Feb 20, 2026
3 min read
An individualized neoantigen mRNA vaccine was tested in patients with triple-negative early-stage breast cancer and demonstrated feasibility, safety, and strong T-cell immune responses.Long-term follow-up suggests durable immune memory with encouraging relapse-free results, although controlled studies are needed to confirm clinical benefit.
A pilot study of a personalized mRNA vaccine revealed a durable immune response in triple-negative breast cancer, providing an initial sign that personalized cancer vaccination may help improve long-term outcomes pending larger trials.
Study: Individualized mRNA vaccines induce persistent T-cell immunity in adjuvant TNBC.Image credit: Guschenkova / Shutterstock
In a recent study published in the journal Nature, researchers evaluated the efficacy, safety, immunogenicity, and long-term clinical outcomes of a personalized neoantigen messenger ribonucleic acid (mRNA) vaccine in patients with early-stage triple-negative breast cancer (TNBC).
Risk of triple negative breast cancer recurrence and treatment mismatch
TNBC accounts for approximately 15% of all breast cancer cases and is associated with an increased risk of early recurrence.TNBC lacks expression of estrogen, progesterone, and epidermal growth factor receptor 2 (HER2), which limits the potential for hormone or HER2 therapy.The risk of recurrence increases in the first three years after diagnosis, especially in high-risk patients.
Advances in next-generation sequencing have enabled the identification of tumor-specific somatic mutations known as neoantigens, which can serve as unique vaccine targets.The mRNA vaccine platform provides a rapid and flexible strategy to trigger an immune response by preventing tumor-specific mutations.However, the long-term immunological durability and proven clinical benefit remain unknown, requiring further research on whether each vaccine can prevent recurrence in high-risk TNBC populations remains unknown.
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 underwent curative intent surgery.Tumor-specific somatic mutations identified through next-generation sequencing of tumor tissue and personalized vaccines.and is selected as a target.
Adaptive vaccines are produced by encoding up to 20 patient-specific cancer mutations into two RNA-lipoplex (RNA-LPX) mRNA molecules encased in liposomal nanoparticles for intravenous administration.
Participants received eight intravenous doses over nine weeks, including six weekly injections and two biweekly injections.Three patients initially had their doses increased before reaching the target dose of 50 micrograms.Peripheral blood samples were taken at baseline and after vaccination to assess the immune response.
Immune Monitoring and T Cell Response Testing
Immune responses were analyzed by enzyme-linked immunosorbent assay (ELISpot).Additional diagnostic tests include human leukocyte antigen multimer staining, intracellular cytokine profiles, T-cell receptor profiles in both monocytes, and transcriptomic phenotyping.Long-term follow-up was conducted to monitor relapse-free survival and to explore possible salvage strategies in patients who developed relapse.
All 14 evaluable patients developed vaccine-induced or enhanced T-cell responses against at least one individual neoantigen.Most responded to multiple mutations, and nine patients developed T-cell responses targeting five or more neoantigens, indicating a comprehensive immune response.
High immune responses were detected in 86% of patients by ex vivo interferon gamma ELISpot assays, with many individuals showing 2,000 to 4,000 interferon gamma-producing cells per million peripheral blood mononuclear cells.Among the evaluated neoantigens, 82.9% had detectable immune responses before the record immunogenic targets arising from insertions, deletions and single nucleotide variants.
Patrone van CD4 en CD8 T-cell activation
In patients with sufficient samples for in vitro stimulation assays, 51.8% of the mutations tested elicited a T-cell response.Among them, 64% were driven exclusively by set of differentiation 4 (CD4) positive T cells, 20% by set of differentiation 8 (CD8) positive cytotoxic T cells, and 16% by both CD4 and CD8 T cells.This distribution of helper T cells and reflects the involvement of cytotoxic compartments, although the assay was designed to establish a direct causal link between immune responses and clinical outcomes.
Multimer staining confirmed rapid proliferation of mutation-specific CD8-positive T cells during vaccination.In some patients, neoantigen-specific cells comprise up to 17.5% of CD8-positive T cells and persist for years.In one case, 10.3% of circulating CD8-positive T cells recognized a single mutation after completion of treatment, with more than 3% still detectable two years after booster vaccination.
Resistant effector cells and stem-like memory T cells
Phenotypic analysis showed that many T cells induced by vaccination differentiated at the late stage in a manner that induces a CD45RA memory cytotoxic effect - cells expressing CD45RA, capable of rapidly killing cancer cells.At the same time, a subset developed into stem cell-like memory cells expressing T-cell factor 1 and interleukin 7 receptor alpha, markers associated with long-term immune system regeneration and a possible response to disruption of defensive checkpoints.
These findings suggest a persistent immune memory capable of persistent tumor monitoring based on mechanistic observations, although not definitively associated with prevention of clinical relapse.
Long-Term Clinical Outcomes and Mechanisms of Immune Escape
After a median follow-up of 62 months (range, 15 to 80 months), 10 of the 14 patients remained relapse-free.One patient remained refractory to death from unrelated causes.Three patients had recurrences.
Of these cases, one patient had the weakest vaccine-induced immune response but achieved a complete response after anti-programmed cell death protein 1 (PD-1) therapy in combination with sequential chemotherapy for 15 months.Another recurrence was due to a genetically different primary tumor that was not taken into account in the vaccine design.The third case demonstrated immune evasion of the tumor accompanied by downregulation and loss of MHC class I expression, impairing antigen presentation but not completely neutralizing circulating T cell responses.
possibilitySafety and future clinical validity
This study demonstrates that personalized mRNA neoantigen vaccines are feasible, safe and highly immunogenic in early-stage TNBC patients.The vaccine induces long-lasting and functional T-cell responses that persist for years without booster doses.Generation of cytotoxic effectors in stem-like memory T cells supports the biological plausibility of long-term immune surveillance.
Although most participants did not relapse during long-term follow-up, the small sample size and lack of a randomized control group limit definitive conclusions about clinical efficacy.The observed immune evasion mechanisms highlight the complexity of tumor-immune interactions and highlight the need for combination or selection strategies of purified antigens.
Overall, these findings position personalized mRNA neoantigen vaccination as a promising adjuvant strategy in high-risk TNBC.Larger controlled clinical trials are needed to determine its impact on long-term recurrence-free survival and overall survival in the broader breast cancer population.
