Impact of metronomic trabectedin combined with low-dose cyclophosphamide on sarcoma microenvironment and correlation with clinical outcome: results from the TARMIC study - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Molecular Cancer Année : 2024

Impact of metronomic trabectedin combined with low-dose cyclophosphamide on sarcoma microenvironment and correlation with clinical outcome: results from the TARMIC study

Xavier Buy
  • Fonction : Auteur
Maud Toulmonde
  • Fonction : Auteur
Mariella Spalato-Ceruso
  • Fonction : Auteur
Florent Peyraud
  • Fonction : Auteur
Alban Bessede
  • Fonction : Auteur
Michèle Kind
  • Fonction : Auteur
Sophie Cousin
  • Fonction : Auteur
Jean Palussiere
  • Fonction : Auteur
Hervé Wolf Fridman
  • Fonction : Auteur
Marina Pulido
  • Fonction : Auteur
Antoine Italiano
  • Fonction : Auteur
  • PersonId : 1072863

Résumé

Soft tissue sarcomas (STS) are diverse mesenchymal tumors with few therapeutic options in advanced stages. Trabectedin has global approval for treating STS patients resistant to anthracycline-based regimens. Recent pre-clinical data suggest that trabectedin’s antitumor activity extends beyond tumor cells to influencing the tumor microenvironment (TME), especially affecting tumor-associated macrophages and their pro-tumoral functions. We present the phase I/II results evaluating a combination of metronomic trabectedin and low-dose cyclophosphamide on the TME in patients with advanced sarcomas. 50 patients participated: 20 in phase I and 30 in phase II. Changes in the TME were assessed in 28 patients using sequential tumor samples at baseline and day two of the cycle. Treatment notably decreased CD68 + CD163 + macrophages in biopsies from tumor lesions compared to pre-treatment samples in 9 of the 28 patients after 4 weeks. Baseline CD8 + T cell presence increased in 11 of these patients. In summary, up to 57% of patients exhibited a positive immunological response marked by reduced M2 macrophages or increased CD8 + T cells post-treatment. This positive shift in the TME correlated with improved clinical benefit and progression-free survival. This study offers the first prospective evidence of trabectedin’s immunological effect in advanced STS patients, highlighting a relationship between TME modulation and patient outcomes. This study was registered with ClinicalTrial.gov, number NCT02406781.
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hal-04583146 , version 1 (22-05-2024)

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Xavier Buy, Cheng-Ming Sun, Maud Toulmonde, Mariella Spalato-Ceruso, Florent Peyraud, et al.. Impact of metronomic trabectedin combined with low-dose cyclophosphamide on sarcoma microenvironment and correlation with clinical outcome: results from the TARMIC study. Molecular Cancer, 2024, 23 (1), pp.37. ⟨10.1186/s12943-024-01942-y⟩. ⟨hal-04583146⟩
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