IMMUNOLOGIC THERAPY OF PROSTATE CANCER

前列腺癌是目前男性最常见的癌症。 六十 诊断时新病例的百分比不受器官限制。 一旦前列腺癌已发展到晚期，治疗的效果就会受到影响。 边缘的。 晚期治疗干预的其他方法 需要疾病。 一种潜在的新型干预措施是 T 细胞 针对前列腺特异性的疫苗和/或 T 细胞疗法 抗原。 越来越多的证据表明存在 许多患者对癌症有免疫反应，其中一些 自体B细胞和T细胞识别的抗原是分化的 抗原。 仍有待确定的是免疫反应是否 可以操纵抗分化抗原来提供保护 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引发或增强这种 免疫可能导致破坏性的自身免疫。 然而，如果 自身免疫是针对具有可有可无的功能的组织（即， 前列腺癌患者的前列腺），破坏性 自身免疫可能会根除源自提名的癌细胞 组织。 其他人已经表明，对啮齿动物进行免疫以匀浆 前列腺组织可诱发T细胞介导的自身免疫性前列腺炎。 然而，目标抗原未知，自身免疫已 观察到是自我限制的。 需要阐明的问题 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- 特定蛋白质可以作为 T 细胞攻击的目标，2) 如何 前瞻性有效规避前列腺自身耐受性 蛋白质，以及 3) 如何维持自身免疫的破坏性 前列腺炎。 目前的资助计划在老鼠身上研究这些问题 模型。 选择用于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肿瘤标志物。 大鼠 PAP，一种仅由前列腺产生的 50kD 分泌糖蛋白 上皮细胞，与人类 PAP 有 79% 的同源性。 因此， 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.