T-cell bispecific antibodies in node-positive breast cancer: novel therapeutic avenue for MHC class I loss variants.
- Messaoudene M Gustave Roussy Cancer Campus (GRCC), Villejuif; National Institute of Health and Medical Research (INSERM) U1015, Villejuif, France.
- Mourikis TP Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
- Michels J Gustave Roussy Cancer Campus (GRCC), Villejuif; University Paris-Sud, University Paris-Saclay, Gustave Roussy Cancer Campus (GRCC), Villejuif; Department of Medical Oncology, Gustave Roussy, Villejuif.
- Fu Y Gustave Roussy Cancer Campus (GRCC), Villejuif.
- Bonvalet M Gustave Roussy Cancer Campus (GRCC), Villejuif; National Institute of Health and Medical Research (INSERM) U1015, Villejuif, France.
- Lacroix-Trikki M Gustave Roussy Cancer Campus (GRCC), Villejuif; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France.
- Routy B Gustave Roussy Cancer Campus (GRCC), Villejuif; Universitéde Montréal Hospital Research Centre (CRCHUM), Onco-Hematology Department, Montreal University Hospital Center (CHUM), Montréal, Québec, Canada.
- Fluckiger A Gustave Roussy Cancer Campus (GRCC), Villejuif; National Institute of Health and Medical Research (INSERM) U1015, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France.
- Rusakiewicz S Center of Experimental Therapeutics (CET), Department of Oncology, Lausanne University Hospital, CHUV, Lausanne, Switzerland.
- Roberti MP Gustave Roussy Cancer Campus (GRCC), Villejuif; National Institute of Health and Medical Research (INSERM) U1015, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France.
- Cotteret S Gustave Roussy Cancer Campus (GRCC), Villejuif.
- Flament C Gustave Roussy Cancer Campus (GRCC), Villejuif; National Institute of Health and Medical Research (INSERM) U1015, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France.
- Poirier-Colame V Gustave Roussy Cancer Campus (GRCC), Villejuif; National Institute of Health and Medical Research (INSERM) U1015, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France.
- Jacquelot N Gustave Roussy Cancer Campus (GRCC), Villejuif; National Institute of Health and Medical Research (INSERM) U1015, Villejuif, France; University Paris-Sud, University Paris-Saclay, Gustave Roussy Cancer Campus (GRCC), Villejuif.
- Ghiringhelli F Georges-François Leclerc center, Medical Oncology, Dijon.
- Caignard A INSERM U1160, University Institute for Haematology, Saint Louis hospital, Paris.
- Eggermont AMM Gustave Roussy Cancer Campus (GRCC), Villejuif.
- Kroemer G Gustave Roussy Cancer Campus (GRCC), Villejuif; University Paris-Sud, University Paris-Saclay, Gustave Roussy Cancer Campus (GRCC), Villejuif; Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Cordeliers Research Center, INSERM, U1138, Université Paris Descartes, Sorbonne Paris Cité; Université Pierre et Marie Curie; Pôle de Biologie, Européen Georges Pompidou Hospital, AP-HP, Paris.
- Marabelle A Gustave Roussy Cancer Campus (GRCC), Villejuif; National Institute of Health and Medical Research (INSERM) U1015, Villejuif, France; University Paris-Sud, University Paris-Saclay, Gustave Roussy Cancer Campus (GRCC), Villejuif; Gustave Roussy Cancer Campus (GRCC), Drug Development Department (DITEP), Villejuif.
- Arnedos M Gustave Roussy Cancer Campus (GRCC), Villejuif; Department of Medical Oncology, Gustave Roussy, Villejuif.
- Vicier C Gustave Roussy Cancer Campus (GRCC), INSERM U981, Villejuif, France.
- Dogan S Gustave Roussy Cancer Campus (GRCC), Villejuif; Department of Medical Oncology, Gustave Roussy, Villejuif; Gustave Roussy Cancer Campus (GRCC), INSERM U981, Villejuif, France.
- Jaulin F Gustave Roussy Cancer Campus (GRCC), Villejuif; Department of Medical Oncology, Gustave Roussy, Villejuif; Gustave Roussy Cancer Campus (GRCC), INSERM U981, Villejuif, France.
- Sammut SJ Cancer Research UK Cambridge Institute and Department of Oncology, University of Cambridge, Cambridge.
- Cope W Cancer Research UK Cambridge Institute and Department of Oncology, University of Cambridge, Cambridge; Cancer Research UK Cancer Centre and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
- Caldas C Cancer Research UK Cambridge Institute and Department of Oncology, University of Cambridge, Cambridge.
