Transfer of in vitro-expanded naïve T cells after lymphodepletion enhances antitumor immunity through the induction of polyclonal antitumor effector T cells

The adoptive transfer of effector T cellscombined with lymphodepletion has demonstrated promising antitumor effects in mice and humans, although the availability of tumor-specific T cellsis limited. We and others have also demonstrated that the transfer of polyclonal naive T cellsinduces tumor-specific effector T cellsand enhances antitumor immunity after lymphodepletion. Because tumors have been demonstrated to induce immunosuppressive networks and regulate the function of T cells, obtaining a sufficient number of fully functional naive T cellsthat are able to differentiate into tumor-specific effector T cellsremains difficult. To establish culture methods to obtain a large number of polyclonal T cellsthat are capable of differentiating into tumor-specific effector T cells, naive T cellswere activated with anti-CD3 mAbs in vitro. These cells were stimulated with IL-2 and IL-7 for the CD8 subset or with IL-7 and IL-23 for the CD4 subset. Transfer of these hyperexpanded T cellsafter lymphodepletion showed significant antitumor efficacy, and tumor-specific effector T cellswere primed from these expanded T cellsin tumor-bearing hosts. Moreover, these ex vivo—expanded T cellsmaintained T cellreceptor diversity and showed long-term persistence of memory against specific tumors. Further analyses revealed that combination therapy consisting of vaccination with dendritic cells that were co-cultured with irradiated whole tumor cells and the transfer of ex vivo—expanded T cellssignificantly enhanced antitumor immunity. These results indicate that the transfer of ex vivo—expanded polyclonal T cellscan be combined with other immunotherapies and augment antitumor effects.