RT Journal Article SR Electronic T1 Introduction of Genetically Modified CD3ζ Improves Proliferation and Persistence of Antigen-Specific CTLs JF Cancer Immunology Research JO Cancer Immunol Res FD American Association for Cancer Research SP 733 OP 744 DO 10.1158/2326-6066.CIR-17-0538 VO 6 IS 6 A1 Miyao, Kotaro A1 Terakura, Seitaro A1 Okuno, Shingo A1 Julamanee, Jakrawadee A1 Watanabe, Keisuke A1 Hamana, Hiroshi A1 Kishi, Hiroyuki A1 Sakemura, Reona A1 Koyama, Daisuke A1 Goto, Tatsunori A1 Nishida, Tetsuya A1 Murata, Makoto A1 Kiyoi, Hitoshi YR 2018 UL http://cancerimmunolres.aacrjournals.org/content/6/6/733.abstract AB The clinical efficacy of T-cell therapies based on T cells transduced with genes encoding tumor-specific T-cell receptors (TCR-T) is related to the in vivo persistence of the T cells. To improve persistence without modifying TCR affinity, we instead modified intracellular signaling, using artificial T cell–activating adapter molecules (ATAM), generated by inserting the intracellular domain (ICD) of activating T-cell signaling moieties into CD3ζ. ATAMs with the ICD of either CD28 or 4-1BB were generated, assembled into the TCR complex as a part of CD3ζ, and enhanced downstream signaling from the supramolecular activation cluster. ATAMs were retrovirally introduced into human CMV-specific or NY-ESO-1–specific TCR-transduced CD8+ T lymphocytes, and downstream functionality was then examined. ATAM-transduced NY-ESO-1 TCR-T cells were also investigated using the U266-xenograft mouse model. ATAMs were successfully transduced and localized to the cell membrane. ATAM-transduced CMV-specific T cells retained their cytotoxic activity and cytokine production against peptide-pulsed target cells without altering antigen-specificity and showed resistance to activation-induced cell death. Upon both single and repeated stimulation, CD3ζ/4-1BB–transduced T cells had superior proliferation to the CD3ζ-transduced T cells in both the CMV-specific and the NY-ESO-1 TCR-T models and significantly improved antitumor activity compared with untransduced T cells both in vitro and in a mouse xenograft model. ATAM-transduced TCR-T cells demonstrated improved proliferation and persistence in vitro and in vivo. This strategy to control the intracellular signaling of TCR-T cells by ATAM transduction in combination with various tumor-specific TCRs may improve the efficacy of TCR-T therapy. Cancer Immunol Res; 6(6); 733–44. ©2018 AACR.