GD2-targeted chimeric antigen receptor T cells prevent metastasis formation by elimination of breast cancer stem-like cells

Abstract

2020) GD2-targeted chimeric antigen receptor T cells prevent metastasis formation by elimination of breast cancer stem-like cells, OncoImmunology, 9:1, 1683345, ABSTRACT Expression of the disialoganglioside GD2 has been identified as a marker antigen associated with a breast cancer stem-like cell (BCSC) phenotype. Here, we report on the evaluation of GD2 as a BCSCspecific target antigen for immunotherapy. GD2 expression was confirmed at variable degree in a set of breast cancer cell lines, predominantly in triple-negative breast cancer (TNBC). To target GD2, we have generated novel anti-GD2 chimeric antigen receptors (GD2-CAR), based on single-chain variable fragments (scFv) derived from the monoclonal antibody (mAb) ch14.18, also known as dinutuximab beta. Expressed on T cells, GD2-CARs mediated specific GD2-dependent T-cell activation and target cell lysis. In contrast to previously described GD2-CARs, no signs of exhaustion by tonic signaling were found. Importantly, application of GD2-CAR expressing T cells (GD2-CAR-T) in an orthotopic xenograft model of TNBC (MDA-MB-231) halted local tumor progression and completely prevented lung metastasis formation. In line with the BCSC model, GD2 expression was only found in a subpopulation (4-6%) of MDA-MB-231 cells before injection. Significant expansion of GD2-CAR-T in tumor-bearing mice as well as T-cell infiltrates in the primary tumor and the lungs were found, indicating site-specific activation of GD2-CAR-T. Our data strongly support previous findings of GD2 as a BCSC-associated antigen. GD2-targeted immunotherapies have been extensively studied in human. In conclusion, GD2-CAR-T should be considered a promising novel approach for GD2-positive breast cancer, especially to eliminate disseminated tumor cells and prevent metastasis formation. ARTICLE HISTORY

Emerging CAR-T Cell Therapy for the Treatment of Triple-Negative Breast Cancer

“…The cell surface and tumor-selective expression of GD2 has made this molecule an appealing anticancer target and has led to the development of antibody-based immunotherapies, as evidenced by the FDA-approval of the anti-GD2 monoclonal antibody dinutuximab beta for the treatment of neuroblastoma(87,88). In fact, the efficacy and long-term persistence of Epstein-Barr-viruson October 31, 2020.…”

Chimeric antigen receptor T-cell immunotherapy in breast cancer: development and challenges

“…One study reported on the evaluation of disialoganglioside GD2 expressed in 35.5% of metastatic TNBC as a breast cancer stem cell specific target antigen for immunotherapy 38 . Importantly, GD2-CAR-T demonstrated excellent cytolytic activity against GD2 positive cell lines, independent of the tumor entity.…”

Disialoganglioside GD2 Expression in Solid Tumors and Role as a Target for Cancer Therapy

“…CAR-T cell therapy killed all 11 GD2-expressing cell lines studied. Seitz et al reported that GD2-directed immunotherapy by GD2-CAR-T can prevent metastasis in a highly aggressive mouse model of triple negative breast cancer (111).…”