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. Arnedos; C. Vicier; S. Dogan; F. Jaulin; S. J. Sammut; W. Cope; C. Caldas; S. Delaloge; N. McGranahan; F. André; L. Zitvogel

doi:10.1093/annonc/mdz112

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

Research output: Contribution to journal › Review article › peer-review

20 Citations (Scopus)

Abstract

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.

Original language	English
Article number	mdz112
Pages (from-to)	934-944
Number of pages	11
Journal	Annals of Oncology
Volume	30
Issue number	6
DOIs	https://doi.org/10.1093/annonc/mdz112
Publication status	Published - 1 Jun 2019
Externally published	Yes

Keywords

breast cancer
CEACAM5
HER2
HLA loss
T-cell bispecific antibodies (TCB)
tumor-infiltrating lymphocytes (TILs)

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Messaoudene, M., Mourikis, T. P., Michels, J., Fu, Y., Bonvalet, M., Lacroix-Trikki, M., Routy, B., Fluckiger, A., Rusakiewicz, S., Roberti, M. P., Cotteret, S., Flament, C., Poirier-Colame, V., Jacquelot, N., Ghiringhelli, F., Caignard, A., Eggermont, A. M. M., Kroemer, G., Marabelle, A., ... Zitvogel, L. (2019). T-cell bispecific antibodies in node-positive breast cancer: Novel therapeutic avenue for MHC class i loss variants. Annals of Oncology, 30(6), 934-944. Article mdz112. https://doi.org/10.1093/annonc/mdz112

@article{a5174afd55544aa8968d12ad888a75e6,

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

abstract = "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.",

keywords = "breast cancer, CEACAM5, HER2, HLA loss, T-cell bispecific antibodies (TCB), tumor-infiltrating lymphocytes (TILs)",

author = "M. Messaoudene and Mourikis, {T. P.} and J. Michels and Y. Fu and M. Bonvalet and M. Lacroix-Trikki and B. Routy and A. Fluckiger and S. Rusakiewicz and Roberti, {M. P.} and S. Cotteret and C. Flament and V. Poirier-Colame and N. Jacquelot and F. Ghiringhelli and A. Caignard and Eggermont, {A. M.M.} and G. Kroemer and A. Marabelle and M. Arnedos and C. Vicier and S. Dogan and F. Jaulin and Sammut, {S. J.} and W. Cope and C. Caldas and S. Delaloge and N. McGranahan and F. Andr{\'e} and L. Zitvogel",

year = "2019",

month = jun,

day = "1",

doi = "10.1093/annonc/mdz112",

language = "English",

volume = "30",

pages = "934--944",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Elsevier Ltd.",

number = "6",

}

Messaoudene, M, Mourikis, TP, Michels, J, Fu, Y, Bonvalet, M, Lacroix-Trikki, M, Routy, B, Fluckiger, A, Rusakiewicz, S, Roberti, MP, Cotteret, S, Flament, C, Poirier-Colame, V, Jacquelot, N, Ghiringhelli, F, Caignard, A, Eggermont, AMM, Kroemer, G, Marabelle, A, Arnedos, M, Vicier, C, Dogan, S, Jaulin, F, Sammut, SJ, Cope, W, Caldas, C, Delaloge, S, McGranahan, N, André, F & Zitvogel, L 2019, 'T-cell bispecific antibodies in node-positive breast cancer: Novel therapeutic avenue for MHC class i loss variants', Annals of Oncology, vol. 30, no. 6, mdz112, pp. 934-944. https://doi.org/10.1093/annonc/mdz112

TY - JOUR

T1 - T-cell bispecific antibodies in node-positive breast cancer

T2 - Novel therapeutic avenue for MHC class i loss variants

AU - Messaoudene, M.

AU - Mourikis, T. P.

AU - Michels, J.

AU - Fu, Y.

AU - Bonvalet, M.

AU - Lacroix-Trikki, M.

AU - Routy, B.

AU - Fluckiger, A.

AU - Rusakiewicz, S.

AU - Roberti, M. P.

AU - Cotteret, S.

AU - Flament, C.

AU - Poirier-Colame, V.

AU - Jacquelot, N.

AU - Ghiringhelli, F.

AU - Caignard, A.

AU - Eggermont, A. M.M.

AU - Kroemer, G.

AU - Marabelle, A.

AU - Arnedos, M.

AU - Vicier, C.

AU - Dogan, S.

AU - Jaulin, F.

AU - Sammut, S. J.

AU - Cope, W.

AU - Caldas, C.

AU - Delaloge, S.

AU - McGranahan, N.

AU - André, F.

AU - Zitvogel, L.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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.

KW - breast cancer

KW - CEACAM5

KW - HER2

KW - HLA loss

KW - T-cell bispecific antibodies (TCB)

KW - tumor-infiltrating lymphocytes (TILs)

UR - http://www.scopus.com/inward/record.url?scp=85070982057&partnerID=8YFLogxK

U2 - 10.1093/annonc/mdz112

DO - 10.1093/annonc/mdz112

M3 - Review article

C2 - 30924846

AN - SCOPUS:85070982057

SN - 0923-7534

VL - 30

SP - 934

EP - 944

JO - Annals of Oncology

JF - Annals of Oncology

IS - 6

M1 - mdz112

ER -

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

Abstract

Keywords

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