SV-BR-1-GM, a clinically effective GM-CSF-secreting breast cancer cell line, expresses an immune signature and directly activates CD4+ T lymphocytes

Markus D. Lacher, Gerhard Bauer, Brian Fury, Sanne Graeve, Emily L. Fledderman, Tye D. Petrie, Dane P. Coleal-Bergum, Tia Hackett, Nicholas H. Perotti, Ying Y. Kong, William W. Kwok, Joseph P. Wagner, Charles L. Wiseman, William V. Williams

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Targeted cancer immunotherapy with irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic cancer cell lines has been an effective approach to reduce tumor burden in several patients. It is generally assumed that to be effective, these cell lines need to express immunogenic antigens coexpressed in patient tumor cells, and antigen-presenting cells need to take up such antigens then present them to patient T cells. We have previously reported that, in a phase I pilot study (ClinicalTrials.gov NCT00095862), a subject with stage IV breast cancer experienced substantial regression of breast, lung, and brain lesions following inoculation with clinical formulations of SV-BR-1-GM, a GM-CSF-secreting breast tumor cell line. To identify diagnostic features permitting the prospective identification of patients likely to benefit from SV-BR-1-GM, we conducted a molecular analysis of the SV-BR-1-GM cell line and of patient-derived blood, as well as a tumor specimen. Compared to normal human breast cells, SV-BR-1-GM cells overexpress genes encoding tumor-associated antigens (TAAs) such as PRAME, a cancer/testis antigen. Curiously, despite its presumptive breast epithelial origin, the cell line expresses major histocompatibility complex (MHC) class II genes (HLA-DRA, HLA-DRB3, HLA-DMA, HLA-DMB), in addition to several other factors known to play immunostimulatory roles. These factors include MHC class I components (B2M, HLA-A, HLA-B), ADA (encoding adenosine deaminase), ADGRE5 (CD97), CD58 (LFA3), CD74 (encoding invariant chain and CLIP), CD83, CXCL8 (IL8), CXCL16, HLA-F, IL6, IL18, and KITLG. Moreover, both SV-BR-1-GM cells and the responding study subject carried an HLA-DRB3*02:02 allele, raising the question of whether SV-BR-1-GM cells can directly present endogenous antigens to T cells, thereby inducing a tumor-directed immune response. In support of this, SV-BR-1-GM cells (which also carry the HLA-DRB3*01:01 allele) treated with yellow fever virus (YFV) envelope (Env) 43-59 peptides reactivated YFV-DRB3*01:01-specific CD4+ T cells. Thus, the partial HLA allele match between SV-BR-1-GM and the clinical responder might have enabled patient T lymphocytes to directly recognize SV-BR-1-GM TAAs as presented on SV-BR-1-GM MHCs. Taken together, our findings are consistent with a potentially unique mechanism of action by which SV-BR-1-GM cells can act as APCs for previously primed CD4+ T cells.

Original languageEnglish (US)
Article number776
JournalFrontiers in Immunology
Volume9
Issue numberMAY
DOIs
StatePublished - May 15 2018

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Granulocyte-Macrophage Colony-Stimulating Factor
HLA-DRB3 Chains
Breast Neoplasms
T-Lymphocytes
Cell Line
Neoplasm Antigens
Yellow fever virus
Antigens
Breast
Alleles
Major Histocompatibility Complex
Neoplasms
HLA-DR alpha-Chains
MHC Class II Genes
Interleukin-18
Adenosine Deaminase
HLA-A Antigens
HLA-B Antigens
Testicular Neoplasms
Antigen-Presenting Cells

Keywords

  • Antigen-presenting cells
  • GVAX
  • SV-BR-1-GM
  • Targeted immunotherapy
  • Therapeutic cancer vaccine
  • Whole-cell vaccine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

SV-BR-1-GM, a clinically effective GM-CSF-secreting breast cancer cell line, expresses an immune signature and directly activates CD4+ T lymphocytes. / Lacher, Markus D.; Bauer, Gerhard; Fury, Brian; Graeve, Sanne; Fledderman, Emily L.; Petrie, Tye D.; Coleal-Bergum, Dane P.; Hackett, Tia; Perotti, Nicholas H.; Kong, Ying Y.; Kwok, William W.; Wagner, Joseph P.; Wiseman, Charles L.; Williams, William V.

In: Frontiers in Immunology, Vol. 9, No. MAY, 776, 15.05.2018.

Research output: Contribution to journalArticle

Lacher, MD, Bauer, G, Fury, B, Graeve, S, Fledderman, EL, Petrie, TD, Coleal-Bergum, DP, Hackett, T, Perotti, NH, Kong, YY, Kwok, WW, Wagner, JP, Wiseman, CL & Williams, WV 2018, 'SV-BR-1-GM, a clinically effective GM-CSF-secreting breast cancer cell line, expresses an immune signature and directly activates CD4+ T lymphocytes', Frontiers in Immunology, vol. 9, no. MAY, 776. https://doi.org/10.3389/fimmu.2018.00776
Lacher, Markus D. ; Bauer, Gerhard ; Fury, Brian ; Graeve, Sanne ; Fledderman, Emily L. ; Petrie, Tye D. ; Coleal-Bergum, Dane P. ; Hackett, Tia ; Perotti, Nicholas H. ; Kong, Ying Y. ; Kwok, William W. ; Wagner, Joseph P. ; Wiseman, Charles L. ; Williams, William V. / SV-BR-1-GM, a clinically effective GM-CSF-secreting breast cancer cell line, expresses an immune signature and directly activates CD4+ T lymphocytes. In: Frontiers in Immunology. 2018 ; Vol. 9, No. MAY.
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T1 - SV-BR-1-GM, a clinically effective GM-CSF-secreting breast cancer cell line, expresses an immune signature and directly activates CD4+ T lymphocytes

AU - Lacher, Markus D.

