Genetically Modified Her2-Specific T Cells Recognize Low and High Her2 Expressing Breast Cancer Cells.

Background: Only patients with breast cancers expressing high levels of Her2 benefit from anti-Her2 monoclonal antibodies such as trastuzumab. In the present study we investigated in vitro, if chimeric T-cell receptors (TCR), which combine the antigen-specificity of monoclonal antibodies with the effector function of T cells can overcome this limitation.

Material and Methods: T cells from healthy donors were transduced with retroviral vectors containing the Her2-specific chimeric TCR gene with a CD28-zeta signaling domain (Her2-CD28-zeta). The specificity of the genetically modified T cells was determined by their ability 1) to kill breast cancer cell lines in cytoxicity assays, and 2) to proliferate and secrete cytokines (IFN-γ and IL-2) after stimulation with breast cancer cell lines. The following panel of cell lines was used: autologous PHA blasts, MDA-MB-468 (both Her2-negative), MCF-7 (Her2-low), Her218 and SKBR-3 (both Her2-high).

Results: Her2-CD28-zeta expressing T cells killed low and high Her2-positive breast cancer cell lines in cytotoxicity assays, where as Her2-negative T cells were not killed. Stimulation of T cells with breast cancer cell lines expressing both high and low levels of Her2 resulted in T-cell proliferation and secretion of IFN-γ and IL-2 in a HER2 dependent manner.

Discussion: We demonstrate that breast cancer cells with low levels of expression of Her2 can effectively activate T cells expressing Her2-specific chimeric T cell receptor, induce T-cell proliferation, and the production of IL-2, an important T-cell growth factor. These results indicate that T cells expressing chimeric TCRs could possibly extend the application of Her2 targeted therapies to malignancies expressing low levels of Her2.