T-cell bispecific antibodies in node-positive breast cancer: Novel therapeutic avenue for MHC class i loss variants

M. Messaoudene, T. P. Mourikis, J. Michels, Y. Fu, M. Bonvalet, M. Lacroix-Trikki, B. Routy, A. Fluckiger, S. Rusakiewicz, M. P. Roberti, S. Cotteret, C. Flament, V. Poirier-Colame, N. Jacquelot, F. Ghiringhelli, A. Caignard, A. M.M. Eggermont, G. Kroemer, A. Marabelle, M. ArnedosC. Vicier, S. Dogan, F. Jaulin, S. J. Sammut, W. Cope, C. Caldas, S. Delaloge, N. McGranahan, F. André, L. Zitvogel

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20 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Artikelnummermdz112
Pagina's (van-tot)934-944
Aantal pagina's11
TijdschriftAnnals of Oncology
Volume30
Nummer van het tijdschrift6
DOI's
StatusGepubliceerd - 1 jun. 2019
Extern gepubliceerdJa

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