- Delaloge S Gustave Roussy Cancer Campus (GRCC), Villejuif; Department of Medical Oncology, Gustave Roussy, Villejuif.
- McGranahan N Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
- André F Gustave Roussy Cancer Campus (GRCC), Villejuif; Department of Medical Oncology, Gustave Roussy, Villejuif; Gustave Roussy Cancer Campus (GRCC), INSERM U981, Villejuif, France.
- Zitvogel L Gustave Roussy Cancer Campus (GRCC), Villejuif; National Institute of Health and Medical Research (INSERM) U1015, Villejuif, France; University Paris-Sud, University Paris-Saclay, Gustave Roussy Cancer Campus (GRCC), Villejuif; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France. Electronic address: Laurence.ZITVOGEL@gustaveroussy.fr.
- 2019-03-30
Published in:
- Annals of oncology : official journal of the European Society for Medical Oncology. - 2019
CEACAM5
HER2
HLA loss
T-cell bispecific antibodies (TCB)
breast cancer
tumor-infiltrating lymphocytes (TILs)
Antibodies, Bispecific
Antineoplastic Combined Chemotherapy Protocols
Biomarkers, Tumor
Breast Neoplasms
Female
Follow-Up Studies
Genetic Variation
Histocompatibility Antigens Class I
Humans
Lymph Nodes
Lymphatic Metastasis
Lymphocytes, Tumor-Infiltrating
Neoadjuvant Therapy
Neoplasm Invasiveness
Prognosis
Prospective Studies
Receptor, ErbB-2
English
BACKGROUND
Tumor-infiltrating lymphocytes (TILs) represent a prognostic factor for survival in primary breast cancer (BC). Nonetheless, neoepitope load and TILs cytolytic activity are modest in BC, compromising the efficacy of immune-activating antibodies, which do not yet compete against immunogenic chemotherapy.
PATIENTS AND METHODS
We analyzed by functional flow cytometry the immune dynamics of primary and metastatic axillary nodes [metastatic lymph nodes (mLN)] in early BC (EBC) after exposure to T-cell bispecific antibodies (TCB) bridging CD3ε and human epidermal growth factor receptor 2 (HER2) or Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 (CEACAM5), before and after chemotherapy. Human leukocyte antigen (HLA) class I loss was assessed by whole exome sequencing and immunohistochemistry. One hundred primary BC, 64 surrounding 'healthy tissue' and 24 mLN-related parameters were analyzed.
RESULTS
HLA loss of heterozygosity was observed in EBC, at a clonal and subclonal level and was associated with regulatory T cells and T-cell immunoglobulin and mucin-domain-3 expression restraining the immuno-stimulatory effects of neoadjuvant chemotherapy. TCB bridging CD3ε and HER2 or CEACAM5 could bypass major histocompatibility complex (MHC) class I loss, partially rescuing T-cell functions in mLN.
CONCLUSION
TCB should be developed in BC to circumvent low MHC/peptide complexes.
Tumor-infiltrating lymphocytes (TILs) represent a prognostic factor for survival in primary breast cancer (BC). Nonetheless, neoepitope load and TILs cytolytic activity are modest in BC, compromising the efficacy of immune-activating antibodies, which do not yet compete against immunogenic chemotherapy.
PATIENTS AND METHODS
We analyzed by functional flow cytometry the immune dynamics of primary and metastatic axillary nodes [metastatic lymph nodes (mLN)] in early BC (EBC) after exposure to T-cell bispecific antibodies (TCB) bridging CD3ε and human epidermal growth factor receptor 2 (HER2) or Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 (CEACAM5), before and after chemotherapy. Human leukocyte antigen (HLA) class I loss was assessed by whole exome sequencing and immunohistochemistry. One hundred primary BC, 64 surrounding 'healthy tissue' and 24 mLN-related parameters were analyzed.
RESULTS
HLA loss of heterozygosity was observed in EBC, at a clonal and subclonal level and was associated with regulatory T cells and T-cell immunoglobulin and mucin-domain-3 expression restraining the immuno-stimulatory effects of neoadjuvant chemotherapy. TCB bridging CD3ε and HER2 or CEACAM5 could bypass major histocompatibility complex (MHC) class I loss, partially rescuing T-cell functions in mLN.
CONCLUSION
TCB should be developed in BC to circumvent low MHC/peptide complexes.
- Language
-
- English
- Open access status
- hybrid
- Identifiers
-
- DOI 10.1093/annonc/mdz112
- PMID 30924846
- Persistent URL
- https://sonar.ch/global/documents/186390
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