Ex Vivo Expansion of HER2-Specific T Cells for the Treatment of HER2- Overexpressing Breast Cancer.

摘要

Adoptive T cell therapy has the potential to eradicate existing malignancy in humans. I have been investigating the immune effector arms most efficacious in eradicating malignancy in the neu-transgenic mouse model. These mice develop spontaneous tumors that are histologically similar to those observed in humans. Two helper peptides, p781-795 and pll66-ll8O, of neu have been identified to which T helper cell lines can be generated. The T cell lines are CD4+ and demonstrate a Thl phenotype with the production of IFN-gamma but not ITh-4. Cell lines derived using these peptides, were tested for the ability to eradicate existing bulky malignancy. It was observed that T cell injection resulted in a partial tumor response when cells line were used individually. Small increases in survival time were observed. When the cell lines were combined, survival was also improved and some tumors had lost antigen neu expression at the cell surface. In addition to ThI immunity it is hypothesized that other immune effector arms, such as Th2, could also be effective. Vaccination strategies have been developed that elicit Th2 T cells. Expansion of Th2 cells ex vivo and their therapeutic efficacy is being examined. A monoclonal antibody therapy strategy has also been developed that will be tested in combination with adoptive T cell transfer. Technigues for optimal ex vivo expansion of human HER-2/neu-specific T cells are also being developed. Peptide presentation during culture can impact antigen-specific T cell responsiveness of human T cell lines. The inclusion of IL-l2 during culture with HER-2/neu peptides can greatly enhance the antigen-specificity of the cultures. The findings in the animal model and ex vivo expansion of human T cells will be directly translated to human clinical trials of adoptive T cell therapy.