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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Amgen Research (Munich) GmbH, Munich, Germany.
Wibke
W
Deisting
Amgen Research (Munich) GmbH, Munich, Germany.
Tobias
T
Raum
Amgen Research (Munich) GmbH, Munich, Germany.
Peter
P
Kufer
MPM Capital, Cambridge, Massachusetts, United States of America.
Patrick A
PA
Baeuerle
Amgen Research (Munich) GmbH, Munich, Germany.
Markus
M
Münz
D000818:Animals; D018033:Antibodies, Bispecific / Q000235:genetics / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology*; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000276:immunology*; D045744:Cell Line, Tumor; D003412:Cricetulus; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D000071858:Epithelial Cell Adhesion Molecule; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D057131:Immune Evasion / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D019253:Proto-Oncogene Proteins c-bcl-2; C102316:SERPINB9 protein, human; D015843:Serpins; D016212:Transforming Growth Factor beta