Adoptive transfer of chimeric FcepsilonRI gene-modified human T cells for cancer immunotherapy.
Immunotherapeutic approaches involving genetic modification of T cells show promise in generating highly specific tumor-reactive effector cells for cancer treatment. Given the high affinity of FcRI (the subtype I Fc receptor for IgE) for IgE monoclonal antibody (mAb), modification of T cells with chimeric FcRI in combination with tumor-specific IgE mAbs is potentially a powerful and effective strategy to specifically target T cells to tumor cells. In this study, we retrovirally transduce human primary T cells with a cDNA encoding the extracellular domain of FcRI linked to the hinge and transmembrane domains of FcRI and the cytoplasmic domains of CD28 and T cell receptor zeta chain (FcRI-CD28-zeta). We demonstrate that human T cells expressing FcRI-CD28-zeta, in the presence of tumor-specific IgE mAb recognizing mouse CD8 antigen (Ly- 2.1+), can specifically secrete cytokine, proliferate, and mediate cytotoxic function after antigen ligation. Furthermore, adoptive transfer of FcRI-CD28-zeta cells incubated with anti-Ly-2.1 IgE mAb significantly enhances the survival of irradiated nonobese diabetic-severe combined immunodeficiency mice bearing Ly-2.1+ tumor compared with control mice. Thus, this set of experiments demonstrates that Fc gene-engineered human T cells mediate effector function in vitro and in vivo in an IgE-dependent manner and thus a novel and valid approach for cancer therapy can now be further developed.
Teng
Michele W L
MW
Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia.
Kershaw
Michael H
MH
Jackson
Jacob T
JT
Smyth
Mark J
MJ
Darcy
Phillip K
PK
D019264:Adoptive Transfer; D000818:Animals; D001483:Base Sequence; D018106:CD28 Antigens / Q000235:genetics; D019496:Cancer Vaccines; D002460:Cell Line; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D004195:Disease Models, Animal; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007167:Immunotherapy; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D017455:Receptors, IgE / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D013945:Thymoma / Q000276:immunology / Q000628:therapy*; D014161:Transduction, Genetic
D018106:CD28 Antigens; D019496:Cancer Vaccines; D016207:Cytokines; C502447:MS4A2 protein, human; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D017455:Receptors, IgE; D011994:Recombinant Proteins; C054979:antigen T cell receptor, zeta chain; D007073:Immunoglobulin E