A pioneering personalized mRNA vaccine study reveals lasting immune responses in triple-negative breast cancer, offering early signals that tailored cancer vaccination may help improve long-term outcomes pending larger trials.
Study: Individualized mRNA vaccines evoke durable T cell immunity in adjuvant TNBC. Image Credit: Guschenkova / Shutterstock
In a recent study published in the journal Nature, researchers evaluated the feasibility, safety, immunogenicity, and long-term clinical outcomes of an individualized neoantigen messenger ribonucleic acid (mRNA) vaccine in patients with early-stage triple-negative breast cancer (TNBC).
Triple-Negative Breast Cancer Recurrence Risk and Treatment Gaps
TNBC accounts for approximately 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.
Advances in next-generation sequencing have enabled the identification of tumor-specific somatic mutations known as neoantigens, which can serve as personalized vaccine targets. mRNA vaccine platforms offer a rapid and adaptable strategy to stimulate immune responses against tumor-specific mutations. However, long-term immune durability and demonstrated clinical benefit remain uncertain, necessitating further investigation into whether personalized vaccination can prevent relapse in high-risk TNBC populations.
First-in-Human Trial of Personalized Neoantigen mRNA Vaccination
This first-in-human exploratory clinical trial enrolled patients with early-stage TNBC within one year of completing standard neoadjuvant or adjuvant chemotherapy, with or without radiotherapy. All participants had undergone surgery with curative intent. 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. Peripheral blood samples were collected at baseline and after vaccination to evaluate immune responses.
Immune Monitoring and T Cell Response Assessment
Immune responses were assessed using interferon gamma enzyme-linked immunospot (ELISpot) assays. Additional immunologic analyses included human leukocyte antigen multimer staining, intracellular cytokine profiling, bulk and single-cell T cell receptor sequencing, and transcriptomic phenotyping. Long-term follow-up was conducted to monitor relapse-free survival and to investigate potential immune-escape mechanisms in patients who experienced recurrence.
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.
CD4 and CD8 T Cell Activation Patterns
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. This distribution reflects engagement of helper and cytotoxic T cell compartments, although the trial was not designed to establish a direct causal link between immune responses and clinical outcomes.
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, with more than 3% remaining detectable two years later without booster vaccination.
Durable Effector and Stem-Like Memory T Cells
Phenotypic analysis demonstrated that many vaccine-induced T cells differentiated into late-stage cytotoxic effector memory CD45RA-expressing cells capable of rapid tumor cell killing. Concurrently, a subset developed into stem cell-like memory T cells expressing T cell factor 1 and interleukin 7 receptor alpha, markers associated with long-term immune regeneration and potential responsiveness to immune checkpoint blockade.
These findings suggest durable immunologic memory capable of sustained tumor surveillance based on mechanistic observations, though not definitively linked to clinical relapse prevention.
Long-Term Clinical Outcomes and Immune Escape Mechanisms
After a median follow-up of 62 months (range, 15 to 80 months), 10 of 14 patients remained relapse-free. One additional patient remained relapse-free until death from unrelated causes. Three patients experienced recurrence.
Among these cases, one patient exhibited the weakest vaccine-induced immune response but subsequently achieved a complete response lasting 15 months following anti-programmed cell death protein 1 (PD-1) therapy combined with sequential chemotherapy. Another recurrence arose from a genetically distinct primary tumor not represented in the vaccine design. The third case demonstrated tumor immune escape associated with downregulation and loss of MHC class I expression, impairing antigen presentation but not fully neutralizing circulating T cell responses.
Feasibility, Safety, and Future Clinical Validation
This study demonstrates that personalized mRNA neoantigen vaccines are feasible, safe, and highly immunogenic in patients with early-stage TNBC. Vaccination induced long-lasting and functional T cell responses that persisted for years without booster doses. The generation of cytotoxic effector and stem-like memory T cells supports the biological plausibility of sustained immune surveillance.
Although most participants remained relapse-free during extended follow-up, the small sample size and absence of a randomized control group limit definitive conclusions regarding clinical efficacy. Observed immune escape mechanisms highlight the complexity of tumor-immune interactions and underscore the need for combination strategies or refined antigen selection.
Overall, these findings position individualized mRNA neoantigen vaccination as a promising adjuvant strategy in high-risk TNBC. Larger, controlled clinical trials are required to determine its impact on long-term relapse-free survival and overall survival in broader breast cancer populations.
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