title: Antitumor activity of chimeric immunoreceptor gene-modified Tc1 and Th1 cells against autologous carcinoembryonic antigen-expressing colon cancer cells.
abstract: To generate tumor-specific and interferon (IFN)-gamma-producing Tc1 and Th1 cells applicable for many cancer patients, we previously developed a protocol for generating carcinoembryonic antigen (CEA)-specific Tc1 and Th1 cells from healthy human T cells by transduction with a lentivirus containing a chimeric immunoglobulin T-cell receptor (cIgTCR) gene composed of single-chain variable fragments from an anti-CEA-specific monoclonal antibody fused to an intracellular signaling domain of CD28 and CD3zeta. These cells, designated Tc1-T and Th1-T bodies, respectively, showed strong antitumor activity against CEA-expressing tumor cells in RAG2-/- mice when both of them were transferred. However, it remains unclear whether it is possible to generate Tc1-T and Th1-T bodies from cancer patients with defective T-cell function because of significant immunosuppression. Here, we prepared Tc1-T and Th1-T bodies from T cells of a colon cancer patient, and asked whether these T bodies can exert effective T-cell function against autologous tumor cells. These T bodies showed high cytotoxicity and produced IFN-gamma in response to CEA-expressing autologous tumor cells, even in the presence of soluble CEA. It was also demonstrated that Th1-T bodies supported the survival of Tc1-T bodies through cell-to-cell interactions. Furthermore, our protocol utilized retrovirus for cIgTCR transduction to achieve better induction efficiency compared to lentivirus-mediated transduction. Taken together, our findings here indicate that retrovirally transduced Tc1-T and Th1-T bodies will become a promising strategy for adoptive immunotherapy of human cancer.
authors.affiliation: Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sasaki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ikeda
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Sato
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ohkuri
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Abe
authors.forename: Masahide
authors.initials: M
authors.lastname: Kuroki
authors.forename: Masafumi
authors.initials: M
authors.lastname: Onodera
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyamoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kondo
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishimura
mesh_terms: D002272:Carcinoembryonic Antigen / Q000276:immunology / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology; D045744:Cell Line, Tumor; D002678:Chimera; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D016086:Lentivirus / Q000235:genetics; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D002272:Carcinoembryonic Antigen; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma