Identification of Relevant Cancer Antigens for Vaccine Development

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Procedures to Augment the Immunogenicity of Antigens in Cancer Vaccines

Tumor-associated antigens are weak immunogens -- as evidenced by the difficulties of detecting anti-tumor immune responses in patients with cancer and the failure of vaccine treatment to stimulate such responses in many patients. Hence, another important aspect of vaccine design is the selection of procedures that can augment the potency of vaccines. Broadly defined, such procedures are called adjuvants.

Several general adjuvant strategies are available. These are not mutually exclusive, and it is probable that combinations of them will have additive or synergistic effects. One is to modify the vaccine itself. The physical or biochemical properties of the tumor antigens in the vaccine can be altered to render it more immunogenic. Examples of this approach include physical aggregation of the antigens, neuraminidase treatment, and coupling of the antigens to strongly immunogenic antigens, such as keyhole limpet hemocyanin (KLH).

Another approach is to use "classical" adjuvants -- substances found empirically to increase the immunogenicity of vaccines, such as alum, BCG, Freund's adjuvant, and various oil-in-water mixtures. Usually, the more potent the adjuvant, the more of a local skin reaction it causes. For that reason potent adjuvants, such as Freund's, are not recommended for use in humans. A number of newer adjuvants, such as SAF-M or QS-21, are claimed to retain the potency of mycobacterial adjuvants without their toxicity. Other adjuvant approaches include infecting tumor cells with live nonpathogenic viruses, such as vaccinia or Newcastle disease virus, presenting the antigen on specialized cells, such as dendritic cells, coating the tumor antigens onto small particles to enable their presentation in multimeric units, encapsulating them into liposomes or other slow-release vehicles to increase the half-life of the antigen, using gene transfer techniques to express the antigen on the surface of nonpathogenic organisms, such as vaccinia; or xenogenization, a process in which the vaccine is mixed with an unrelated strong immunogen.

Another approach involves using immunomodulators, such as IL-2, GM-CSF, or other cytokines, alone or in combination, to more vigorously drive forward immune responses stimulated by vaccines. These clearly can be effective, as evidenced by several clinical trials in which encapsulating a polyvalent melanoma vaccine into liposomes containing IL-2 or GM-CSF markedly increased the ability of the vaccine to induce DTH responses. [26,27]

The broad range of different approaches available to boost the potency of vaccines, the probability that some of these approaches can be combined, and the lack of information on their relative effectiveness in humans make the process of selecting the most appropriate procedure difficult. This process is further complicated by the fact that different procedures potentiate different types of immune responses preferentially and that the same procedure can have different effects on the immune system depending on which antigen it is used with. Lastly, it must be remembered that some of these procedures are toxic in their own right and/or require repeated administration in a hospital or physician's office. Clearly, these features negate 2 of the qualities most desired in tumor vaccines: safety and ease of use.


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