Cancer Therapy: Preclinical Chimeric Rat/Human HER2 Efficiently Circumvents HER2 Tolerance in Cancer Patients

Purpose:Despite the great success of HER2 vaccine strategies in animal models, effective clinical results have not yet been obtained.We studied the feasibility of usingDNA coding for chimeric rat/humanHER2 as a tool to break the unresponsiveness of T cells from patients with HER2-overexpressing tumors (HER2-CP). Experimental Design: Dendritic cells (DCs) generated from patients with HER2-overexpressing breast (n1⁄4 28) and pancreatic (n1⁄4 16) cancer were transfected with DNA plasmids that express human HER2 or heterologous rat sequences in separate plasmids or as chimeric constructs encoding rat/humanHER2 fusion proteins and used to activate autologous T cells. Activation was evaluated by IFN-g ELISPOT assay, perforin expression, and ability to halt HER2þ tumor growth in vivo. Results: Specific sustained proliferation and IFN-g production by CD4 and CD8 T cells from HER2-CP was observed after stimulation with autologous DCs transfected with chimeric rat/human HER2 plasmids. Instead, T cells from healthy donors (n 1⁄4 22) could be easily stimulated with autologous DCs transfected with any human, rat, or chimeric rat/human HER2 plasmid. Chimeric HER2-transfected DCs from HER2CP were also able to induce a sustained T-cell response that significantly hindered the in vivo growth of HER2þ tumors. The efficacy of chimeric plasmids in overcoming tumor-induced T-cell dysfunction relies on their ability to circumvent suppressor effects exerted by regulatory T cells (Treg) and/or interleukin (IL)-10 and TGF-b1. Conclusions: These results provide the proof of concept that chimeric rat/humanHER2 plasmids can be used as effective vaccines for any HER2-CP with the advantage of being not limited to specific MHC. Clin Cancer Res; 20(11); 1–12. 2014 AACR.