T-cell triggering by CD3- and CD28-binding molecules linked to a human virus-modified tumor cell vaccine.
The aim was to develop T cell costimulatory molecules that are broadly applicable to augment anti-tumor immune responses upon application of a virus-modified tumor vaccine to cancer patients. We generated recombinant bispecific single-chain antibodies with one specificity directed against the CD3 or the CD28 antigen on human T cells and the other against the viral target molecule hemagglutinin-neuraminidase (HN) of Newcastle Disease Virus (NDV). By re-directing unstimulated primary human T cells against HN-expressing NDV-infected tumor cells, the bispecific molecule bsHN-CD3 cross-linked effector and target cells and rapidly induced cytotoxicity at nanomolar concentrations. The bsHN-CD28 molecule exerted T cell co-stimulatory function. Maximal T cell activation was achieved with tumor cells infected by NDV and modified with both new stimulatory molecules. This was revealed by T cell proliferation, upregulation of CD69 and CD25 and by release of cytokines, interferons and chemokines. The new molecules combine high-effectivity with specificity and safety.
Haas
Claudia
C
German Cancer Research Center (DKFZ), Division of Cellular Immunology, D010, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Lulei
Maria
M
Fournier
Philippe
P
Arnold
Annette
A
Schirrmacher
Volker
V
D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000276:immunology*; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000032:analysis; D003602:Cytotoxicity, Immunologic; D015707:HN Protein / Q000276:immunology; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000032:analysis; D051379:Mice; D009522:Newcastle disease virus / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology*; D000099192:CD69 Antigens
D000906:Antibodies; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000956:Antigens, Viral; D018106:CD28 Antigens; D017252:CD3 Complex; D019496:Cancer Vaccines; D016207:Cytokines; D015707:HN Protein; D007135:Immunoglobulin Variable Region; D037181:Lectins, C-Type; D008222:Lymphokines; D015375:Receptors, Interleukin-2; D000099192:CD69 Antigens