| Autor: |
Nederlof, Iris, Isaeva, Olga I., de Graaf, Manon, Gielen, Robbert C. A. M., Bakker, Noor A. M., Rolfes, Adrianne L., Garner, Hannah, Boeckx, Bram, Traets, Joleen J. H., Mandjes, Ingrid A. M., de Maaker, Michiel, van Brussel, Thomas, Chelushkin, Maksim, Champanhet, Elisa, Lopez-Yurda, Marta, van de Vijver, Koen, van den Berg, José G., Hofland, Ingrid, Klioueva, Natasja, Mann, Ritse M., Loo, Claudette E., van Duijnhoven, Frederieke H., Skinner, Victoria, Luykx, Sylvia, Kerver, Emile, Kalashnikova, Ekaterina, van Dongen, Marloes G. J., Sonke, Gabe S., Linn, Sabine C., Blank, Christian U., de Visser, Karin E., Salgado, Roberto, Wessels, Lodewyk F. A., Drukker, Caroline A., Schumacher, Ton N., Horlings, Hugo M., Lambrechts, Diether, Kok, Marleen |
| Zdroj: |
Nature Medicine; 20240101, Issue: Preprints p1-13, 13p |
| Abstrakt: |
Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II–III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8+T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8+T cells, follicular helper T cells and shorter distances between tumor and CD8+T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon’s two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890. |
| Databáze: |
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