Chimeric Rat/Human HER2 Efficiently Circumvents HER2 Tolerance in Cancer Patients

Abstract

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 using DNA coding for chimeric rat/human HER2 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 (n ¼ 28) and pancreatic (n ¼ 16) cancer were transfected with DNA plasmids that express human HER2 or heterologous rat sequences in separate plasmids or as chimeric constructs encoding rat/human HER2 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 ¼ 22) could be easily stimulated with autologous DCs transfected with any human, rat, or chimeric rat/human HER2 plasmid. Chimeric HER2-transfected DCs from HER2-CP were also able to induce a sustained T-cell response that significantly hindered the in vivo growth of HER2 þ 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/human HER2 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); 2910-21. Ó2014 AACR.

Nonviral Oncogenic Antigens and the Inflammatory Signals Driving Early Cancer Development as Targets for Cancer Immunoprevention

“…The serum isolated from HuRT-DNA vaccinated mice was able to inhibit the growth of huHER-2 positive tumors in immunodeficient xenograft-carrying mice (25). The results of this study show that chimeric human/rat HER-2 plasmid vaccine is a promising immunopreventative treatment for its ability to break immunological tolerance to huHER-2 in a huHER-2 tolerant host (25, 26). The chimeric human/rat HER-2 plasmid vaccine can also generate robust memory via production of high levels of specific anti-huHER-2 antibodies, which is an important component of any preventive vaccine (25).…”

“…Despite the widespread clinical use of HER-2 targeted small molecule inhibitors and monoclonal antibodies, trastuzumab and pertuzumab, there remains a lack of HER-2/neu prophylactic and therapeutic vaccines implemented in the clinic (25, 26). In a study conducted by Giovanni et al, FVB-huHER2 transgenic mice were vaccinated with tumor cells expressing human HER-2 with recombinant IL-12 adjuvant (HER-2 cell vaccine) or chimeric human/rat HER-2 DNA plasmid (HuRT-DNA vaccine) (25).…”

Microenvironment, Oncoantigens, and Antitumor Vaccination: Lessons Learned from BALB-neuT Mice

“…As a consequence, the predominant effector T-cells in the TME are presumably constituted of low avidity OA-specific T cells whose activity is inhibited by Tregs that first expand in the spleen and tumor draining lymph nodes during cancer progression and in TME in later phases [100, 132, 133]. This situation reproduces what normally happens in tumor bearing patients [134] and is part of the ability to suppress immune reactivity that the tumor acquires during progression [104]. Indeed, natural immune surveillance somehow counteracts Treg expansion in the early phases of carcinogenesis in BALB-neuT mice.…”

Gastric cancer: The times they are a-changin’

“…have not yet been obtained [75] . HER2 vaccines, DNA or peptidebased, are studied mainly for breast cancer, often in combination with other HER2 targeted therapies [76] .…”