Cancer vaccines: a brief introduction

From the time of the first documented vaccine against smallpox by Edward Jenner, developing an effective vaccine to prevent deadly disease caused by existing or newly emerging pathogens has been the goal of many microbiologists and immunologists. With a single exception, that of the rabies vaccine, all vaccines developed previously have been prophylactic, meaning that they are administered in order to prevent the onset of disease. The concept of a vaccine has slowly evolved to currently include a therapeutic vaccine, meant to ameliorate an existing disease state by potentially strengthening an ongoing but not fully effective immune response against a pathogen.  Further broadening of the concept of a vaccine has come about with the realization that in addition to eliciting an immune response where there was none, a vaccine could also be designed to change an existing immune response from one type to another. Most recently, vaccines are being considered not only for elicitation of immunity but also potentially for induction of tolerance [1, 2]. This concept has also increased potential targets of vaccines from diseases caused by pathogens to any disease that involves the immune system, such as cancer, autoimmunity and graft rejection. [3-6].

Challenges facing cancer vaccines
Choosing the right antigen and adjuvant are the sine qua non of an effective vaccine.

The “right” antigen: Antigens used in cancer vaccines should preferably be molecules that are different between normal cells and tumor cells ensuring that the immune response generated by vaccination will target for destruction antigen-bearing tumor cells and not normal cells [7, 8]. This requirement is satisfied more easily in the case of vaccines against pathogens because their antigens are all foreign to the host and thus immunity generated against them, in most instances, does not cross-react with normal host tissues. In cancer, most antigens are derived from mutated or modified self-proteins against which there is often a certain level of immune tolerance. This creates particular challenges for the appropriate design of vaccines that have to overcome this tolerance in order to elicit anti-tumor immunity without autoimmunity [9].

The “right” adjuvant: Adjuvants are diverse molecules that can activate antigen presenting cells (APC) to stimulate a potent and robust cellular immune response (T cells). Adjuvants can also activate natural killer cells or other cells of the innate immune system to produce cytokines that can promote survival of antigen-specific T cells [10]. Although at the present time, there are only two adjuvants approved worldwide for clinical use – aluminium-based salts (alum) and a squalene-oil-water emulsion (MF56) – many other molecules, such as cytokines, bacterial products (toll-like receptor (TLR) agonists), heat-shock proteins [11-13], microspheres [14, 15], virus-like particles [16, 17] and immunostimulatory complexes (ISCOMs) are being tested [18].

The “right” immune response: An effective vaccine must be able to generate and sustain a potent immune response that would ensure eradication and prevent recurrence of existing tumors, in the case of a therapeutic vaccine, or in the case of a prophylactic vaccine, prevent de novo tumor formation [19]. Thus the immune response generated must result in long-term memory to provide life-long protection from cancer. It is now clear that the generation of an immune response that can eliminate the tumor depends on the ability of a vaccine to activate both the innate and the adaptive immune system [20].  More importantly, the end result of this activation should be an immune response that is the “right” type for the tumor that is being treated.  Different types of immune responses include systemic versus mucosal immunity, T-helper 1 (Th1) versus T-helper 2 (Th2), [21, 22] or primarily antibodies versus primarily cytotoxic T lymphocyte (CTL). Recent realization that every vaccine is capable of simultaneous induction of effector cells as well as regulatory T cells [23](reviewed in [24] has added another requirement, that of preferential induction of effector T cells.

Tumor antigens, candidates for cancer vaccines
Since the pioneering work of Boon and Rosenberg leading to the isolation of the first human melanoma antigens [25-27], work on the discovery of tumor antigens has been pursued by many researchers employing many different methods [28-31].
Tumor antigens can be broadly classified into two categories: shared tumor antigens and unique tumor antigens. Shared tumor antigens are expressed by many tumors and either not on normal tissues or expressed by normal tissue in a quantitatively and qualitatively different form. Examples of such shared tumor antigens are the cancer testes antigens (MAGE, GAGE and NY-ESO1) (reviewed in [32]). Unique tumor antigens, on the other hand, are products of random mutations induced by physical or chemical carcinogens, and therefore expressed uniquely by individual tumors [33]. These include specific mutations in oncogenes, such as p53 and Kras (reviewed in [32]). An interesting variation on this theme are tumor-derived heat shock proteins that are being developed as cancer vaccines [34, 35].  The heat shock proteins themselves are conserved proteins but the tumor peptides bound to them are derived from both shared and unique tumor antigens.

Undefined tumor antigen-based vaccines
A recent report shows that colon and breast cancers contain on an average at least 11 different mutations in proteins involved in a wide range of cellular functions, including transcription, adhesion and invasion [36].  Many of these mutations are candidates for tumor antigens. This supports a long-held notion that one way to expose the immune system to many potential tumor antigens is to immunize with whole tumor cells.  This approach mimics many vaccines against infectious diseases that use the whole, attenuated forms of the pathogens.  The benefit of such vaccines is that it allows the immune system rather than the vaccinologist to select most immunogenic tumor specific antigens.  The danger is that in the presence of adjuvants, tolerance to normal molecules might be broken resulting in autoimmunity.

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