The generation of both T killer and Th cell clones specific for the tumor-associated antigen HER2 using retrovirally transduced dendritic cells

Induction of antitumor immunity involves the presence of both CD8(+) CTLs a nd CD4(+) Th cells specific for tumor-associated Ags. Attempts to eradicate cancer by adoptive T cell transfer have been limited due to the difficulty of generating T cells with defined Ag specificity. The current study focus es on the generation of CTL and Th cells against the tumor-associated Ag HE R2 using autologous dendritic cells (DC) derived from CD34(+) hematopoietic progenitor cells which have been retrovirally transduced with the human ep idermal growth factor receptor 2 (HER2) gene. HER2-transduced DC elicited H ER2-specific CD8(+) CTL that lyse HER2-overexpressing tumor cells in contex t of distinct HLA class I alleles. The induction of both HLA-A2 and -A3-res tricted HER2-specific CTL was verified on a clonal level. In addition, retr ovirally transduced DC induced CD4(+) Th1 cells recognizing HER2 in context with HLA class II. HLA-DR-restricted CD4(+) T cells were cloned that relea sed IFN-gamma upon stimulation with DC pulsed with the recombinant protein of the extracellular domain of HER2. These data indicate that retrovirally transduced DC expressing the HER2 molecule present multiple peptide epitope s and subsequently elicit HER2-specific CTI, and Th1 cells. The method of s timulating HER2-specific CD8(+) and CD4(+) T cells with retrovirally transd uced DC was successfully implemented for generating HER2-specific CTL and T h1 clones from a patient with HER2-overexpressing breast cancer. The abilit y to generate and expand HER2-specific, HLA-restricted CTL and Th1 clones i n vitro facilitates the development of immunotherapy regimens, in particula r the adoptive transfer of both autologous HER2-specific T cell clones in p atients with HER2-overexpressing tumors without the requirement of defining immunogenic peptides.