Single chain Ig/gamma gene-redirected human T lymphocytes produce cytokines, specifically lyse tumor cells, and recycle lytic capacity.
To enable construction of CTL with known predefined Ab specificity for adoptive immunotherapy, we constructed a chimeric scFv/gamma gene composed of the variable regions of a mAb joined to the Fc(epsilon)RI signaling receptor gamma-chain of mast cells. Introduction of this chimeric receptor into CTL rendered these lymphocytes specific for renal cell carcinoma. This approach combines the specificity of tumor-selective Abs with the efficacy of CTL to destroy tumor cells. We not only demonstrated that the transduced CTL functionally express the scFv/gamma receptor for a prolonged period of time (4.5 mo of in vitro culture), but also showed high levels of Ab-dictated lysis of renal cell carcinoma similar to that of normal CTL, and importantly, we demonstrated that these CTL can recycle their lytic activity. Moreover, these scFv/gamma-expressing T lymphocytes produce cytokines upon stimulation with the relevant target cell. These results together with the donor independence of our gene transduction protocol demonstrate the feasibility of redirecting T lymphocytes for cancer treatment.
Weijtens
M E
ME
Department of Clinical and Tumor Immunology, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Willemsen
R A
RA
Valerio
D
D
Stam
K
K
Bolhuis
R L
RL
D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D005803:Genes, Immunoglobulin / Q000276:immunology*; D005822:Genetic Vectors / Q000276:immunology; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics*; D007074:Immunoglobulin G / Q000235:genetics*; D008969:Molecular Sequence Data; D017455:Receptors, IgE / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*; D014162:Transfection / Q000276:immunology; D014407:Tumor Cells, Cultured
D016207:Cytokines; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D017455:Receptors, IgE; D011993:Recombinant Fusion Proteins; C055966:immunoglobulin Fv