Generation of gene-modified T cells reactive against the angiogenic kinase insert domain-containing receptor (KDR) found on tumor vasculature.
The destruction of newly forming tumor vasculature is a promising approach to inhibit tumor growth. The goal of the present study was to investigate whether human lymphocytes gene modified to express a chimeric receptor specific for the angiogenic endothelial cell receptor, KDR, could react against KDR(+) cells. Gene-modified lymphocytes specifically lysed KDR(+) cells and secreted cytokines in response to KDR(+) target cells including human umbilical vein endothelial cells (HUVECs). Anti-KDR lymphocytes induced HUVECs to secrete the chemokine interleukin 8 and upregulate the adhesion molecules VCAM and E-selectin, which may be important in the recruitment of further immune effector cells to tumor. These KDR-specific lymphocytes may be useful in the adoptive immunotherapy of a broad range of cancers by inducing immune-mediated destruction of tumor neovasculature.
Kershaw
M H
MH
Tumor Immunology Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Westwood
J A
JA
Zhu
Z
Z
Witte
L
L
Libutti
S K
SK
Hwu
P
P
D018106:CD28 Antigens / Q000235:genetics; D002448:Cell Adhesion; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D011961:Receptors, Fc / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics* / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D013601:T-Lymphocytes / Q000378:metabolism*; D014161:Transduction, Genetic; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D018106:CD28 Antigens; D016207:Cytokines; D019040:E-Selectin; D016209:Interleukin-8; D011961:Receptors, Fc; D017978:Receptors, Growth Factor; D019010:Vascular Cell Adhesion Molecule-1; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor