Adoptive immunotherapy of cancer with polyclonal 108-fold hyperexpanded CD4+ and CD8+ T cells

摘要

T cell-mediated cancer immunotherapy is dose dependent and optimally requires participation of antigen-specific CD4⁺ and CD8⁺ T cells. Here, we isolated tumor-sensitized T cells and activated them in vitro using conditions that led to greater than 10⁸-fold numerical hyperexpansion of either the CD4⁺ or CD8⁺ subset while retaining their capacity for in vivo therapeutic efficacy. Murine tumor-draining lymph node (TDLN) cells were segregated to purify the CD62L^low subset, or the CD4⁺ subset thereof. Cells were then propagated through multiple cycles of anti-CD3 activation with IL-2 + IL-7 for the CD8⁺ subset, or IL-7 + IL-23 for the CD4⁺ subset. A broad repertoire of TCR Vβ families was maintained throughout hyperexpansion, which was similar to the starting population. Adoptive transfer of hyper-expanded CD8⁺ T cells eliminated established pulmonary metastases, in an immunologically specific fashion without the requirement for adjunct IL-2. Hyper-expanded CD4⁺ T cells cured established tumors in intracranial or subcutaneous sites that were not susceptible to CD8⁺ T cells alone. Because accessibility and antigen presentation within metastases varies according to anatomic site, maintenance of a broad repertoire of both CD4⁺ and CD8⁺ T effector cells will augment the overall systemic efficacy of adoptive immunotherapy.