Her-2 vaccines: Mechanism of action and clinical implications .

摘要

Her-2 overexpression which occurs in 25-30% of breast cancers, is associated with a poor prognosis, making Her-2 an important target of cancer therapy. To compare the efficacy of DNA versus cell vaccines that target Her-2, wild type and human Her-2 transgenic (Tg) mice were immunized by i.m. electrovaccination with pGM-CSF and pE2TM encoding Her-2 extracellular and transmembrane domains or xenogeneic SKOv3 cells, a human ovarian cancer cell line with amplified Her-2. In wild type C57BL/6 mice, 2 time vaccination with DNA and cell vaccines induced comparable levels of Her-2 antibody (Ab) at 41.9 +/- 17 and 45.1 +/- 22 mug/ml, respectively, in BALB/c mice, 50.6 +/- 28 and 33.6 +/- 12 mug/ml, respectively. A more profound T cell response in BALB/c mice was generated by DNA vaccine at 694 +/- 23 IFN-gamma producing T cells/106 splenocytes, compared to 71 +/- 9/10 6 by the SKOv3 vaccine. To test the efficacy, tolerant hosts were vaccinated four times after regulatory T cell depletion with CD25 monoclonal Ab (mAb). Her-2 Ab response induced by DNA and SKOv3 vaccine was comparable at 109.3 +/- 43 and 93.9 +/- 26 mug/ml, respectively. In C57BL/6 Her-2 Tg mice, only low level Ab was induced by either DNA or cell vaccine indicating genetic regulation of Her-2 immune reactivity. In (C57BL/6xDR3) Her-2 Tg mice that expressed the thyroiditis susceptible allele, HLA-DR3, DNA vaccine induced modest Ab at 35 +/- 28 mug/ml. But SKOv3 induced significantly higher levels of Her-2 Ab at 117 +/- 35 mug/ml, suggesting additional genetic regulation of Her-2 activity. DNA vaccine provided greater protection against Her-2+ tumors compared to cell vaccine, indicating DNA as the preferred vaccine formulation.; Her-2/neu+ tumor cells resistant to antibody and/or receptor tyrosine kinase inhibitor (RTKI) are emerging in treated patients. To investigate if such resistant tumor cells can be controlled by active vaccination, four BALB/c mouse mammary tumor (MMT) lines expressing rat neu were tested. TUBO and Bam1a were established from spontaneous tumors of neu transgenic mice. Bam IR-5 was derived from Bam1a by serial passage in gefitinib containing medium and D2F2/neu was a hormone induced mammary tumor transfected with neu. Treatment of TUBO and Bam1a with gefitinib or anti-neu antibody reduced cell proliferation and phosphorylation of neu, ERK and Akt. Gefitinib had little or no effect on the proliferation or signaling of Bam IR-5 and D2F2/neu cells. Anti-neu antibody inhibited Bam IR-5 proliferation slightly, but had no effect on D2F2/neu cells. Therefore, TUBO and Bam1a are sensitive to both antibody and RTKI. Bam IR-5 is resistant to RTKI, and less sensitive to antibody. D2F2/neu is resistant to both. Neu DNA vaccination induced antibody and T cell responses to neu and completely protected mice from these four tumors. After depleting CD4 and CD8 T cells in immunized mice, protection against Bam IR-5 and D2F2/neu was diminished 60% and 30% respectively, yet protection from TUBO and Bam1a tumors was not tempered. These results demonstrate the rejection of drug and antibody resistant tumor cells by vaccine activated T cells. Anti-neu CD8 T cells response induced by pcytE2 or pcytneu in the absence of anti-neu Ab protected 75%-100% mice from all drug sensitive or resistant tumor cells independent of drug/Ab resistance, further supporting the therapeutic effect of vaccine induced T cells. These results warrant vaccination of patients undergoing antibody or RTKI therapy for Her-2 positive tumors.