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

• Published in: Clinical cancer research Vol. 14; no. 24; pp. 8112 - 8122
• Main Authors: Emtage, Peter C R, Lo, Agnes S Y, Gomes, Erica M, Liu, David L, Gonzalo-Daganzo, Rosa M, Junghans, Richard P
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 15-12-2008
• Subjects: Animals; Apoptosis; Carcinoembryonic Antigen - immunology; CD28 Antigens - genetics; Cell Proliferation; Chimeric Immune Receptor; Cytokines - metabolism; Cytotoxicity, Immunologic; Female; Gene Therapy; Humans; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Neoplasms, Experimental - therapy; Receptors, Antigen, T-Cell - genetics; T-Lymphocytes - immunology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-4910

Purpose: This report describes the development and preclinical qualification tests of second-generation anti-carcinoembryonic (CEA)
designer T cells for use in human trials.
Experimental Design: 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, TCRζ, 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 IFNγ 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.
Conclusion: 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.