Phase 1 open-label trial of intravenous administration of MVA-BN-brachyury-TRICOM vaccine in patients with advanced cancer

Abstract

BackgroundMVA-BN-brachyury-TRICOM is a recombinant vector-based therapeutic cancer vaccine designed to induce an immune response against brachyury. Brachyury, a transcription factor overexpressed in advanced cancers, has been associated with treatment resistance, epithelial-to-mesenchymal transition, and metastatic potential. MVA-BN-brachyury-TRICOM has demonstrated immunogenicity and safety in previous clinical trials of subcutaneously administered vaccine. Preclinical studies have suggested that intravenous administration of therapeutic vaccines can induce superior CD8+ T cell responses, higher levels of systemic cytokine release, and stronger natural killer cell activation and proliferation. This is the first-in-human study of the intravenous administration of MVA-BN-brachyury-TRICOM.MethodsBetween January 2020 and March 2021, 13 patients were treated on a phase 1, open-label, 3+3 design, dose-escalation study at the National Institutes of Health Clinical Center. The study population was adults with advanced solid tumors and was enriched for chordoma, a rare sarcoma of the notochord that overexpresses brachyury. Vaccine was administered intravenously at three DLs on days 1, 22, and 43. Blood samples were taken to assess drug pharmacokinetics and immune activation. Imaging was conducted at baseline, 1 month, and 3 months post-treatment. The primary endpoint was safety and tolerability as determined by the frequency of dose-limiting toxicities; a secondary endpoint was determination of the recommended phase 2 dose.ResultsNo dose-limiting toxicities were observed and no serious adverse events were attributed to the vaccine. Vaccine-related toxicities were consistent with class profile (ie, influenza-like symptoms). Cytokine release syndrome up to grade 2 was observed with no adverse outcomes. Dose-effect trend was observed for fever, chills/rigor, and hypotension. Efficacy analysis of objective response rate per RECIST 1.1 at the end of study showed one patient with a partial response, four with stable disease, and eight with progressive disease. Three patients with stable disease experienced clinical benefit in the form of improvement in pain. Immune correlatives showed T cell activation against brachyury and other tumor-associated cascade antigens.ConclusionsIntravenous administration of MVA-BN-brachyury-TRICOM vaccine was safe and tolerable. Maximum tolerated dose was not reached. The maximum administered dose was 109 infectious units every 3 weeks for three doses. This dose was selected as the recommended phase 2 dose.Trial registration numberNCT04134312.

Viral Delivery of IL-7 Is a Potent Immunotherapy Stimulating Innate and Adaptive Immunity and Confers Survival in Sepsis Models

“…route, the i.v. route has recently be documented by DeMaria et al (81). The authors report on good tolerance of the MVA-BN-brachyury-TRICOM vaccine in advanced solid tumor The Journal of Immunology indications.…”

Emerging target discovery and drug repurposing opportunities in chordoma

“…Despite a low tumor mutational burden, a significant proportion of chordomas appear to be characterized by complex genomic rearrangements ( 20 , 37 ), which may lead to high neoantigen expression. In addition to the examples noted above, documented patient responses to vaccines ( 142 ) and PD-1 inhibitors ( 143 – 146 ) provide important proof-of-concept for the use of immunotherapies in chordoma, and prompt evaluation of different immune checkpoints and combinations thereof. For example, strong scientific rationale exists for co-blockade of the PD-1 and TIGIT checkpoints in cancer ( 147 ), and a new clinical study enrolling chordoma patients is testing this concept with atezolizumab plus tiragolumab (NCT05286801).…”

Research hotspots and trends of chordoma: A bibliometric analysis

“…GI-6301, which delivers antigens through dendritic cells, specifically activates CD4 + and CD8 + cell and has a lethal effect on brachyury-expressing tumor cells (76,77). Additionally, modified vaccinia Ankara (MVA) poxviral vaccine vector encodes human brachyury, and adenovirus serotype 5 (Ad5) has been developed and applied in clinical trials (5,78). Thus, immunotherapy is regarded as one future trend in the basic research and clinical treatment of chordoma.…”