Accéder directement au contenu Accéder directement à la navigation
Article dans une revue

Use of PD-1 Targeting, Macrophage Infiltration, and IDO Pathway Activation in Sarcomas

Abstract : Importance There is a strong rationale for treating sarcomas with immunotherapy. Objective To assess the efficacy and safety of programmed cell death protein 1 (PD-1) targeting in combination with metronomic chemotherapy in sarcomas. Design, Setting, and Participants This was an open-label, multicenter, phase 2 study of 4 cohorts of patients with advanced soft-tissue sarcoma (STS), including leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), other sarcomas (others), and gastrointestinal stromal tumor (GIST). All patients received 50 mg twice daily cyclophosphamide 1 week on and 1 week off and 200 mg of intravenous pembrolizumab every 3 weeks. Intervention or Exposure Pembrolizumab in combination with metronomic cyclophosphamide. Main Outcomes and Measures There was a dual primary end point, encompassing both the nonprogression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 for LMS, UPS, and others and 6-month nonprogression for GIST. An objective response rate of 20% and/or a 6-month nonprogression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from patient tumor and plasma samples. Results Between June 2015 and July 2016, 57 patients were included (median [range] age, 59.5 [18.5-84.0] years; 24 women [42%]); 50 patients were assessable for the efficacy end point. Three patients experienced tumor shrinkage, resulting in a partial response in a single solitary fibrous tumor. The 6-month nonprogression rates were 0%, 0%, 14.3% (95% CI, 1.8%-42.8%) for LMS, UPS, and others, respectively, and 11.1% (95% CI, 2.8%-48.3%) for GIST. The most frequent adverse events were grade 1 or 2 fatigue, diarrhea, and anemia. The only patient who experienced partial response was the only one with strong programmed cell death 1 ligand 1–positive staining in immune cell. Strong infiltration by macrophage expressing the inhibitory enzyme indoleamine 2,3-dioxygenase 1 (IDO1) was observed in the majority of cases. Moreover, a significant increase in the kynurenine to tryptophan ratio was observed in patient plasma samples during the study treatment. Conclusions and Relevance We found that PD-1 inhibition has limited activity in selected STS and GIST. This may be explained by an immunosuppressive tumor microenvironment resulting from macrophage infiltration and IDO1 pathway activation. Trial Registration clinicaltrials.gov Identifier: NCT02406781
Type de document :
Article dans une revue
Liste complète des métadonnées

https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01708092
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : mardi 13 février 2018 - 12:33:25
Dernière modification le : mercredi 14 octobre 2020 - 04:07:20

Lien texte intégral

Identifiants

Citation

Maud Toulmonde, Nicolas Penel, Julien Adam, Christine Chevreau, Jean-Yves Blay, et al.. Use of PD-1 Targeting, Macrophage Infiltration, and IDO Pathway Activation in Sarcomas. JAMA oncology, American Medical Association, 2018, 4 (1), pp.93-97. ⟨10.1001/jamaoncol.2017.1617⟩. ⟨hal-01708092⟩

Partager

Métriques

Consultations de la notice

256