Targeted superantigens for immunotherapy of haematopoietic tumours.
With the exception of childhood common acute lymphoblastic leukaemia (cALL), treatment of other hematopoietic B cell lineage tumours such as non-Hodgkin's lymphoma (B-NHL), adult ALL and multiple myeloma (MM) is unsatisfactory. Similarly, the therapeutic outcome of acute and chronic myeloid leukaemia (AML, CML) is frequently dismal. At the same time, leukaemia/lymphoma cells represent ideal targets for immunotherapy. The present review summarizes our preclinical experience with a novel type of cytotoxic T cell based immunotherapy for B-lineage and myeloid tumours. Staphylococcal enterotoxin-derived superantigens (SAgs) are among the most potent T cell activators known, linking the T cell receptor to HLA-DR on natural target cells. SAgs were genetically engineered to reduce DR binding and were then fused to Fab parts of tumour-directed monoclonal antibodies (mAbs). Using these "targeted" SAgs, highly efficient lysis of B-lineage (B-NHL, B-CLL, ALL, MM) and myeloid (AML, CML) tumour cells by T-cells was achieved in vitro and in an animal model. We are entering an interesting era of innovative cancer therapy based on novel man-made biotherapeutic agents.
Department of Clinical Immunology, University Hospital, Uppsala, Sweden. Thomas.Totterman@KlinImm.uu.se
T H
TH
Tötterman
C
C
Gidlöf
L
L
Ragnarsson
E
E
Högbom
M
M
Lindeberg
N
N
von der Lehr
A
A
Einarsson
M
M
Soegaard
K
K
Kristensson
T
T
Kalland
M
M
Dohlsten
D000328:Adult; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002648:Child; D004768:Enterotoxins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D005240:Feasibility Studies; D006684:HLA-DR Antigens / Q000276:immunology; D019337:Hematologic Neoplasms / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000276:immunology*; D007167:Immunotherapy; D008213:Lymphocyte Activation; D015202:Protein Engineering; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013211:Staphylococcus aureus / Q000235:genetics / Q000276:immunology; D018089:Superantigens / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000942:Antigens, Bacterial; D018941:Antigens, CD19; D004768:Enterotoxins; D006684:HLA-DR Antigens; D007140:Immunoglobulin Fab Fragments; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal