Second-generation anti-carcinoembryonic antigen designer T cells resist activation-induced cell death, proliferate on tumor contact, secrete cytokines, and exhibit superior antitumor activity in vivo: a preclinical evaluation.
OBJECTIVE
This report describes the development and preclinical qualification tests of second-generation anti-carcinoembryonic (CEA) designer T cells for use in human trials.


METHODS
The progenitor first-generation immunoglobulin-T-cell receptor (IgTCR) that transmits Signal 1-only effectively mediated chimeric immune receptor (CIR)-directed cytotoxicity, but expressor T cells succumbed to activation-induced cell death (AICD). The second-generation CIR (termed "Tandem" for two signals) was designed to transmit TCR Signal 1 and CD28 Signal 2 to render T cells resistant to AICD and provide prolonged antitumor effect in vivo.


RESULTS
A CIR was created that combines portions of CD28, TCRzeta, and a single chain antibody domain (sFv) specific for CEA into a single molecule (IgCD28TCR). As designed, the gene-modified Tandem T cells exhibit the new property of being resistant to AICD, showing instead an accelerated proliferation on tumor contact. Tandem T cells are more potent than first generation in targeting and lysing CEA+ tumor. Tandem T cells secrete high levels of interleukin-2 and IFNgamma on tumor contact that first-generation T cells lacked, but secretion was exhaustible, suggesting a need for interleukin-2 supplementation in therapy even for these second-generation agents. Finally, second-generation T cells were more effective in suppressing tumor in animal models.


CONCLUSIONS
An advanced generation of anti-CEA designer T cells is described with features that promise a more potent and enduring antitumor immune response in vivo. These preclinical data qualify the human use of this agent that is currently undergoing trial in patients with CEA+ cancers.
Emtage
Peter C R
PC
Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Institute of Human Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Lo
Agnes S Y
AS
Gomes
Erica M
EM
Liu
David L
DL
Gonzalo-Daganzo
Rosa M
RM
Junghans
Richard P
RP
D000818:Animals; D017209:Apoptosis; D018106:CD28 Antigens / Q000235:genetics; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
D018106:CD28 Antigens; D002272:Carcinoembryonic Antigen; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell