**4.2 HER-1, HER-3, HER-4**

HER-1 is a non-tissue specific peptide that has been implicated in the oncogenesis of multiple malignancies including breast, colorectal, pancreatic adenocarcinoma, brain glioma multiforme and non-small cell lung cancer [60]. The Food and Drug Administration (FDA) recently approved the use of a novel HER-1 directed tyrosine kinase inhibitor, erlotinab, in conjunction with other established medications for the treatment of advanced pancreatic and non-small cell lung cancers [61]. In addition, cetuximab is an anti-HER-1 monoclonal antibody that has been approved to treat patients with advanced colorectal cancer [62]. Although no anti-tumor vaccines have been formulated that are directed against HER-1, it is a feasible possibility to target this protein in order to develop an anti-HER-1 T cell response.

Targeting Molecular Pathways

**cancer** 

well tolerated and caused minimal toxicity [18].

breast cancer vaccines is beyond the scope of this chapter.

circumvent tumor escape mechanisms.

**5.1 Dendritic cells** 

for Prevention of High Risk Breast Cancer: A Model for Cancer Prevention 139

The feasibility of HER-2 targeted vaccines has been demonstrated in animal models [71]. In addition, a number of phase I and II trials using HER-2 based vaccines of all types have been performed in patients with high risk breast cancer. The vaccines in all of these studies were

**5. Development of dendritic cell vaccines for the treatment and prevention of** 

The concept of producing a vaccine aimed at specific breast cancer antigens is theoretically straightforward although the details and execution are obviously complex to carry out. There are several different vaccine approaches under investigation for the treatment of early and late stage breast cancer (dendritic cells, whole tumor cells, peptide-based and viralbased) [72, 73]. Breast cancer vaccines utilizing all of these different strategies are in various stages of development [18, 38, 72-74]. A comprehensive review of the published data on all

The advent of dendritic cell (DC) vaccines, propelled by the ability to culture human DC cells, has provided promise for a novel vaccine strategies [75]. Despite preclinical evidence and high expectations for the potential effectiveness of DC-based cancer vaccines, initial results of clinical trials were somewhat disappointing with discordant tumor response rates [43, 76, 77]. However, continued interest in therapeutic possibilities of DC vaccines has led to recent successes and promising data in breast and other cancers. The efficacy of DC vaccines continues to improve as efforts have been made to optimize DC vaccines and

DC vaccines represent one of a number of strategies for vaccinating patients against tumorassociated antigens. DCs are the most powerful of the APCs and are the primary means by which naïve T cells become immunized to specific antigens. DCs are unique in their ability to activate both the innate and adaptive immune systems. Immature DCs arise from progenitors in the bone marrow and then enter the blood stream and circulate throughout the peripheral tissues where they are exposed to foreign antigens. After capturing antigens, DCs undergo a maturation process that ultimately guides their travel to secondary lymphoid tissues. Once in the regional lymph nodes, the DCs process the captured antigen and then display the antigen as a peptide on their MHC molecules. DCs present the

In addition to T cell stimulation, contact with DCs causes activation of B lymphocytes which leads them to differentiate into plasma cells that subsequently release antibodies targeted against the initial pathogen. After antigen exposure, DCs also release cytokines which can activate the cells of the innate immune system, including eosinophils, macrophages, and NK cells. In this way, DCs are capable of activating both the innate and adaptive immunity and

No standard protocol exists for the production of DC vaccines, but there are some general components that are often involved. First, the DCs are collected from the patient via

peptides to naïve T cells resulting in T lymphocyte expansion and differentiation.

are central to the communication between the two immune systems [36, 78-80].

**5.2 Production and adminstration of DC vaccines** 

Fig. 1. The EGF receptor family.

HER-3 has a more ambiguous role in tumorigenesis compared to the other members of the EGFR family. It is frequently expressed in breast, ovarian and lung cancers [62-64]. The role of HER-4 in relationship to tumor development is also not clear. HER-4 mutations have recently been shown to augment proliferation and cell survival in melanomas. Agents that target HER-4 may be found to be effective against melanoma and other cancers [60].
