Individualized mRNA vaccines evoke durable T cell immunity in adjuvant TNBC

Nature News · Feb 18, 2026 · Collected from RSS

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MainTNBC tends to recur and metastasize even at early stages of disease, with the recurrence rate peaking after about three years and declining rapidly thereafter1. DNA repair deficiency, intrinsic genomic instability and an immunogenic tumour microenvironment make TNBC an interesting candidate for individualized vaccination with somatic cancer mutations that can act as neoantigens2,3.We developed an individualized neoantigen RNA vaccine approach that uses next generation sequencing (NGS) for mutation calling and predicts potentially T cell immunity-inducing neoantigens. This approach is being studied in patients with melanoma and pancreatic and other solid cancers4,5,6,7 (Extended Data Fig. 1a). To create the vaccine, multiple cancer mutations from an individual patient are concatemerized and encoded on two strings of immunostimulatory, non-nucleoside-modified uridine mRNA. Molecular designs of the cap, 5′ and 3′ untranslated regions, and the poly(A) tail of the mRNA enhance translation of the coding sequence in human dendritic cells8,9. A secretion signal and an MHC class I trafficking domain (MITD) tag are fused to the coding sequence to augment human leukocyte antigen (HLA) class I and II presentation of the encoded antigen and recognition by CD8+ and CD4+ T cells10. Formulation in liposomal nanoparticles (LPXs) for intravenous administration targets resident dendritic cells in all lymphoid compartments of the body11,12 (Fig. 1a). The use of uridine mRNA in the RNA–LPX vaccine technology links antigen delivery with co-stimulation via Toll-like receptor (TLR)-mediated, type-I-interferon-driven antiviral immune responses, resulting in profound expansion of antigen-specific T cells in humans, which is effective even against non-mutant self-antigens11,12,13.Fig. 1: Trial design, RNA vaccine design and clinical course of patients with TNBC.a, Top, clinical trial design. Patients with early TNBC after surgery and neoadjuvant and adjuvant chemotherapy (CTx), with or without radiotherapy (RTx), were eligible within one year after having received standard of care treatment. Middle, a run-in cohort (n = 3, intra-patient dose escalation: 14.4 µg, 29 µg and 50 µg, followed by 5 × 50 µg) preceded the main cohort (n = 12) with patients dosed with 8 × 50 µg mRNA–LPX vaccine. Patients in the run-in cohort received pre-treatment (off-the-shelf mRNA–LPX vaccine assembled according to the tumour expression profile of the patient from a pre-manufactured warehouse of eight non-mutated TAAs) as a bridge until their personalized vaccine was available. Bottom, the individualized neoantigen mRNA vaccine consisted of 20 neoantigen vaccine targets encoded on two poly-lipoplexed mRNA molecules. For SNVs, the 27mer peptide region with the changed amino acid in the centre was used, and for frameshift-inducing insertions or deletions the sequence from the changed amino acid to the next stop codon was used. Open reading frames encoding the neoantigen target concatemers were flanked by a secretory signal peptide (SEC) and an MITD for enhanced HLA presentation. The 5′ and 3′ untranslated regions (UTRs) and the poly(A) tail designs of mRNAs were optimized for stability and translational efficiency. The three patients pretreated with bridging TAA vaccine were followed up passively. b, Prior treatment, trial regimen and disease course of patients enrolled in this trial. Out of 15 consented patients, 1 was discontinued after 3 vaccinations owing to TEAEs (hypotension, grade 3; nausea, grade 2; chills, grade 1) and is not displayed here. FU, follow-up; LT-FU, long-term follow-up; q1w, once a week; q2w, twice a week; TNM, tumour, nodes and metastasis grading system.Full size imageThe neoantigen vaccine was evaluated in one of the arms of the exploratory first-in-human TNBC-MERIT (Mutanome Engineered RNA Immuno-Therapy) umbrella study14 (ClinicalTrials.gov: NCT02316457), which explored the feasibility, safety and ability to induce antigen-specific immune responses of various types of mRNA cancer vaccines in a non-comparative manner in patients with early-stage TNBC. Patients were eligible within one year of completing standard therapy. Tumour tissue was used for mutation detection and customized vaccine design. Patients received eight doses (6× weekly, 2× biweekly, last dose at day 64) of their personalized neoantigen vaccine composed of a maximum of 20 individual cancer mutations encoded by 2 RNA–LPX molecules (Fig. 1a). Fourteen out of fifteen consented patients received the per protocol treatment and were evaluable (Fig. 1b and Extended Data Table 1). The first three patients started with a 14.4-µg dose of RNA and were escalated to the target dose level of 50 µg. These patients also received an off-the-shelf RNA–LPX-based vaccine encoding non-mutated, shared tumour-associated self-antigens (TAAs) as a bridge until the on-demand manufactured personalized