This final chapter aims to update the reader with recent developments in the field of cancer vaccines.

Dendritic cells (DCs) and the control of T-cell activation

A key area of basic research likely to influence the development of cancer vaccines is the increasing understanding of the processes whereby T cells are activated or anergized by interaction with DCs.

An important new concept is of early events which cause immature DCs to sense and relay information about the nature of the danger which subsequently influences the character of the responses. The first step in the activation process for DCs derives from the local microenvironment (pathogen-induced or-derived, or constitutively produced tissue factors) when encountering a specific damage or danger. Following DC maturation and differentiation with presentation of processed antigen and acquisition of co-stimulatory potential, there is a polarization of the T-helper type of response selected in the draining lymph node (LN). Thus, control of the development of naíve T-helper cells into T-helper type 1 (CTL, NK etc.) or type 2 (B-cell activation, isotype switching, etc.) subsets is biased by the first experiences of the DC. Therefore, specific T cells are presented not only with the antigen structure but also the nature of the pathogenicity (danger). Since the window of sampling for such DC-mediated polarization is short it may not necessarily be the same in every LN, allowing for independent regulation.

Features of breast cancer

Breast cancer is the most common malignancy in women in the ‘developed’ world, with the number of new cases per year in the UK and USA being 34000 and 180000, respectively. Breast cancer is rare below the age of 30 but the incidence increases up to the age of 50. Beyond the age of 50, the incidence continues to rise but more slowly compared with premenopausal women. Although the incidence of breast cancer is increasing, recent data suggest that the mortality rate is decreasing. Nevertheless, with a death rate of 20 to 25 per 100000 in the West and a prevalence over three times the incidence, breast cancer continues to be a significant public health problem. Factors conferring an increased risk of breast cancer include mutations in the breast cancer susceptibility genes BRCA-1 and BRCA-2. While mutations in these genes account for the majority of familial breast cancers, they account for only 5 to 10% of all breast cancers. Other factors conferring increased risk include the presence of atypical hyperplasia and carcinoma in situ (cytologically malignant cells confined within a duct or lobule). Obesity, high alcohol consumption, prolonged use of oestrogens and previous radiotherapy to the breast are thought to confer an increase in risk of less than twice the background risk.

The majority of cases of breast cancer present with a lump in the breast which may be associated with nipple discharge and/or deformity of the breast.

Introduction

A correlation between human papillomavirus (HPV) infection of cervical epithelial cells and cervical cancer has been unequivocally established. A significant proportion of early-stage precancerous lesions, cervical intraepithelial neoplasia (CIN) and essentially all cervical carcinomas are positive for certain high-risk types of HPV. The potential for immunotherapeutic intervention directed against viral targets expressed in cervical neoplasia is discussed in this chapter.

Human papillomaviruses and cervical neoplasia

Epidemiology

Human papillomaviruses (HPVs) are the most common sexually transmitted viruses and there are over 90 different HPV types described so far, of which about 35 types infect the anogenital tract. The risk of infection is approximately the same for men as for women, but in general the infection rate for HPV is greater at a younger age (below 25 years) than later in life. Most HPV infections are subclinical and go unnoticed, although some infections may progress into benign lesions, like the common genital warts in the anogenital region. HPV genomic DNA is detected in approximately 10–15% of the sexually active adults in the United States, whereas approximately only 1% of the population show clinical manifestations of infection, cervical intraepithelial neoplasia CIN. Only a minority of these CIN lesions will later progress into cervical carcinomas and adenocarcinomas.

Analysis of biopsy material of CIN lesions and cervical carcinomas showed the prevalence of HPV 6 or HPV 11 in low-grade CIN lesions, whereas HPV 16 and HPV 18 dominated in high-grade CIN and cervical carcinoma samples.

Introduction

While the term ‘magic bullet’ has resulted in the association of cancer immunotherapy with the use of monoclonal antibodies to target tumours, it is clear that the most effective way to exploit the immune system to clear tumours is by generating tumour-specific cytotoxic T cells (CTLs). The major question for cancer immunotherapy must thus be, how can an effective antitumour CTL response best be elicited? The surprisingly universal answer that has emerged from a number of different studies is that this requires the stimulation of T cells by a specific antigen-presenting cell (APC), the dendritic cell (DC). DCs were first described as the morphologically distinct Langerhans cells in the skin and have since been shown to be the most efficient APC for the activation of naíve T cells. The main impetus for their study as APCs was the development of simple methods for the isolation of DC-precursors from blood and the expansion of these cells in vitro to yield potent APCs. For clinical researchers, DCs have the promise of providing a vehicle for effective anticancer immunotherapy. However, many questions remain. Is a defect in APC function a significant component of the failure of the immune system to eradicate cancer? Is the restoration of competent APC function sufficient to permit the execution of an effective CTL response (or is the augmentation of DC function sufficient to overcome other defects in a cell-mediated immune response to cancer)? What are the optimum schedules for the preparation and administration of DC?