Induction of neoantigen-specific immune responses by VB10.NEO in combination with atezolizumab in heavily pretreated patients with advanced solid tumors: Final analysis of the phase 1b VB N-02 trial.

Abstract

2639 Background: VB10.NEO, a personalized DNA-based neoantigen vaccine, was evaluated with atezolizumab in a Phase 1b trial to assess safety, clinical activity, and immune responses in heavily pretreated patients with advanced solid tumors. The NeoSELECT platform enriches for clonal neoantigens by analyzing RNA and circulating tumor DNA, incorporating frameshift antigens and single nucleotide variants. Methods: This open-label, dose-escalation trial investigated VB10.NEO across three dose levels (3, 6 and 9 mg) combined with atezolizumab (1200 mg Q3W). Eligible patients had advanced or metastatic solid tumors, sufficient tumor material for vaccine manufacturing, at least 10 identified tumor neoantigens, and measurable disease. Immune responses were assessed using ELISpot assays (in vitro stimulation and ex vivo), T cell receptor sequencing, and flow cytometry. Endpoints included safety, immune response, and antitumor activity per RECIST v1.1. Results: At study completion (October 2024), 26 patients (median age 61 years, range 28–72; 62% female) received at least one dose of VB10.NEO. Median prior therapy lines for advanced disease were three (range 1–6), and 54% had prior immunotherapy, including checkpoint inhibitors. Tumor types included head and neck squamous cell carcinoma (15%), triple-negative breast cancer (15%), and others (31%; most were tumors with low tumor mutational burden). The majority (69%) of evaluable patients had low or negative PD-L1 expression. Injection site reactions (15%) and fatigue (12%), mainly Grades 1–2, were the most common adverse events. A dose-limiting Grade 3 transient blood pressure increase occurred in the 9 mg cohort. No treatment-related serious events or deaths occurred. Across all dose levels, VB10.NEO induced robust and durable neoantigen-specific immune responses. In vitro stimulated ELISpot assays detected vaccine-induced T cell responses in 85% (11/13) of evaluable patients and in 58% of evaluated neoantigens, while ex vivo ELISpot demonstrated responses in 22% (4/18) of patients and 5% of evaluated neoantigens. T cell receptor sequencing showed persistent T cell clone expansion in 9/11 patients, indicating durable immune responses. Putative neoantigen-specific clones were detected in 6/7 analyzed patients, with persistent expansion in 4. All patients achieving stable disease (34.8%, 8/23) exhibited neoantigen-specific immune responses. Conclusions: VB10.NEO combined with atezolizumab demonstrated a favorable safety profile while eliciting robust, durable immune responses across all dose levels, even in heavily pretreated patients with advanced solid tumors. The potential correlation between immunogenicity and clinical benefit supports further exploration in earlier treatment settings. Clinical trial information: NCT05018273 .