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Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. / Voorwerk, Leonie; Slagter, Maarten; Horlings, Hugo M.; Sikorska, Karolina; van de Vijver, Koen K.; de Maaker, Michiel; Nederlof, Iris; Kluin, Roelof J. C.; Warren, Sarah; Ong, SuFey; Wiersma, Terry G.; Russell, Nicola S.; Lalezari, Ferry; Schouten, Philip C.; Bakker, Noor A. M.; Ketelaars, Steven L. C.; Peters, Dennis; Lange, Charlotte A. H.; van Werkhoven, Erik; van Tinteren, Harm; Mandjes, Ingrid A. M.; Kemper, Inge; Onderwater, Suzanne; Chalabi, Myriam; Wilgenhof, Sofie; Haanen, John B. A. G.; Salgado, Roberto; de Visser, Karin E.; Sonke, Gabe S.; Wessels, Lodewyk F. A.; Linn, Sabine C.; Schumacher, Ton N.; Blank, Christian U.; Kok, Marleen.

In: Nature medicine, Vol. 25, No. 6, 06.2019, p. 920-928.

Research output: Contribution to journalComment/Letter to the editorAcademic

Harvard

Voorwerk, L, Slagter, M, Horlings, HM, Sikorska, K, van de Vijver, KK, de Maaker, M, Nederlof, I, Kluin, RJC, Warren, S, Ong, S, Wiersma, TG, Russell, NS, Lalezari, F, Schouten, PC, Bakker, NAM, Ketelaars, SLC, Peters, D, Lange, CAH, van Werkhoven, E, van Tinteren, H, Mandjes, IAM, Kemper, I, Onderwater, S, Chalabi, M, Wilgenhof, S, Haanen, JBAG, Salgado, R, de Visser, KE, Sonke, GS, Wessels, LFA, Linn, SC, Schumacher, TN, Blank, CU & Kok, M 2019, 'Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial', Nature medicine, vol. 25, no. 6, pp. 920-928. https://doi.org/10.1038/s41591-019-0432-4

APA

Voorwerk, L., Slagter, M., Horlings, H. M., Sikorska, K., van de Vijver, K. K., de Maaker, M., ... Kok, M. (2019). Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nature medicine, 25(6), 920-928. https://doi.org/10.1038/s41591-019-0432-4

Vancouver

Author

Voorwerk, Leonie ; Slagter, Maarten ; Horlings, Hugo M. ; Sikorska, Karolina ; van de Vijver, Koen K. ; de Maaker, Michiel ; Nederlof, Iris ; Kluin, Roelof J. C. ; Warren, Sarah ; Ong, SuFey ; Wiersma, Terry G. ; Russell, Nicola S. ; Lalezari, Ferry ; Schouten, Philip C. ; Bakker, Noor A. M. ; Ketelaars, Steven L. C. ; Peters, Dennis ; Lange, Charlotte A. H. ; van Werkhoven, Erik ; van Tinteren, Harm ; Mandjes, Ingrid A. M. ; Kemper, Inge ; Onderwater, Suzanne ; Chalabi, Myriam ; Wilgenhof, Sofie ; Haanen, John B. A. G. ; Salgado, Roberto ; de Visser, Karin E. ; Sonke, Gabe S. ; Wessels, Lodewyk F. A. ; Linn, Sabine C. ; Schumacher, Ton N. ; Blank, Christian U. ; Kok, Marleen. / Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. In: Nature medicine. 2019 ; Vol. 25, No. 6. pp. 920-928.

BibTeX

@article{b0a5cd4fca1943ddbc17e5a9acfc900d,
title = "Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial",
abstract = "The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low 1–5 , 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 irradiation 6–13 . 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; iRECIST 14 ) 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.",
author = "Leonie Voorwerk and Maarten Slagter and Horlings, {Hugo M.} and Karolina Sikorska and {van de Vijver}, {Koen K.} and {de Maaker}, Michiel and Iris Nederlof and Kluin, {Roelof J. C.} and Sarah Warren and SuFey Ong and Wiersma, {Terry G.} and Russell, {Nicola S.} and Ferry Lalezari and Schouten, {Philip C.} and Bakker, {Noor A. M.} and Ketelaars, {Steven L. C.} and Dennis Peters and Lange, {Charlotte A. H.} and {van Werkhoven}, Erik and {van Tinteren}, Harm and Mandjes, {Ingrid A. M.} and Inge Kemper and Suzanne Onderwater and Myriam Chalabi and Sofie Wilgenhof and Haanen, {John B. A. G.} and Roberto Salgado and {de Visser}, {Karin E.} and Sonke, {Gabe S.} and Wessels, {Lodewyk F. A.} and Linn, {Sabine C.} and Schumacher, {Ton N.} and Blank, {Christian U.} and Marleen Kok",
year = "2019",
month = "6",
doi = "10.1038/s41591-019-0432-4",
language = "English",
volume = "25",
pages = "920--928",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "6",

}

RIS

TY - JOUR

T1 - Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial

AU - Voorwerk, Leonie

AU - Slagter, Maarten

AU - Horlings, Hugo M.

AU - Sikorska, Karolina

AU - van de Vijver, Koen K.

AU - de Maaker, Michiel

AU - Nederlof, Iris

AU - Kluin, Roelof J. C.

AU - Warren, Sarah

AU - Ong, SuFey

AU - Wiersma, Terry G.

AU - Russell, Nicola S.

AU - Lalezari, Ferry

AU - Schouten, Philip C.

AU - Bakker, Noor A. M.

AU - Ketelaars, Steven L. C.

AU - Peters, Dennis

AU - Lange, Charlotte A. H.

AU - van Werkhoven, Erik

AU - van Tinteren, Harm

AU - Mandjes, Ingrid A. M.

AU - Kemper, Inge

AU - Onderwater, Suzanne

AU - Chalabi, Myriam

AU - Wilgenhof, Sofie

AU - Haanen, John B. A. G.

AU - Salgado, Roberto

AU - de Visser, Karin E.

AU - Sonke, Gabe S.

AU - Wessels, Lodewyk F. A.

AU - Linn, Sabine C.

AU - Schumacher, Ton N.

AU - Blank, Christian U.

AU - Kok, Marleen

PY - 2019/6

Y1 - 2019/6

N2 - The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low 1–5 , 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 irradiation 6–13 . 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; iRECIST 14 ) 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.

AB - The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low 1–5 , 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 irradiation 6–13 . 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; iRECIST 14 ) 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.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85065759990&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/31086347

U2 - 10.1038/s41591-019-0432-4

DO - 10.1038/s41591-019-0432-4

M3 - Comment/Letter to the editor

C2 - 31086347

VL - 25

SP - 920

EP - 928

JO - Nature medicine

JF - Nature medicine

SN - 1078-8956

IS - 6

ER -

ID: 6455166