Prostate Cancer Immunotherapy

描述(申请人提供)：前列腺癌已经扩散到腺体之外，在雄激素停药或阻断后消退，在化疗后复发。在这两种情况下，结果是相似的：大多数细胞经历了生长停滞，但只有少数细胞经历了凋亡死亡。我们假设，一种基于免疫的方法可以消除非增殖但仍有活力的细胞，特别是在肿瘤肿块缩小后。前列腺癌在测试新的肿瘤免疫疗法方面提供了几个优势。血清前列腺特异性抗原(PSA)水平提供了一种简单但极好的治疗反应标志物。PSA升高的患者预后不佳，可以在功能健康的情况下被识别出来。由于消除生长停滞细胞对这类患者至关重要，因此它们非常适合肿瘤免疫治疗。 我们的目的是证明，前列腺癌患者用自体树突状细胞(DC)交叉呈递凋亡的前列腺肿瘤细胞免疫可以安全地诱导细胞溶解T细胞对肿瘤抗原的反应。我们将建立一个检测前列腺癌患者肿瘤特异性T细胞反应的系统，该系统与我们实验室建立的正常人流感特异性T细胞反应的方法平行。凋亡的前列腺肿瘤细胞将与DC共同培养，允许摄取和呈递所有MHC I分子上的多种肿瘤抗原。然后这些DC将被用来为患者接种疫苗。我们将监测患者的急性毒性和T细胞对已建立的(例如，前列腺特异性膜抗原)和存在于凋亡的前列腺癌细胞中的新标记抗原的反应，以确定我们的免疫活性。我们的免疫方法和抗原特异性T细胞反应的关键检测方法与患者的单倍型无关，允许所有单倍型的患者进入研究。我们的策略在抗原呈递的广度和使用交叉启动途径所产生的效力方面是不同的--效率高达多肽冲击的DC的10,000倍。我们的结果应该表明，这种基于DC的免疫治疗新方法是否在前列腺癌和其他恶性肿瘤的治疗中具有潜在的作用。

DESCRIPTION (provided by applicant): Prostate cancers that have spread beyond the confines of the gland regress following the withdrawal or blockade of androgens, and at relapse, following chemotherapy. In both settings the outcomes are similar: most cells undergo growth arrest, but only few undergo apoptotic death. We hypothesize that an immune based approach can eliminate the non-proliferating yet viable cells, particularly after tumor mass has been de-bulked. Prostate cancer offers several advantages in testing new tumor immunotherapies. Serum prostate specific antigen (PSA) levels provide a simple, yet excellent marker of response to therapy. Patients with rising PSA, who have a poor prognosis, can be identified while they are still functionally healthy. As elimination of growth-arrested cells is essential in such patients, they are ideally suited for tumor immunotherapy. Our objective is to demonstrate that immunization of prostate cancer patients with autologous dendritic cells (DC's) cross-presenting apoptotic prostate tumor cells safely induces cytolytic T cell responses to tumor antigens. We will establish a system for the detection of tumor-specific T cell responses in prostate cancer patients that parallels methods established in our laboratory for influenza-specific T cell responses in normal individuals. Apoptotic prostate tumor cells will be co-cultured with DC's, allowing uptake and presentation of multiple tumor antigens on all MHC I molecules. These DC's will then be used to immunize patients. We will monitor patients for acute toxicity and T cell responses to established (e.g. prostate-specific membrane antigen) and new marker antigens present in the apoptotic prostate tumor cells to determine activity of our immunization. Our immunization method and key assays for antigen-specific T cell response are independent of patient HLA haplotype, allowing patients of all haplotype to enter the study. Our strategy is distinct in the breadth of antigen presented and potency resulting from use of the cross-priming pathway--up to 10,000 times more efficient than peptide pulsed DCs. Our results should indicate whether this new approach to DC based, immunotherapy has a potential role in the treatment of prostatic cancer as well as other malignancies.