Primary polyclonal human T lymphocytes targeted to carcino-embryonic antigens and neural cell adhesion molecule tumor antigens by CD3zeta-based chimeric immune receptors.
Antigen-specific T lymphocytes are attractive as potential anticancer agents. The generation of large numbers of antigen-specific T cells is possible through the use of gene therapy to express targeting receptors on the T lymphocyte. Activated T lymphocytes were transduced to express carcino-embryonic antigen or neural cell adhesion molecule targeted CD3zeta chimeric immune receptors. The chimeric receptors were expressed as homodimers and also as heterodimers with the native CD3zeta. T lymphocyte populations were expanded in the absence of selection for the modified cells and were shown to produce cytokines when cultured in the presence of immobilized purified protein antigen. These lymphocytes also responded by cytokine production and cytolytic activity when challenged with tumor-cell lines expressing the antigen recognized by the chimeric immune receptor. The cytolytic activity appears to be largely perforin mediated. Furthermore, soluble carcino-embryonic antigen did not interfere with the functional activity of the carcino-embryonic antigen-targeted lymphocytes. Long-term (5-day) stimulation of the modified lymphocytes by protein antigen resulted in reduced viability similar to that induced by anti-CD3 antibodies alone. Viability was improved by a costimulatory signal indicating that such signals may be vital in the maintenance of long-term functional activity of receptor modified T lymphocytes.
Gilham
David E
DE
CRC Department of Medical Oncology, Paterson Institute for Cancer Research, University of Manchester, UK.
O'Neil
Allison
A
Hughes
Chris
C
Guest
Ryan D
RD
Kirillova
Natalia
N
Lehane
Margaret
M
Hawkins
Robert E
RE
D000951:Antigens, Neoplasm; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D016923:Cell Death; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis; D017730:Ki-1 Antigen / Q000378:metabolism; D008213:Lymphocyte Activation; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D019006:Neural Cell Adhesion Molecules / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic
D000951:Antigens, Neoplasm; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D002272:Carcinoembryonic Antigen; D017730:Ki-1 Antigen; D019006:Neural Cell Adhesion Molecules; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma