title: Adoptive immunotherapy of cancer with polyclonal, 108-fold hyperexpanded, CD4+ and CD8+ T cells.
abstract: 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 CD62Llow 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 Vbeta 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.
authors.affiliation: Center for Surgery Research, The Cleveland Clinic Foundation, Cleveland, OH, USA. plautzg@ccf.org.
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Wang
authors.forename: Wen-Xin
authors.initials: WX
authors.lastname: Huang
authors.forename: Hallie
authors.initials: H
authors.lastname: Graor
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cohen
authors.forename: Julian A
authors.initials: JA
authors.lastname: Kim
authors.forename: Suyu
authors.initials: S
authors.lastname: Shu
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Plautz