Original Research ARTICLE
SV-BR-1-GM, a Clinically Effective GM-CSF-Secreting Breast Cancer Cell Line, Expresses an Immune Signature and Directly Activates CD4+ T Lymphocytes
- 1BriaCell Therapeutics Corp., United States
- 2GMP Facility, UC Davis Health System, United States
- 3GMP facility, University of California, Davis, United States
- 4Benaroya Research Institute, Virginia Mason Medical Center, United States
Targeted cancer immunotherapy with irradiated, 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 co-expressed 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 antigen-presenting cells for previously primed CD4+ T cells.
Keywords: SV-BR-1-GM, GVAX, Targeted immunotherapy, whole-cell vaccine, Therapeutic cancer vaccine, Antigen-Presenting Cells
Received: 26 Jul 2017;
Accepted: 28 Mar 2018.
Edited by:José Mordoh, Leloir Institute Foundation (FIL), Argentina
Reviewed by:Alex Y. Huang, School of Medicine, Case Western Reserve University, United States
Derre Laurent, Centre Hospitalier Universitaire Vaudois (CHUV), Switzerland
Copyright: © 2018 Lacher, Bauer, Fury, Graeve, Fledderman, Petrie, Coleal-Bergum, Hackett, Perotti, Kong, Kwok, Wagner, Wiseman and Williams. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: PhD. Markus D. Lacher, BriaCell Therapeutics Corp., 820 Heinz Avenue, Berkeley, 94710, California, United States, email@example.com