Targeting Tumor Antigens Antigen Specific Vaccines

The ideal breast cancer vaccine would induce broadly reactive immunity to multiple types of breast cancer without causing clinically significant autoimmunity and, most important, be clinically effective. One approach to minimize autoimmunity and enhance specificity of vaccines is to target them to specific protein antigens that are overexpressed on the tumor cells but that have limited distribution in normal tissue. Many breast cancer tumor antigens are also expressed on tumor cells in other epithelial-derived cancers, such as ovarian cancer and colon cancer, and have been targeted in early-phase clinical trials in breast cancer and other solid tumors. In addition to MUC-1, HER2/neu, and telomerase (see subsequently), target antigens include CEA (59,60), cyp1B1 (61), survivin (62,63), and others (Table 1).

MUC-1

Overexpression and aberrant glycosylation of mucin-1 (MUC-1) antigen by epithelial tumors results in endogenous antibody responses in cancer patients to

MUC-1 antigen (64). This finding has led to the identification of MUC-1-derived peptide epitopes that induce T-cell responses. MUC-1-based clinical trials have used peptides (65-69), protein (70), pulsed dendritic cells (61), or keyhole limpet hemocyanin (KLH) adjuvant (31).

HER2/neu

The HER2/neu antigen is a well-known target of antibody-mediated immunotherapy in breast cancer. The initial demonstration of multiple HLA-A2-binding peptides derived from the HER2/neu protein has led to multiple clinical vaccine trials. Initial studies using peptide and adjuvant have demonstrated safety with minimal toxicity (61,71-73), but induced cytotoxic T-cells that failed to lyse tumor cells (21). To augment CD4+ T-cell immunity, HER2-derived class II peptides (26,74), or the HER2 intracellular domain (75,76), have been used for vaccination. A recent study of vaccination of high-risk patients in the adjuvant setting showed a trend toward improved disease-free survival in patients who received a HER2 peptide-based vaccine (85.7% vs. 59.8% in unvaccinated patients).

hTERT

The catalytic subunit of telomerase, hTERT, is a widely expressed tumor antigen, present in more than 85% of all human cancers (22). Initial clinical trials of dendritic cells pulsed with hTERT-derived peptides or hTERT RNA resulted in measurable hTERT-specific immunity (78,79), but hTERT peptide vaccination with adjuvant generated T-cells that did not recognize endogenously-processed telomerase (80).

Overall, these antigen-specific therapies have been well tolerated, with minimal toxicity, but only sporadic disease responses have been observed. The majority of these vaccines have been tested in the advanced disease setting. The optimal method of delivery of tumor antigens is not yet known, although many approaches have been tried (Table 1). These include adoptive immunotherapy with ex vivo expanded T-cells (81), peptide-based vaccines, proteins, RNA, DNA, and viral vectors such as vaccinia and fowlpox, that also encode three costimulatory molecules [CD80/B7.1, ICAM-1, and LFA-3; designated TRICOMâ„¢ (59)].

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