Cancer Res Treat.  2024 Jan;56(1):208-218. 10.4143/crt.2022.1328.

First-in-Human Phase 1 Study of a B Cell– and Monocyte-Based Immunotherapeutic Vaccine against HER2-Positive Advanced Gastric Cancer

• Jung M
• Lee JB
• Kim HS
• Kwon WS
• Kim HO
• Kim S
• Park M
• Kim W
• Choi KY
• Oh T
• Kang CY
• Chung HC
• Rha SY

• KMID: 2550337
• DOI: http://doi.org/10.4143/crt.2022.1328

Abstract

Purpose
BVAC-B is an autologous B cell– and monocyte-based immunotherapeutic vaccine that contains cells transfected with a recombinant human epidermal growth factor receptor 2 (HER2) gene and loaded with the natural killer T cell ligand alpha-galactosylceramide. Here, we report the first BVAC-B study in patients with HER2-positive advanced gastric cancer.
Materials and Methods
Patients with advanced gastric cancer refractory to standard treatment with HER2+ immunohistochemistry ≥ 1 were eligible for treatment. Patients were administered low (2.5×10⁷ cells/dose), medium (5.0×10⁷ cells/dose), or high dose (1.0×10⁸ cells/dose) of BVAC-B intravenously four times every 4 weeks. Primary endpoints included safety and maximum tolerated BVAC-B dose. Secondary endpoints included preliminary clinical efficacy and BVAC-B-induced immune responses.
Results
Eight patients were treated with BVAC-B at low (n=1), medium (n=1), and high doses (n=6). No dose-limiting toxicity was observed, while treatment-related adverse events (TRAEs) were observed in patients treated with medium and high doses. The most common TRAEs were grade 1 (n=2) and grade 2 (n=2) fever. Out of the six patients treated with high-dose BVAC-B, three had stable disease with no response. Interferon gamma, tumor necrosis factor-α, and interleukin-6 increased after BVAC-B treatment in all patients with medium and high dose, and HER2-specific antibody was detected in some patients.
Conclusion
BVAC-B monotherapy had a safe toxicity profile with limited clinical activity; however, it activated immune cells in heavily pretreated patients with HER2-positive gastric cancer. Earlier treatment with BVAC-B and combination therapy is warranted for evaluation of clinical efficacy.

Keyword

Stomach neoplasms; HER2; Immunotherapeutic vaccine; First in-human study

Figure

• 

  Fig. 1 Mode of action of BVAC-B. After BVAC-B is injected into the human body, it interacts with and activates NKT cells (1). Activated NKT cells secrete cytokines such as IFN-γ and IL-4, which activate NK cells. Activated NK and NKT cells promote anti-tumor immune responses (2). BVAC-B also activates both antigen-specific CD4+ and CD8+ T cells. Cytokines secreted by activated NKT cells facilitate this process (3). CD8+ T cells differentiate into tumor-killing CTLs, which directly kill cancer cells. Activated CD4+ T cells activate CD8+ T cells, and B cells produce tumor Ag-specific antibodies (4). In addition, BVAC-B can induce the functional recovery of exhausted NK and CD8+ T cells through NKT cell activation (5). α-GC, α-galactosylceramide; APC, antigen presenting cell; CTL, cytotoxic T lymphocyte; IFN-γ, interferon gamma; IL-4, interleukin-4; MHC, major histocompatibility complex class; NK, natural killer; NKT, natural killer T cell.

• 

  Fig. 2 Tumor response. Changes from baseline in the sum of the largest target lesion diameters per patient (A). Swimmer plot for PFS and subsequent treatments (B). Kaplan-Maier’s curve for PFS (C) and OS in eight patients (D). CI, confidence interval; OS, overall survival; PD, progression of disease; PFS, progression-free survival; SD, stable disease.

• 

  Fig. 3 Study flow chart and immune response results. Study flow chart for BVAC-B injection and blood sampling (A). Relative serum cytokine changes at each time point; IFN-γ (B), TNF-α (C), IL-4 (D), and IL-6 (E). Relative IFN-γ spot ratios by ELISPOT (F). Relative HER2-specific antibody at each time point (G). HER2, human epidermal growth factor receptor 2; IFN-γ, interferon gamma; IL-4, interleukin-4; IL-6, interleukin-6; PD, progression of disease; SD, stable disease; TNF-α, tumor necrosis factor-α; w, week. a)Statistically significant between patients with PD and SD.

Reference

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