Data from Genetically Targeted T Cells Eradicate Established Breast Cancer in Syngeneic Mice

Abstract

<div>Abstract<p><b>Purpose:</b> The purpose of the present study was to evaluate the capacity and mechanisms of genetically modified <i>erb</i>B2-specific T cells to eradicate <i>erb</i>B2<sup>+</sup> tumors in syngeneic mice.</p><p><b>Experimental Design:</b> Primary mouse T cells were modified to target the breast tumor–associated antigen <i>erb</i>B2 through retroviral-mediated transfer of a chimeric antigen receptor, termed single-chain antibody (scFv)–CD28–ζ. Antitumor efficacy of scFv-CD28-ζ–modified T cells was analyzed in mice bearing D2F2/E2 breast tumors.</p><p><b>Results:</b> The scFv-CD28-ζ–modified T cells were shown to specifically secrete T cytotoxic-1 cytokines and lyse <i>erb</i>B2<sup>+</sup> breast tumor cells following receptor stimulation <i>in vitro</i>. Treatment with scFv-CD28-ζ–modified T cells was able to lead to long-term, tumor-free survival in mice bearing <i>erb</i>B2<sup>+</sup> 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 <i>erb</i>B2<sup>+</sup> D2F2/E2 tumor cells and parental <i>erb</i>B2<sup>-</sup> D2F2 tumor cells. In addition, scFv-CD28-ζ T-cell expression of perforin and interferon-γ were essential for complete antitumor efficacy.</p><p><b>Conclusions:</b> Treatment with scFv-CD28-ζ–modified T cells was able to induce a host antitumor immunity in syngeneic mice. Complete tumor elimination by scFv-CD28-ζ–modified T cells required T cell–derived interferon-γ and perforin, indicating that cytotoxicity and cytokine secretion play a role in the <i>in vivo</i> response.</p></div>