAAs.
- Clinical activity included one partial response, confirmed PSA declines in five patients, and stable disease in five patients for over six months.
Conclusions:
- The Ad5 PSA/MUC-1/brachyury vaccine is safe, well-tolerated, and achieves its primary endpoints, establishing 5×10^11 VP as the recommended phase II dose.
- The vaccine demonstrated immunogenicity and preliminary clinical activity, including partial and PSA responses.
- Further research is warranted to explore the vaccine's clinical benefit and immunogenicity in combination with other immuno-oncology agents or palliative radiation therapy.
