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

Abstract

Background: MVA-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.

Methods: Between 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.

Results: No 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.

Conclusions: Intravenous 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 number: NCT04134312.

Keywords: clinical trials as topic; immunogenicity; immunotherapy; sarcoma; vaccine.

Conflict of interest statement

Competing interests: BK: Bavarian Nordic (E). TA: Bavarian Nordic (E). CP-N: Bavarian Nordic (E). CH: Arcellx (E) (previously employed by Bavarian Nordic). The other authors indicate no financial relationships. (E) Employment.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Consort flow diagram. Of 14 patients officially screened for the trial, only one patient was unable to obtain imaging with MRI to confirm eligibility. The other 13 patients screened were treated (3 at DL1, 4 at DL2 and 6 at DL3). One patient (patient #7) treated at DL2 was replaced for failure to complete the DLT period due to treatment delay associated with the SARS-CoV-2 pandemic. DL, dose level; DLT, dose-limiting toxicity.

Figure 2

Change in vital signs within 48 hours post-vaccination. A transient increase in temperature and decrease in blood pressure were observed with a dose-effect trend. DL, dose level; Inf. U., infectious units.

Figure 3

Development of multifunctional antigen specific CD4+ and CD8+ T cell responses post- (vs pre-) MVA-BN-brachyury-TRICOM vaccine. TAA responses againstbrachyury and the cascade antigens CEA and MUC1 were compared in thirteen patients pre- and post-1, 2, and 3 vaccinations, where sufficient research bloods were available. The absolute number of multifunctional TAA responses (CD4+ or CD8+ T cells expressing two or more of the following: IFN-γ, TNF-α, IL-2, or CD107a) per 1×106 PBMCs plated at the start of the stimulation assay was calculated. Any background signal obtained with the HLA peptide pool was subtracted. Patients were scored as having a >3-fold (or if no cells at pre, >100/1×106 cells at post, +) or >10-fold (or if no cells at pre, >1000/1×106 cells at post, ++) increase in CD4+ or CD8+ multifunctional cells post- (vs pre) vaccine. Gray indicates where an insufficient number of viable PBMCs were recovered for analysis. BOR, best overall response; CEA, carcinoembryonic antigen; MUC, mucin; PD, progressive disease; PR, partial response; PT, patient; SD, stable disease; TAA, tumor-associated antigen.

Figure 4

Patient #9 (responder). Before and after treatment photos and CT imaging for patient #9, a 59-year-old man with metastatic chordoma of the lumbar spine extending through the anterior abdomen. He had previously failed multiple lines of treatment. Following three doses of the investigational intravenous brachyury-targeting vaccine (DL3) given over a 2-month treatment window, the patient’s tumor shrank 33% per RECIST 1.1% and 66% per exploratory volumetric analysis. Left top: clinic photograph from August 14, 2020, prior to first dose of DL3 vaccine. Left bottom: baseline CT from August 14, 2020. Right top: clinic photograph from October 27, 2020, after three vaccine doses. Right bottom: End-of-treatment CT from October 27, 2020. DL, dose level; RECIST, Response Evaluation Criteria in Solid Tumors.