Identification of Relevant Cancer Antigens for Vaccine Development

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Rationale for Preparing Partially Purified Cancer Vaccines From Shed Antigens

Partially purified cancer vaccines address the most essential requirements of cancer vaccines: the need to include antigens that can stimulate tumor protective immunity and that circumvent the antigenic heterogeneity of tumors and the heterogeneity in patients' immune responses to these antigens. This design strategy seeks to retain the advantages of constructing cancer vaccines from whole tumor cells and from purified tumor antigens, while minimizing the problems associated with each of these approaches. One way to prepare such a vaccine is to use material shed by viable tumor cells into culture medium.

Tumor cells rapidly release into culture medium a broad range of molecules, including tumor antigens, expressed on their external surface. This process, which is called shedding, is of interest because cell-surface material is released much more rapidly than the bulk of unrelated cellular material in the cytoplasm or nucleus of the cells. Consequently, shed material is highly enriched in cell-surface antigens since it is separated from poorly shed cytoplasmic and nuclear material. Shed material provides a simple means of obtaining a broad range of cell-surface tumor antigens in a partially purified form.

The major advantages of this method of vaccine production are 2-fold. It provides for a vaccine that is both polyvalent and partially purified. As with nonpurified vaccines, it results in a vaccine that contains a broad range of tumor antigens. The polyvalent nature of the vaccine confers a number of advantages that have been described above. The range of antigens in the vaccine can be further increased by preparing the vaccine from a pool of cancer cells, selected because they express different patterns of tumor antigens. As shed antigens are partially purified, they retain some of the advantages of pure vaccine preparations. In addition, the antigens in shed vaccines are more likely to be clinically relevant, as they are expressed on the external surface of the cancer cells, where they can be seen by anti-tumor immune responses. Lastly, the procedure for preparing shed antigen vaccines is simple and can easily be applied to make vaccines against any cancer.

Vaccines prepared using this strategy appear to be clinically effective. We have used this strategy to construct a polyvalent, shed antigen vaccine for melanoma. The vaccine contains multiple melanoma-associated antigens, including MAGE-1, MAGE-2, MAGE-3, MART-1/Melan A, tyrosinase, gp100, TRP-2, and other antigens ranging in size from 45 to 110 kD that are expressed by melanoma cells in vivo. [6,7,15] The vaccine has minimal toxicity. [22] There have been minor side effects in only 3 of more than 600 patients treated with multiple vaccine immunizations for periods of up to 5 years. The vaccine stimulates antibody responses to multiple antigens expressed by melanoma in vivo, [6] peptide-specific CD8+ T-cell responses to important melanoma antigens, including MAGE-1, MAGE-3, MART-1/Melan A, tyrosinase, gp100, MC1R, and TRP-2, [7,15] and cellular immune responses that infiltrate into melanoma nodules in vivo. [24] The vaccine appears to be clinically effective, as the recurrence-free and overall survival of vaccine-treated patients with resected stage III melanoma are both prolonged by 50% compared with historical controls. [22,24] More convincingly, in a double-blind, prospectively randomized, placebo-controlled trial involving 38 patients with resected AJCC stage III melanoma, the median recurrence-free survival was 2.5 times longer (P = .03 by Cox proportional hazard analysis) and overall survival 40% longer in patients treated with the melanoma vaccine compared with similar patients treated with a placebo vaccine. [25]

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