Prostate Cancer Immunotherapy

描述（由申请人提供）：前列腺癌已经扩散到腺体范围之外，在雄激素停药或阻断后消退，并在化疗后复发。在这两种情况下，结果是相似的：大多数细胞经历生长停滞，但只有少数细胞经历凋亡死亡。我们假设基于免疫的方法可以消除非增殖但存活的细胞，特别是在肿瘤块已经缩小之后。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）水平提供了一个简单的，但对治疗反应的优秀标志物。PSA升高的患者预后不良，可以在功能健康的情况下进行识别。由于在这些患者中消除生长停滞细胞是必不可少的，因此它们非常适合肿瘤免疫治疗。 我们的目的是证明用自体树突状细胞（DC）交叉呈递凋亡前列腺肿瘤细胞免疫前列腺癌患者安全地诱导对肿瘤抗原的溶细胞性T细胞应答。 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细胞反应的方法相似。将凋亡的前列腺肿瘤细胞与DC共培养，允许在所有MHC I分子上摄取和呈递多种肿瘤抗原。这些DC随后将用于免疫患者。我们将监测患者对凋亡前列腺肿瘤细胞中存在的已建立的（例如前列腺特异性膜抗原）和新的标志物抗原的急性毒性和T细胞应答，以确定我们的免疫活性。 我们的免疫方法和抗原特异性T细胞应答的关键测定不依赖于患者HLA单倍型，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宽度和使用交叉引发途径产生的效力方面是不同的-比肽脉冲的DC效率高10，000倍。我们的研究结果应该表明，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.