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

While a widely efficacious tumour vaccine is not yet available, a great deal of progress has been made in the development of effective cancer vaccines. Vaccines designed to treat patients with metastatic cancer have shown the first evidence of efficacy in the clinic. In this chapter, we will focus on efforts in which recombinant poxviruses have been used in the clinical and preclinical treatment of cancer. This work is based on a ‘reductionistic’ approach which has made possible an understanding of the interactions between the immune system and tumour cells on a molecular level. The thrust of this work comes from observations, discussed at greater length below, that infection of a tumour-bearing animal with a recombinant poxvirus encoding a tumour-associated antigen can result in tumour destruction and prolong the survival of the animal.

While viruses are demonstrably immunogenic, tumour cells have notoriously poorimmunogenicity.The reasons for this apparent lack of immunogenicity (as discussed in Chapter 1) may be that cancer antigens are generally not presented to the immune system in a micro-environment that favours the activation of immune cells. Although no single known mechanism can explain poor tumour immunogenicity in all experimental models studied, the molecular bases can be separated conceptually into four distinct groupings: (1) lack of expression of co-stimulatory molecules; (2) production of immuno-inhibitory substances; (3) poor antigen processing and presentation; and (4) variability in the expression of antigen by tumours.

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.