Identification of Relevant Cancer Antigens for Vaccine Development

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Implications for Cancer Vaccine Development

Three distinct design strategies can be used to construct cancer vaccine. These can be distinguished by the degree of purity of the resulting vaccine (Table 1). None is completely satisfactory, as none fully satisfies all the multiple requirements for a cancer vaccine. In fact, these strategies can result in vaccine formulations with mutually exclusive desirable properties (Table 2).

This is the traditional method to construct a cancer vaccine. The vaccine consists of whole tumor cells or nonpurified extract of these cells. The cells are usually admixed with an adjuvant, such as BCG [16] or Detox, [17] to improve potency. Other procedures to augment the immunogenicity of the tumor cells include infection with nonpathogenic virus, such as vaccinia or Newcastle disease virus, stripping cell-surface carbohydrates with neuraminidase, or conjugating strongly immunogenic haptens, such as dinitrophenyl (DNP), to the cells. [18] More recently, the tumor cells have been engineered to express cytokines, such as interleukin-2 (IL-2), granulocyte macrophage-colony-stimulating factor (GM-CSF), or gamma-interferon [19] -- which can upregulate antigen driven immune responses -- or HLA or other accessory molecules such as B7, which facilitate the interaction of tumor antigen with immune cells. [20]

The major advantage of nonpurified vaccines is that they are polyvalent -- they contain a broad representation of different tumor antigens. This design markedly increases the chances that the vaccine will contain the still unidentified antigens that are essential for vaccine activity and obviates the need to identify and purify each such antigen. In addition, the broad range of antigens present in the vaccine increases the likelihood that it will contain antigens present on the tumor to be treated, circumventing both the antigenic heterogeneity of tumors and the heterogeneity in the ability of individual antigens to stimulate immune responses in different persons. Lastly, stimulating immune responses to multiple targets on cancer cells increases the chances of killing these cells. Vaccines prepared from whole tumor cells may also be inherently more immunogenic, since vaccines lose potency as they are purified.

The major limitation of this approach is that most of the material in the vaccine consists of irrelevant cellular components, such that the desired tumor antigens account for only a very small fraction of the material in the vaccine. At best, this creates difficulties in reproducing, standardizing, and characterizing the vaccine. At worst, it may mean decreased potency, increased toxicity, and/or decreased effectiveness owing to the presence of suppressive factors or to competitive inhibition of immune responses induced by irrelevant antigens. In addition, the presence of multiple antigens is no guarantee that the vaccine contains all the relevant tumor antigens.

An alternate and more elegant approach is to formulate the vaccine from a pure antigen(s). Preparations in clinical trials include vaccines derived from gangliosides, [4] recombinant proteins, immunogenic peptides, [3] mucin-derived carbohydrates, [21] or anti-idiotype monoclonal antibodies. Again, a variety of adjuvants are used to increase the immunogenicity of the antigens. A favored one at present, particularly when using peptides, is the use of antigen-pulsed dendritic cells.

An advantage of this approach is that the concentration of tumor antigen(s) in the vaccine is much higher and can be quantitated easily. In addition, the purified vaccines are easier to characterize and to prepare in a reproducible manner, features that perhaps may ease the burden of obtaining approval by regulatory agencies. Being purer, they may in theory also be safer, although the safety record of nonpurified vaccines is excellent.

Unfortunately, pure antigen vaccines are associated with several problems. The major one is that the tumor antigens that are actually responsible for inducing clinically beneficial tumor-protective responses have not yet been identified. Thus, the actual antigen(s) that should be selected and purified to formulate such vaccines is still unknown. Identifying the correct antigen(s) is a formidable task, as it requires long-term, large-scale, phase III randomized trials of clinical outcome in patients treated with each purified tumor antigen being considered for vaccine construction. The expense and duration required for such trials preclude their use as a screening approach to evaluate vaccines. In addition, such vaccines will likely need to be constructed from a cocktail of purified antigens to circumvent the antigenic heterogeneity of tumors, the heterogenicity in patients' responses to antigens, and to increase their potency, thereby losing some of the advantages of purified preparations.

In an attempt to balance the advantages and disadvantages of vaccines prepared from whole tumor cells or pure antigens, a third vaccine design strategy has evolved -- to prepare the vaccine from a cellular fraction that is most likely to contain antigens relevant for vaccine therapy and depleted of material likely to be irrelevant. [22] The major advantage of this approach is that it retains the most critical elements for vaccine effectiveness -- a cocktail of antigens that can stimulate tumor-protective immunity and circumvent the heterogeneity in the antigenic properties of tumors and in patients ability to respond to these antigens -- while being much purer than vaccines prepared from whole tumor cells. However, these vaccines, too, may be difficult to standardize, and there is no guarantee that they include the most relevant and exclude the most irrelevant antigens.

Most of the work on partially purified cancer vaccines has been conducted with a polyvalent vaccine prepared from antigens shed into culture medium. The rationale for this approach is summarized below.

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