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Developing Models to Facilitate the Appropriate Selection and Effective Targeting of Candidate Antigens for Specific Cellular Immunotherapy of Prostate Cancer

机译:开发模型以促进适当选择和有效靶向候选抗原用于前列腺癌的特异性细胞免疫治疗

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Immunologically targeting prostate cancer has received increasing attention, 1- 3, in part because collateral normal tissue injury is an acceptable toxicity. However, many questions must be resolved, including the nature of antigens that can be effectively targeted, the requisite T cell response, and the relationship between tumor development and progression and the immune system. Many candidate human prostate cancer antigens have been identified, including PSA, PSMA, PAP, PSCA, and TARP 2, 4-11. These targets, and others suggested by analysis of differential gene expression 6, 12-15, include cytosolic, transmembrane, and secreted proteins, which interface differently with the immune system. Predicting which one or class of antigens might be most effectively targeted is difficult to resolve in human trials, and thus the use of relevant mouse tumor models might provide essential insights into prostate cancer immunobiology that can then be translated to human clinical trials. The Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model, developed by our collaborator Norm Greenberg, appears particularly useful as a foundation for addressing these questions. The TRAMP model is focused on a mouse strain genetically engineered to express from a minimal rat probasin promoter the pro-oncogenic SV40 early genes in prostatic epithelium in a developmentally and hormonally regulated fashion 16. Transgene expression, associated with puberty and increased androgen levels, can be detected in prostate tissue as early as 4 weeks of age 17. Disease begins as prostatic intraepithelial hyperplasia (PIN), and progresses to well-differentiated adenocarcinoma as early as 12 weeks 17, 18, to moderately differentiated over the next 6-weeks, and to poorly differentiated carcinoma by 24-30 weeks. Distant metastases, by both hematogenous and lymphatic spread, have been detected as early as 12 weeks, and approach 100% by 24-30 weeks of age 18.

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