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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

Authors' Affiliations: ¹ Division of Surgical Research, Department of Surgery, Boston University School of Medicine, Roger Williams Medical Center, Providence, Rhode Island and ² Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Institute of Human Genetics, Harvard Medical School, Boston, Massachusetts

Requests for reprints: R.P. Junghans, Roger Williams Medical Center, 825 Chalkstone Avenue, Providence, RI. Phone: 401-456-2507; Fax: 401-456-4812; E-mail: rpj{at}bu.edu.

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, TCR, 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 IFN 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.