In vivo antitumor function of tumor antigen‐specific CTLs generated in the presence of OX40 co‐stimulation in vitro. Issue 11 (21st January 2018)

• Record Type: Journal Article
• Authors: Pham Minh, Ngoc; Murata, Satoshi; Kitamura, Naomi; Ueki, Tomoyuki; Kojima, Masatsugu; Miyake, Toru; Takebayashi, Katsushi; Kodama, Hirokazu; Mekata, Eiji; Tani, Masaji
• Is Part Of: International journal of cancer. Volume 142:Issue 11(2018)
• Page Start: 2335
• Page End: 2343
• Publication Date: 2018-01-21
• Subjects: adoptive cell transfer -- immunotherapy -- OX40(CD134) -- CTL generation -- adoptively transferred T cells; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31244
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Adoptive cell transfer (ACT) is an emerging and promising cancer immunotherapy that has been improved through various approaches. Here, we described the distinctive characteristics and functions of tumor Ag‐specific effector CD8 + T‐cells, co‐cultured with a tumor‐specific peptide and a stimulatory anti‐OX40 antibody, before being used for ACT therapy in tumor‐bearing mouse recipients. Splenic T‐cells were obtained from wild‐type FVB/N mice that had been injected with a HER2/neu (neu)‐expressing tumor and a neu‐vaccine. The cells were then incubated for 7 days in vitro with a major histocompatibility complex (MHC) class I peptide derived from neu, in the presence or absence of an agonistic anti‐OX40 monoclonal antibody, before CD8 + T cells were isolated for use in ACT therapy. The proliferative ability of OX40‐driven tumor Ag‐specific effector CD8 + T‐cells in vitro was less than that of non‐OX40‐driven tumor Ag‐specific effector CD8 + T‐cells, but they expressed significantly more early T‐cell differentiation markers, such as CD27, CD62L and CCR7, and significantly higher levels of Bcl‐2, an anti‐apoptotic protein. These OX40‐driven tumor Ag‐specific effector CD8 + T‐cells, when transferred into tumor‐bearing recipients, demonstrated potent proliferation capability and successfully eradicated the established tumor. In addition, these cells exhibited long‐term antitumor function, and appeared to be established as memory T‐cells. Our findings suggest a possible in vitro approach for improving the efficacy of ACT, which is simple, requires only a small amount of modulator, and can potentially avoid several toxicities associated with co‐stimulation in vivo . Abstract : What's new? The OX40 co‐stimulatory pathway is a promising enhancer of anti‐tumor immunity but activation showed mild‐to‐moderate toxicity in a phase I clinical trial. Here, in vitro co‐culture of effector CD8+ T‐cells with a tumor peptide and an agonistic OX40 antibody prior to use in adoptive cell transfer markedly improved tumor clearance in a mouse model. The OX40‐driven tumor‐specific effector CD8+ T‐cells provided long‐term antitumor function while the ex vivo activation of OX40 pathway is expected to reduce toxicity in patients.