SV-BR-1-GM, a Clinically Effective GM-CSF-Secreting Breast Cancer Cell Line, Expresses an Immune Signature and Directly Activates CD4+ T Lymphocytes
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 i...
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Format: | Article |
Language: | English |
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Frontiers Media S.A.
2018-05-01
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Series: | Frontiers in Immunology |
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Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2018.00776/full |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 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 SV-BR-1-GM GVAX targeted immunotherapy whole-cell vaccine therapeutic cancer vaccine antigen-presenting cells |
author_facet |
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 |
author_sort |
Markus D. Lacher |
title |
SV-BR-1-GM, a Clinically Effective GM-CSF-Secreting Breast Cancer Cell Line, Expresses an Immune Signature and Directly Activates CD4+ T Lymphocytes |
title_short |
SV-BR-1-GM, a Clinically Effective GM-CSF-Secreting Breast Cancer Cell Line, Expresses an Immune Signature and Directly Activates CD4+ T Lymphocytes |
title_full |
SV-BR-1-GM, a Clinically Effective GM-CSF-Secreting Breast Cancer Cell Line, Expresses an Immune Signature and Directly Activates CD4+ T Lymphocytes |
title_fullStr |
SV-BR-1-GM, a Clinically Effective GM-CSF-Secreting Breast Cancer Cell Line, Expresses an Immune Signature and Directly Activates CD4+ T Lymphocytes |
title_full_unstemmed |
SV-BR-1-GM, a Clinically Effective GM-CSF-Secreting Breast Cancer Cell Line, Expresses an Immune Signature and Directly Activates CD4+ T Lymphocytes |
title_sort |
sv-br-1-gm, a clinically effective gm-csf-secreting breast cancer cell line, expresses an immune signature and directly activates cd4+ t lymphocytes |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2018-05-01 |
description |
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. |
topic |
SV-BR-1-GM GVAX targeted immunotherapy whole-cell vaccine therapeutic cancer vaccine antigen-presenting cells |
url |
http://journal.frontiersin.org/article/10.3389/fimmu.2018.00776/full |
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doaj-be434467daf447fe95c59f3f971bd7722020-11-24T22:55:24ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-05-01910.3389/fimmu.2018.00776297974SV-BR-1-GM, a Clinically Effective GM-CSF-Secreting Breast Cancer Cell Line, Expresses an Immune Signature and Directly Activates CD4+ T LymphocytesMarkus D. Lacher0Gerhard Bauer1Brian Fury2Sanne Graeve3Emily L. Fledderman4Tye D. Petrie5Dane P. Coleal-Bergum6Tia Hackett7Nicholas H. Perotti8Ying Y. Kong9William W. Kwok10Joseph P. Wagner11Charles L. Wiseman12William V. Williams13BriaCell Therapeutics Corp., Berkeley, CA, United StatesGMP Facility, Institute for Regenerative Cures, University of California, Davis (UCD), Sacramento, CA, United StatesGMP Facility, Institute for Regenerative Cures, University of California, Davis (UCD), Sacramento, CA, United StatesBriaCell Therapeutics Corp., Berkeley, CA, United StatesGMP Facility, Institute for Regenerative Cures, University of California, Davis (UCD), Sacramento, CA, United StatesGMP Facility, Institute for Regenerative Cures, University of California, Davis (UCD), Sacramento, CA, United StatesGMP Facility, Institute for Regenerative Cures, University of California, Davis (UCD), Sacramento, CA, United StatesGMP Facility, Institute for Regenerative Cures, University of California, Davis (UCD), Sacramento, CA, United StatesGMP Facility, Institute for Regenerative Cures, University of California, Davis (UCD), Sacramento, CA, United StatesBenaroya Research Institute at Virginia Mason, Seattle, WA, United StatesBenaroya Research Institute at Virginia Mason, Seattle, WA, United StatesBriaCell Therapeutics Corp., Berkeley, CA, United StatesBriaCell Therapeutics Corp., Berkeley, CA, United StatesBriaCell Therapeutics Corp., Berkeley, CA, United StatesTargeted 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.http://journal.frontiersin.org/article/10.3389/fimmu.2018.00776/fullSV-BR-1-GMGVAXtargeted immunotherapywhole-cell vaccinetherapeutic cancer vaccineantigen-presenting cells |