AU - Bauer, Gerhard

AU - Fury, Brian

AU - Graeve, Sanne

AU - Fledderman, Emily L.

AU - Petrie, Tye D.

AU - Coleal-Bergum, Dane P.

AU - Hackett, Tia

AU - Perotti, Nicholas H.

AU - Kong, Ying Y.

AU - Kwok, William W.

AU - Wagner, Joseph P.

AU - Wiseman, Charles L.

AU - Williams, William V.

PY - 2018/5/15

Y1 - 2018/5/15

N2 - Targeted cancer immunotherapy with irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic cancer cell lines has been an effective approach to reduce tumor burden in several patients. It is generally assumed that to be effective, these cell lines need to express immunogenic antigens coexpressed in patient tumor cells, and antigen-presenting cells need to take up such antigens then present them to patient T cells. We have previously reported that, in a phase I pilot study (ClinicalTrials.gov NCT00095862), a subject with stage IV breast cancer experienced substantial regression of breast, lung, and brain lesions following inoculation with clinical formulations of SV-BR-1-GM, a GM-CSF-secreting breast tumor cell line. To identify diagnostic features permitting the prospective identification of patients likely to benefit from SV-BR-1-GM, we conducted a molecular analysis of the SV-BR-1-GM cell line and of patient-derived blood, as well as a tumor specimen. Compared to normal human breast cells, SV-BR-1-GM cells overexpress genes encoding tumor-associated antigens (TAAs) such as PRAME, a cancer/testis antigen. Curiously, despite its presumptive breast epithelial origin, the cell line expresses major histocompatibility complex (MHC) class II genes (HLA-DRA, HLA-DRB3, HLA-DMA, HLA-DMB), in addition to several other factors known to play immunostimulatory roles. These factors include MHC class I components (B2M, HLA-A, HLA-B), ADA (encoding adenosine deaminase), ADGRE5 (CD97), CD58 (LFA3), CD74 (encoding invariant chain and CLIP), CD83, CXCL8 (IL8), CXCL16, HLA-F, IL6, IL18, and KITLG. Moreover, both SV-BR-1-GM cells and the responding study subject carried an HLA-DRB3*02:02 allele, raising the question of whether SV-BR-1-GM cells can directly present endogenous antigens to T cells, thereby inducing a tumor-directed immune response. In support of this, SV-BR-1-GM cells (which also carry the HLA-DRB3*01:01 allele) treated with yellow fever virus (YFV) envelope (Env) 43-59 peptides reactivated YFV-DRB3*01:01-specific CD4+ T cells. Thus, the partial HLA allele match between SV-BR-1-GM and the clinical responder might have enabled patient T lymphocytes to directly recognize SV-BR-1-GM TAAs as presented on SV-BR-1-GM MHCs. Taken together, our findings are consistent with a potentially unique mechanism of action by which SV-BR-1-GM cells can act as APCs for previously primed CD4+ T cells.

AB - Targeted cancer immunotherapy with irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic cancer cell lines has been an effective approach to reduce tumor burden in several patients. It is generally assumed that to be effective, these cell lines need to express immunogenic antigens coexpressed in patient tumor cells, and antigen-presenting cells need to take up such antigens then present them to patient T cells. We have previously reported that, in a phase I pilot study (ClinicalTrials.gov NCT00095862), a subject with stage IV breast cancer experienced substantial regression of breast, lung, and brain lesions following inoculation with clinical formulations of SV-BR-1-GM, a GM-CSF-secreting breast tumor cell line. To identify diagnostic features permitting the prospective identification of patients likely to benefit from SV-BR-1-GM, we conducted a molecular analysis of the SV-BR-1-GM cell line and of patient-derived blood, as well as a tumor specimen. Compared to normal human breast cells, SV-BR-1-GM cells overexpress genes encoding tumor-associated antigens (TAAs) such as PRAME, a cancer/testis antigen. Curiously, despite its presumptive breast epithelial origin, the cell line expresses major histocompatibility complex (MHC) class II genes (HLA-DRA, HLA-DRB3, HLA-DMA, HLA-DMB), in addition to several other factors known to play immunostimulatory roles. These factors include MHC class I components (B2M, HLA-A, HLA-B), ADA (encoding adenosine deaminase), ADGRE5 (CD97), CD58 (LFA3), CD74 (encoding invariant chain and CLIP), CD83, CXCL8 (IL8), CXCL16, HLA-F, IL6, IL18, and KITLG. Moreover, both SV-BR-1-GM cells and the responding study subject carried an HLA-DRB3*02:02 allele, raising the question of whether SV-BR-1-GM cells can directly present endogenous antigens to T cells, thereby inducing a tumor-directed immune response. In support of this, SV-BR-1-GM cells (which also carry the HLA-DRB3*01:01 allele) treated with yellow fever virus (YFV) envelope (Env) 43-59 peptides reactivated YFV-DRB3*01:01-specific CD4+ T cells. Thus, the partial HLA allele match between SV-BR-1-GM and the clinical responder might have enabled patient T lymphocytes to directly recognize SV-BR-1-GM TAAs as presented on SV-BR-1-GM MHCs. Taken together, our findings are consistent with a potentially unique mechanism of action by which SV-BR-1-GM cells can act as APCs for previously primed CD4+ T cells.

KW - Antigen-presenting cells

KW - GVAX

KW - SV-BR-1-GM

KW - Targeted immunotherapy

KW - Therapeutic cancer vaccine

KW - Whole-cell vaccine

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