Phase I study of a multitargeted recombinant Ad5 PSA/MUC-1/brachyury-based immunotherapy vaccine in patients with metastatic castration-resistant prostate cancer (mCRPC)

Abstract

BackgroundAntitumor 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.MethodsPatients 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.ResultsEighteen 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.ConclusionsAd5 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 numberNCT03481816.

Intranasal plus subcutaneous prime vaccination with a dual antigen COVID-19 vaccine elicits T-cell and antibody responses in mice

“…Importantly, this next generation Ad vector has demonstrated safety in over 125 patients with solid tumors. In these Phase I/II studies in cancer patients, CD4 + and CD8 + antigen-specific T cells were successfully generated to multiple somatic antigens (CEA, brachyury, MUC1, PSA) even in the presence of pre-existing Ad immunity 8 , 11 , 12 .…”

Oncolytic Adenovirus: Prospects for Cancer Immunotherapy

“…There were only temporary treatment-related AEs, including injection site reactions and flu-like symptoms ( Gatti-Mays et al, 2020 ). Recently, Bilusic et al (2021) combined three therapeutic vaccines (ETBX-071, ETBX-061, ETBX-051) to treat 18 patients with metastatic castration-resistant prostate cancer (NCT03481816). ETBX-071 is a PSA-targeting vaccine that employs Ad5 [E1-, E2b-] platform inserting a PSA gene (Ad5 [E1-, E2b-]-PSA).…”

“…There was no grade > 3 treatment-related AEs or DLTs in all patients, indicating that these three vaccines were tolerable and safe. The median PFS was 22 weeks and 47% of patients mounted immune responses to PSA, MUC-1, and brachyury ( Bilusic et al, 2021 ).…”

Cancer Vaccines for Genitourinary Tumors: Recent Progresses and Future Possibilities

“…In a phase I/II trial enrolling 17 patients with nmCRPC, MUC1 loaded-DCs improved PSA-DT (p=0.037) [50]. More recently, a vaccine using the adenoviral vector Ad5 targeting PSA, MUC-1, and Brachyury, induced a PSA decline in 2/12 mCRPC patients in a phase I trial [51].…”