Human cancer vaccines

Vaccines have traditionally been used to generate protection against infectious pathogens; they have been used successfully to control, or in the case of smallpox, eradicate infectious agents [1]. The diseases targeted by vaccines, in the main, have a rapid onset and life-threatening consequences. Persistent infections can also result in the development of life-threatening diseases over a longer time frame. Several human cancers are caused by infectious agents and overall these cancers have been estimated to constitute 17.7% of the global cancer burden [2]. Recently, a vaccine to prevent infection by oncogenic human papillomaviruses has been approved for use by the US Federal Drugs Administration (FDA). There has been much publicity about these vaccines for cervical cancer as “Cancer vaccines”, however these are really anti-viral vaccines that are similar to conventional prophylactic vaccines i.e. they induce a host neutralising antibody response to prevent infection. The vaccines that will be discussed in this issue are different in their mode of operation in several important aspects. Cancer vaccines aim to treat established disease, rather than preventing it. This is achieved in the main by induction of a strong T cell response, although some cancer vaccines contain antigens that are capable of inducing both antibody and T cell responses. Prophylactic vaccines are generally given in childhood and provide long-lived immunity. By contrast, cancer tends to be a disease of the ageing population, so cancer vaccines will have a different target population, and at present the duration of immunity is unknown. A comparison of the two types of vaccine is shown in Table 1 .

Table 1.

Comparison between conventional prophylactic vaccines and therapeutic cancer vaccines

Conventional vaccines	Cancer vaccines
Promote resistance to disease	Promote therapy of disease
Mostly administered to children	Mostly administered to adults
Vaccinees are disease free	Vaccinees have established disease
Induce neutralising antibodies	Induce T cells
Disease resistance long lasting	Duration of efficacy unknown
Safety tested in large cohorts	Safety tested in small cohorts

There are, however, many similarities between conventional prophylactic and therapeutic cancer vaccines, not least in the delivery technology used. Traditionally, prophylactic vaccines used attenuated or killed pathogens, however this approach is ineffective when dealing with outbreaks caused by new pathogens such as SARS-CoV or Avian Influenza. Increasingly, modern vaccines whether prophylactic or therapeutic, focus on subunit immunogens in the form of proteins, peptides or nucleic acids. These then require delivery either in conjunction with adjuvants, or associated with vector systems that have adjuvant properties e.g. recombinant viruses or heat shock proteins. In concert with developments in “vaccinology” there have been tremendous advances in our understanding of immunology and cancer cell biology. This has lead to intense research into the development of cancer vaccines. The field is now poised at a key juncture, as several candidate vaccines have progressed to phase III clinical trials, and a dendritic cell based vaccine for prostate cancer (Dendreon corporation) has been given fast-track status for licensing by the FDA.

The articles in this issue provide a wide coverage of the field, describing relevant vaccine and host parameters that need to be considered in cancer vaccine design. Drs Tabi and Man look in more detail at some of the challenges involved in cancer vaccine development, particularly focussing on tumour cell biology and how tumours can escape from the immune system. They also provide a summary of the current cancer vaccines in commercial development, and review the different approaches taken. This is followed by three articles focussing on individual vaccine approaches. Harrop et al. review the use of recombinant viral vectors as cancer vaccines, describing the development of candidate vaccines and their clinical testing. Van der Burg and colleagues describe the rationale behind the use of synthetic peptide vaccines, and the key parameters involved in maximising their efficacy. There are then three articles that detail how the host environment can also influence the success of cancer vaccines. Slettenaar and Wilson review how chemokines can influence the migration and function of immune effector cells. Betts et al review how these effector cells can also be regulated by a subset of naturally occurring T regulatory cells (Tregs). They describe the accumulating evidence in mice and humans that Tregs can be detrimental to anti-cancer responses, and how manipulation of Tregs can be beneficial to cancer vaccination strategies. Finally Nowak and colleagues review another system for improving the performance of cancer vaccines, by using them in combination with standard chemotherapy treatments.

Despite recent research developments that provide the impetus for new clinical trials, the field of human cancer vaccines remains challenging. Recent high profile set backs for companies working on therapeutic vaccines against melanoma (Cancervax), kidney (Antigenics) and pancreatic cancer (Therion), are perceived to have a negative effect on the field. This is unfair because cancer vaccine companies use different specialised technologies for their vaccines, and target different cancers. The major challenge remains in obtaining a significant clinical effect in patients with advanced disease, who have failed with conventional therapies. The conventional wisdom was that the combination of advanced disease, and chemo or radiotherapeutic treatments, would constrain development of immune responses following vaccination. However it is becoming increasingly appreciated that standard treatments for cancer such as chemotherapy [3] and radiation therapy [4] can have a positive immune effect by direct and indirect mechanisms. This has exciting clinical implications. First the testing of many cancer vaccines may have been sub-optimal, as trials have been carried out after patients have failed standard treatments. Second, it may be beneficial to combine treatments to have a synergistic effect, and this has the further benefit to allow vaccine trials to be “piggy-backed” onto large scale trials of chemotherapeutic and radiotherapeutic regimes.

So what are the future prospects for cancer vaccines? The successful development of monoclonal antibodies as licensed cancer therapeutics, particularly for lymphoid cancers, provides some key pointers [5]. Firstly, there was a long lag period between discovery (1970s) and therapeutic success (late 1990s). Secondly, there were incremental improvements in technology that lead to greater efficacy. Thirdly, that for a given target, the anti-cancer effects could be mediated through multiple mechanisms including non-immunological ones. Fourthly, the realisation that larger doses of antibodies were needed for efficacy. Cancer vaccines have the potential to target a much broader range of cancers than monoclonal antibodies, but patience and some fortitude will be needed for this potential to be realised.