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Nat Med. 2019 Jun;25(6):920-928. doi: 10.1038/s41591-019-0432-4. Epub 2019 May 13.

Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.

Author information

1
Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
2
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
3
Oncode Institute, Utrecht, the Netherlands.
4
Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
5
Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
6
Department of Pathology, Ghent University Hospital, Ghent, Belgium.
7
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
8
Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
9
NanoString Technologies, Inc., Seattle, WA, USA.
10
Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
11
Department of Radiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
12
Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
13
Core Facility Molecular Pathology & Biobanking, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
14
Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
15
Department of Gastrointestinal Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
16
Department of Pathology, GZA-ZNA Ziekenhuizen, Antwerp, Belgium.
17
Division of Research, Peter Mac Callum Cancer Center, Melbourne, Victoria, Australia.
18
Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. m.kok@nki.nl.
19
Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. m.kok@nki.nl.

Abstract

The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low1-5, highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation6-13. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST14) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1-PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNF-α signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.

PMID:
31086347
DOI:
10.1038/s41591-019-0432-4
[Indexed for MEDLINE]

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