Introduction

The volume has covered aspects of the development of therapeutic cancer vaccine strategies against a variety of molecular targets and diseases with a strong bias to the generation of specific cell-mediated (CTL) responses. This brief overview will consider some common lessons with respect to: (1) target molecules; (2) delivery systems; and (3) evaluation methodology relevant to success of immunotherapy for cancer. A summary of the rationale, optimism, limitations and further keys for development for the various cancer vaccine approaches outlined in this volume is given in Table 14.1.

Target molecules

Viral targets

When there is an established viral aetiology for particular malignancies such as HPV with cancer of the uterine cervix or EBV with nasopharyngeal carcinoma, virally encoded tumour-associated molecules offer exogenous cancer vaccine targets where there is unlikely to be immunological tolerance at the immune repertoire level. However, prevention will always be better than cure, so immunization to reduce infection is likely to be more efficacious and cost-effective than immuno-therapeutic approaches. This is clearly shown by the example of the association of hepatitis B virus with hepatocellular carcinoma, where classical prophylactic vaccination programmes have dramatically influenced the incidence of the cancer in at risk populations. A similar strategy for the high risk papillomaviruses associated with cervical neoplasia is also planned.

Overall, the implementation of worldwide immunization against viruses such as HPV, where the malignant disease is a late complication of the viral infection, may be difficult.

Introduction

As early as the turn of the century, Paul Erhlich suggested that ‘aberrant germs’ (tumours) occurred at a high frequency in all humans but were kept in check by the immune system. Developments in understanding of the protective roles of antibodies and phagocytes in infectious disease in the early years of the century led to attempts to stimulate the immune system to reject tumours. The New York surgeon, Coley, used bacterial vaccines to cause a ‘commotion in the blood’ and occasional regressions following treatment or occurring spontaneously were taken as evidence of an effective immune response.

Early experimental work demonstrated that transplanted (allogeneic) tumours usually regressed. However, it was soon realized that this was a consequence of the genetic disparity of host and tumour and was revealing immune responses to foreign tissue transplants, not tumour antigens. However, what these early studies did show was that a strong immune response could prevent the growth of a tumour and cure the animal.

Immune surveillance

In the 1950s, Burnett and Thomas restated Erhlich's idea as the theory of ‘immune surveillance’. It was proposed that the immune system was able to recognize abnormal cells, which were destroyed before they could develop into a tumour. Since tumours do develop in many individuals it was also suggested that the immune system played a role in delaying growth or causing regression of established tumours.

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.

Introduction

Cervical cancer and pre-cancer form a disease continuum ranging from cervical intraepithelial neoplasia (CIN) through microinvasion to invasive carcinoma; about 70% of the tumours are squamous and 30% are adeno- and adenosquamous carcinomas (Buckley & Fox, 1989). Most tumours are thought to develop from an area of intraepithelial neoplasia within the transformation zone (Coppelston & Reid, 1967). Cervical cancer is estimated to be the second most common female cancer with approximately 500 000 new cases per annum worldwide (Parkin, Laara & Muir, 1980). Sexually transmitted infections are recognized as one of the major risk factors and the active agents are thought to be specific types of human papillomavirus (HPV) (Munoz et al., 1992).

Papillomaviruses are small DNA viruses associated with benign and malignant proliferative lesions of cutaneous epithelium. Over 60 different types of papillomavirus have been described and they can be segregated into groups distinguished by DNA sequence homology and the specific lesions with which they are associated (de Villiers, 1989). HPV 6 and 11 are found most commonly in cervical condyloma, benign lesions that tend to regress spontaneously, and low-grade CIN. HPV 16 and 18 are the types most commonly associated with high-grade CIN lesions and invasive carcinoma of the cervix. The viruses will replicate only in specific differentiation stages of epithelia, which limits the use of in vitro culture methods for producing HPV. To circumvent this, molecular biological techniques have been utilized extensively to characterize HPV.