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.