Genetically targeted T cells eradicate established breast cancer in syngeneic mice.

Abstract

The purpose of the present study was to evaluate the capacity and mechanisms of genetically modified erbB2-specific T cells to eradicate erbB2+ tumors in syngeneic mice. Primary mouse T cells were modified to target the breast tumor-associated antigen erbB2 through retroviral-mediated transfer of a chimeric antigen receptor, termed single-chain antibody (scFv)-CD28-zeta. Antitumor efficacy of scFv-CD28-zeta-modified T cells was analyzed in mice bearing D2F2/E2 breast tumors. The scFv-CD28-zeta-modified T cells were shown to specifically secrete T cytotoxic-1 cytokines and lyse erbB2+ breast tumor cells following receptor stimulation in vitro. Treatment with scFv-CD28-zeta-modified T cells was able to lead to long-term, tumor-free survival in mice bearing erbB2+ D2F2/E2 breast tumors. Importantly, the surviving mice developed a host memory response to D2F2/E2 tumor cells, and this host response was able to protect against a rechallenge with erbB2+ D2F2/E2 tumor cells and parental erbB2(-) D2F2 tumor cells. In addition, scFv-CD28-zeta T-cell expression of perforin and interferon-gamma were essential for complete antitumor efficacy. Treatment with scFv-CD28-zeta-modified T cells was able to induce a host antitumor immunity in syngeneic mice. Complete tumor elimination by scFv-CD28-zeta-modified T cells required T cell-derived interferon-gamma and perforin, indicating that cytotoxicity and cytokine secretion play a role in the in vivo response.