Ugur Sahin, Professor for Translational Oncology and Immunology at University Medical Center Mainz, shared a post on LinkedIn:
“Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes. It lacks the three receptors (ER/PR/HER2) that enable targeted therapies in other forms of breast cancer and recurs early (often peaking ~3 years after diagnosis). Its genomic instability and immunogenic microenvironment make it a strong candidate for individualized immunotherapy.
In a Phase 1 clinical trial led by Prof. Marcus Schmidt and investigators from Germany and Sweden, just published in Nature, we evaluated an individualized neoantigen mRNA vaccine approach in 14 patients with early-stage TNBC after surgery and (neo)adjuvant therapy. Each vaccine encoded up to 20 patient-specific neoantigens on two mRNA molecules, delivered intravenously via lipid nanoparticles to target dendritic cells.
The results showed robust immune responses:
- All patients in the clinical trial developed vaccine-induced T cell responses against multiple neoantigens.
- Vaccine-induced CD8⁺ T cells reached frequencies commonly achieved with adoptive T cell therapies and persisted functionally for years without boosters – evolving into both “ready-to-act” cytotoxic effector cells and stem-like memory T cells.
- 11 of 14 patients remained relapse-free for up to six years post-vaccination.
Furthermore, the findings in three patients with relapses were instructive for potential future combination treatment strategies to overcome resistance – each revealing a distinct escape mechanism to be addressed:
- Enhancing response magnitude: The patient with the weakest vaccine-induced response relapsed but achieved complete remission on subsequent anti – PD-1, suggesting a response threshold and supporting combination strategies.
- Targeting antigen-presentation loss: One patient showed near-complete loss of MHC class I (likely via B2M downregulation), despite vaccine-induced T cells being present, highlighting the need to address HLA-loss escape (e.g., antibodies or strategies restoring recognition).
- Comprehensive tumor sequencing: In another patient the relapse originated from a contralateral, genetically independent tumor not covered by the vaccine design, underscoring the importance of sequencing multiple lesions in hereditary settings.
Overall, these results demonstrate feasibility and durable neoantigen-specific immunity in TNBC supporting personalized mRNA cancer vaccines as platform technology, while pointing to novel treatment strategies to overcome resistance – especially through informed treatment combinations.”
Title: Individualized mRNA vaccines evoke durable T cell immunity in adjuvant TNBC
Authors: U. Sahin, M. Schmidt, E. Derhovanessian, A. Cortini, I. Vogler, T. Omokoko, E. Godehardt, S. Attig, S. Newrzela, J. Grützner, N. Bidmon, S. Bolte, S. Brachtendorf, T. Stuhlmann, D. Langer, D. Brüne, J. Blake, A. Feldner, H. Lindman, A. Schneeweiss, M. Eichbaum and Ö. Türeci
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