IMMUNOLOGIC THERAPY OF PROSTATE CANCER

前列腺癌是目前男性最常见的癌症。六十 确诊时新病例的百分比不受器官限制。 前列腺癌一旦发展到晚期，治疗的影响就是 边缘。晚期患者进行治疗性干预的其他方法 疾病是需要的。一种潜在的新干预手段是T细胞 针对前列腺特异性的疫苗和/或T细胞疗法 抗原。有越来越多的证据表明，存在着 许多患者对癌症的免疫反应，其中一些 自体B细胞和T细胞识别的抗原是分化的 抗原。有待确定的是，免疫反应 抗分化抗原可以被操纵来提供保护 对抗癌症。靶向T细胞的一个主要理论问题 针对分化抗原的治疗是诱导或增强这种 免疫可导致破坏性的自身免疫。但是，如果 自身免疫是针对具有可有可无功能的组织引起的(即， 前列腺癌患者的前列腺癌)，具有破坏性 自身免疫可能根除起源于提名的 组织。其他研究表明，免疫啮齿动物使其匀浆 前列腺组织可诱导T细胞介导的自身免疫性前列腺炎。 然而，靶抗原是未知的，自身免疫已经 被观察到是自我限制的。需要澄清的问题 在尝试开发自身免疫性前列腺炎作为 人类前列腺癌的治疗包括：1)哪种前列腺癌- 特定的蛋白质可以作为T细胞攻击的目标，2)如何 前瞻性有效地规避对前列腺自身的耐受性 蛋白质，以及3)如何维持自身免疫的破坏性 前列腺炎。目前的格兰特建议在一只大鼠身上研究这些问题 模特。选择进行研究的原型抗原是前列腺酸。 磷酸酶(PAP)，一种已知的人类前列腺癌的肿瘤标志物。 大鼠PAP，50kD前列腺特异性分泌型糖蛋白 上皮细胞，与人类PAP有79%的同源性。因此， 在大鼠模型中阐明的原理可能适用于人类 情况。

Prostate cancer is currently the commonest cancer in men. Sixty percent of new cases at the time of diagnosis are not organ confined. Once prostate cancer is far advanced, the impact of therapy has been marginal. Additional methods to intervene therapeutically in advanced disease are needed. One potential novel intervention would be T cell vaccines and/or T cell therapy directed against prostate specific antigens. There is increasing evidence, that there is an existent immune response to cancer in many patients and that some of the antigens recognized by autologous B cells and T cells are diffentiation antigens. What remains to be determined is whether immune responses against diffentiation antigens can be manipulated to confer protection against the cancer. A major theoretical problem with targeting T cell therapy against differentiation antigens is that eliciting or boosting such immunity can result in destructive autoimmunity. However, if autoimmunity is elicited against tissues with dispensable function, (i.e., the prostate gland in patients with prostate cancer), the destructive autoimmunity might eradicate cancer cells originating in the nominated tissue. Others have shown that immunizing rodents to homogenate prostate tissue can induce T cell mediated autoimmune prostatitis. However, the target antigens are unknown, and the autoimmunity has been observed to be self limited. Issues that need to be elucidated before attempting to develop the use of autoimmune prostatitis as therapy in humans for prostate cancer include: 1) which prostate- specific proteins can serve as targets for T cell attack, 2) how to prospectively and effectively circumvent tolerance to prostate self proteins, and, 3) how to sustain the destructiveness of autoimmune prostatitis. Current grant proposes to examine these issues in a rat model. The prototype antigen selected for study is prostatic acid phosphatase (PAP), a known tumor marker for human prostate cancer. Rat PAP, a 50kD secreted glycoprotein made exclusively by prostatic epithelial cells, is 79 percent homologous to human PAP. Thus, principles elucidated in the rat model might be applicable to the human situation.