Personalized mRNA Vaccine Induces Durable T Cell Responses in Triple-Negative Breast Cancer

A first-in-human exploratory clinical trial enrolled patients with early-stage triple-negative breast cancer (TNBC) within one year of completing standard neoadjuvant or adjuvant chemotherapy, with or without radiotherapy. All participants had undergone surgery with curative intent. The study, published in the journal Nature, evaluated the feasibility, safety, immunogenicity, and long-term clinical outcomes of an individualized neoantigen messenger ribonucleic acid (mRNA) vaccine.

TNBC accounts for approximately 10-15% of all breast cancer cases and is associated with a high risk of early recurrence. TNBC lacks expression of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2), which limits eligibility for targeted hormonal or HER2-directed therapies. Recurrence risk peaks within the first three years after diagnosis, particularly among high-risk patients.

Tumor-specific somatic mutations were identified through next-generation sequencing of resected tumor tissue and selected as individualized vaccine targets. Personalized vaccines were manufactured by encoding up to 20 patient-specific cancer mutations into two RNA-lipoplex (RNA-LPX) mRNA molecules formulated in liposomal nanoparticles for intravenous administration. This design aimed to enhance antigen presentation via major histocompatibility complex (MHC) class I and class II pathways to stimulate both cytotoxic and helper T cell responses.

Participants received eight intravenous doses over nine weeks, consisting of six weekly and two biweekly administrations. Three initial patients underwent dose escalation before receiving the target dose of 50 micrograms. The process begins at the time of surgery, where tumor tissue and matched normal tissue are subjected to next-generation sequencing to identify somatic mutations unique to the cancer. Bioinformatic algorithms then predict which mutations are most likely to generate neoantigens capable of being presented on the patient's HLA molecules and recognized by T cells.

All 14 evaluable patients generated vaccine-induced or amplified T cell responses against at least one personalized neoantigen. Most individuals mounted responses against multiple mutations, and nine patients developed T cell responses targeting five or more neoantigens, indicating broad immune activation. High-magnitude immune responses were detected in 86% of patients via ex vivo interferon gamma ELISpot assays, with several individuals demonstrating 2,000 to 4,000 interferon gamma-producing cells per million peripheral blood mononuclear cells.

Among the evaluated neoantigens, 82.9% elicited measurable immune responses that were not detectable before vaccination. Immunogenic targets arose from insertions, deletions, and single-nucleotide variants. In patients with sufficient samples for in vitro stimulation assays, 51.8% of tested mutations elicited T cell responses. Among these, 64% were mediated exclusively by cluster of differentiation 4 (CD4) positive T cells, 20% by cluster of differentiation 8 (CD8) positive cytotoxic T lymphocytes, and 16% by both CD4 and CD8 T cells.

Multimer staining confirmed rapid expansion of mutation-specific CD8 positive T cells during vaccination. In certain patients, neoantigen-specific cells constituted up to 17.5% of circulating CD8 positive T cells and persisted for years. In one case, 10.3% of circulating CD8 positive T cells recognized a single mutation at treatment completion.

TNBC's genomic instability means tumors often harbor numerous somatic mutations. Some of these mutations give rise to abnormal protein fragments found only in cancer cells. Because the immune system has not been tolerized to these mutated sequences, these neoantigens represent attractive targets for T cell-mediated immunity. The trial was not designed to establish a direct causal link between immune responses and clinical outcomes.

BioNTech received their second FDA Fast Track designation for an mRNA vaccine program in early 2026. While these two programs, BNT113 (HPV16+ head and neck cancer) and BNT111 (advanced melanoma), use a fixed set of neoantigens, this progress is laying the groundwork for BioNTech's path to regulation with its growing personalized RNA neoantigen vaccine platform.