vaccine was available. The subsequent 11 patients were vaccinated with the neoantigen vaccine at 50-μg RNA dose without the bridging TAA vaccine (Extended Data Fig. 1).Five out of fourteen patients were node-positive at initial diagnosis (Fig. 1b), and all patients had surgery with curative intent (Extended Data Table 1). Pathological complete response (pCR) status was available for three out of seven individuals with prior neoadjuvant chemotherapy—one exhibited pCR (P14) and two exhibited non-pCRs (P3 and P9). The interval between initial diagnosis and enrolment in this trial ranged from 0.56 to 1.53 years. On-demand manufacturing was demonstrated to be feasible in a standard clinical setting, and all intention-to-treat patients received their individualized vaccine. The average turnaround time for vaccine production—defined as the period from sample receipt to vaccine release—was 69 days (range: 34–125 days). Notably, the primary aim was not to optimize turnaround time, but rather to robustly establish an end-to-end manufacturing workflow from surgery to vaccination using this technological platform.The most frequently reported treatment-emergent adverse events (TEAEs) related to the study drug were typical reactogenicity symptoms such as pyrexia, headache, chills, nausea and fatigue (Extended Data Table 2), which appeared within the first 1–3 days and were mostly of grade 1 or 2 severity. TEAEs were transient in nature, manageable with antipyretics and typically resolved within a day, as previously reported for other cancer vaccines based on this RNA–LPX platform6,11,15.Neoantigen-specific T cell responses in blood samples obtained at baseline and 7–14 days following the eighth (final) vaccine dose were assessed by two complementary IFNγ enzyme-linked immunospot (ELISpot) assay approaches. For all 14 individuals, we performed ex vivo ELISpot, which detects high-magnitude, late-differentiated T cell responses following overnight incubation of peripheral blood mononuclear cells (PBMCs) with overlapping peptides (OLPs) spanning the sequence of vaccine-encoded neoantigens for each individual. Eight patients had sufficient PBMCs left for additional testing by ELISpot after in vitro stimulation (IVS) of CD4+ and CD8+ T cells for 1.5 weeks with autologous antigen-presenting cells loaded with OLPs spanning vaccine-encoded neoantigens. This method captures low-frequency, early-differentiated T cells with high proliferative potential, which facilitates detection of CD4+ T cell responses (which tend to be of low frequency).All 14 patients mounted vaccine-induced or amplified T cell responses against one to ten of their individual vaccine targets, as detected by at least one ELISpot method (Fig. 2a). In all but one individual, responses were directed against multiple vaccine antigens. Nine patients had responses to at least five neoantigens (exemplified by patient P12 with eight vaccine neoantigen-directed de novo T cell responses in Fig. 2a). In 12 patients (86%), responses against individual vaccine neoantigens were measurable by ex vivo ELISpot. Eight of these twelve individuals demonstrated responses to single neoantigens reaching 2,000–4,000 IFNγ+ spots per 106 PBMCs (Fig. 2a,b and Extended Data Fig. 2a). T cells against 41 of the 251 mutations used across the 14 patients were not detectable prior to vaccination and became detectable after vaccination. T cells against two neoantigens were present at baseline and were further expanded by vaccination (Fig. 2c, top left and Supplementary Data 1). Four individuals exhibited de novo responses against known cancer driver genes (CREBBP, DAXX, IGF1R or TP53) (Supplementary Data 1, second tab).Fig. 2: Neoantigen vaccine-specific T cells were induced in all patients and were mostly high-magnitude, durable, poly-epitopic and polyfunctional, and of Teff or TEM phenotype.a, Number of neoantigen vaccine-induced T cell responses in patients (P1−P14) measured in PBMCs by IFNγ ELISpot ex vivo (n = 14) and after IVS (n = 8). Total number of immunogenic mutations is shown above the bars. b, Left, magnitude of T cell responses to individual neoantigens detected by ex vivo IFNγ ELISpot for all participants. Right, ELISpot data for P11. TNTC, too numerous to count. c, IFNγ ELISpot T cell responses. Top, ex vivo (left; 251 vaccine-encoded mutations across 14 patients) and post-IVS (right; 85 out of 115 vaccine-encoded mutations across 8 patients, owing to limited sample availability). Bottom, comparison of ex vivo and IVS responses for SNVs (clear bars) and indels (dashed bars) as percentage of evaluable targets. d, T cell response type by IFNγ ELISpot post-IVS at individual (left) and cohort (middle, showing positive responses) levels. Right, ELISpot data for P7. Data in a–d are T cell responses detected 7–14 days after final vaccination. e, Magnitude of vaccine-induced multi-neoantigen responses per patient over time, showing sum of spots measured in ex vivo INFγ+ ELISpot for each of their immunogenic vaccine neoantigens (range: 2–8). For P14, only one out of two neoa