Impact of Diverse Immune Evasion Mechanisms of Cancer Cells on T Cells Engaged by EpCAM/CD3-Bispecific Antibody Construct AMG 110

• Published in: PloS one 2015-10, Vol.10 (10), p.e0141669-e0141669
• Main Authors: Deisting, Wibke, Raum, Tobias, Kufer, Peter, Baeuerle, Patrick A, Münz, Markus
• Format: Article
• Language: English
• Subjects: Adenosine; Animals; Antibodies, Bispecific - genetics; Antibodies, Bispecific - immunology; Antigens; Antigens, Neoplasm - immunology; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Bcl-2 protein; Bispecific antibodies; Cancer; CD3 antigen; CD3 Complex - immunology; Cell Adhesion Molecules - immunology; Cell culture; Cell growth; Cell Line, Tumor; Cell proliferation; CHO Cells; Cloning; Cricetulus; Cytokines; Cytotoxicity; Cytotoxicity, Immunologic - genetics; Cytotoxicity, Immunologic - immunology; Epithelial Cell Adhesion Molecule; Gene Expression; Genetic aspects; Genetic Vectors - genetics; Humans; Immune evasion; Immune Evasion - genetics; Immunoglobulins; Immunology; Immunotherapy; Interleukin 10; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Lysis; Major histocompatibility complex; Medical research; Melanoma; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Ovarian cancer; Patients; PD-L1 protein; Peptides; Physiological aspects; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Response rates; Risk factors; Serpins - genetics; Serpins - metabolism; T cell receptors; T-cell receptor; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transfection; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Transforming growth factors; Tumor cell lines; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0141669

Bispecific T cell engager (BiTE®) are single-chain bispecific antibody constructs with dual specificity for CD3 on T cells and a surface antigen on target cells. They can elicit a polyclonal cytotoxic T cell response that is not restricted by T cell receptor (TCR) specificity, and surface expression of MHC class I/peptide antigen complexes. Using human EpCAM/CD3-bispecific BiTE® antibody construct AMG 110, we here assessed to what extent surface expression of PD-L1, cytoplasmic expression of indoleamine-2,3-deoxygenase type 1, Bcl-2 and serpin PI-9, and the presence of transforming growth factor beta (TGF-β), interleukin-10 (IL-10) and adenosine in culture medium can impact redirected lysis by AMG 110-engaged T cells. The seven factors, which are all involved in inhibiting T cell functions by cancer cells, were tested with human EpCAM-expressing Chinese hamster ovary (CHO) target cells at levels that in most cases exceeded those observed in a number of human cancer cell lines. Co-culture experiments were used to determine the impact of the evasion mechanisms on EC50 values and amplitude of redirected lysis by AMG 110, and on BiTE®-induced proliferation of previously resting human peripheral T cells. An inhibitory effect on redirected lysis by AMG 110-engaged T cells was seen upon overexpression of serpin PI-9, Bcl-2, TGF-β and PD-L1. An inhibitory effect on induction of T cell proliferation was only seen with CHO cells overexpressing IDO. In no case, a single evasion mechanism rendered target cells completely resistant to BiTE®-induced lysis, and even various combinations could not. Our data suggest that diverse mechanisms employed by cancer cells to fend off T cells cannot inactivate AMG 110-engaged T cells, and that inhibitory effects observed in vitro may be overcome by increased concentrations of the BiTE® antibody construct.