Rendering the Tumour Microenvironment More Sensitive to PD-1 Blockade

Results of the TONIC trial

A group of investigators from The Netherlands Cancer Institute, Amsterdam, the Netherlands published in a letter in the Nature Medicine on 13 May 2019 the results from the TONIC trial. Clinical and translational data from the study indicate that short-term doxorubicin and cisplatin may induce a more favourable tumour microenvironment and increase the likelihood of response to PD-1 blockade in triple negative breast cancer (TNBC).

Dutch investigators led by Marleen Kok wrote in the study background that efficacy of PD-1 blockade in metastatic TNBC is low. They emphasized a need for strategies to render the tumour microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and radiotherapy.

In the first stage of TONIC, adaptive, non-comparative phase II trial, 67 patients with metastatic TNBC were randomised 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) per iRECIST was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts.

After doxorubicin and cisplatin induction, the investigators detected an upregulation of immune-related genes involved in PD-1–PD-L1 and T cell cytotoxicity pathways. It was further supported by enrichment among upregulated genes related to inflammation, JAK–STAT and TNF-α signalling after doxorubicin.

These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.

DNA and RNA sequencing data have been deposited in the European Genome-phenome Archive and will be made available from the corresponding author on reasonable request. The TCR sequencing data are available from Adaptive Biotechnologies, but restrictions apply to their availability.

BMS/II-ON and the Dutch Cancer Society funded the study and a fellowship to Marleen Kok. Pink Ribbon, the Breast Cancer Research Foundation and BMS/II-ON are acknowledged for the funding of the translational research.

In terms of authorship, Leonie Voorwerk and Maarten Slagter contributed equally.



Voorwerk L, Slagter M, Horlings HM, et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nature Medicine; Published online 13 May2019. doi: 10.1038/s41591-019-0432-4.