A Randomized Phase II Clinical trial to Determine the Safety, Tolerability and Ef

确定安全性、耐受性和疗效的随机 II 期临床试验

• 批准号: 8128728
• 负责人: STANIMIR VUK-PAVLOVIC
• 金额: $ 18.39万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8128728
• 关键词: Acute; Aftercare; Allogenic; Antigen-Presenting Cells; Antigens; Attention; Autoantigens; Autologous; Autologous Dendritic Cells; CD80 gene; CD8B1 gene; Cancer Patient; Cancer Vaccines; Cell Culture Techniques; Cell Differentiation process; Cells; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Clinical effectiveness; Cyclic GMP; Cytolysis; Cytotoxic T-Lymphocytes; DNA; Dendritic Cell Vaccine; Dendritic Cells; Disease Progression; Engineering; England; Enrollment; Environment; Evaluation; Generations; Gleason Grade for Prostate Cancer; Goals; Heterogeneity; Hormones; Human; Human Glandular Kallikrein 2; IL2 gene; Immune; Immune response; Immunity; Immunotherapy; In Vitro; Interleukin-12; Interleukin-6; Letters; Malignant Neoplasms; Malignant neoplasm of prostate; Manufacturer Name; Membrane; Metastatic Prostate Cancer; Metastatic to; Myelogenous; Neoplasm Metastasis; Patients; Peptides; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Phenotype; Plasma Kallikrein; Procedures; Process; Progression-Free Survivals; Prostate-Specific Antigen; Quality Control; Randomized; Recombinant DNA; Refractory; Regulatory T-Lymphocyte; Reporting; Research Infrastructure; Resources; Role; Safety; Serum; Source; Staging; Standardization; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Toxic effect; Training; Tumor Antigens; Tumor Cell Line; Tumor Expansion; Tumor Tissue; Tumor-Derived; Vaccinated; Vaccination; Vaccines; Viral Vector; Whole Cell Vaccine; antigen processing; arm; base; cancer cell; cancer therapy; cell preparation; clinical efficacy; cytokine; experience; hormone refractory prostate cancer; hydroxy-aluminum polymer; immune function; immunoregulation; improved; men; monocyte; novel; open label; peripheral blood; phenome; pre-clinical; prostatic fraction Acid phosphatase isoenzyme; response; standard of care; success; tumor

There are no treatments available to men with non-metastatic hormone-refractory (NMHR) prostate cancer (PC). For such patients immunotherapy may be beneficial. This proposal aims to enhance the clinical effectiveness of therapeutic vaccination against PC and test it in patients in the NMHR stage such that progression to metastatic hormone-refractory prostate cancer (HRPC) may be delayed. The study aims to combine two hitherto separately applied modes of immunotherapy: vaccination with autologous dendritic cells and vaccination with allogeneic PC cells (APCCs). Recently our collaborators reported that a vaccine consisting solely of APCCs reduced PSA velocity in 42 percent of patients and extended the median time to progression in men suffering from NMHR-PC to 58 weeks compared to historical controls of 26 weeks (Michael et al., Clin Cancer Res, 11: 4469-4478; 2005). We hypothesize that clinical efficacy of this APCC vaccine will be enhanced by combination with fully mature autologous myeloid dendritic cells (amDCs) that are engineered to secrete IL-6 and IL-12; these cytokines are expected to stimulate expansion of cytotoxic T cells over the suppressing T regulatory cells. The specific aims of this study are: 1) To conduct a two-arm randomized phase 2 clinical trial of the APCC vaccine administered alone (Arm I) or in combination with amDCs (Arm II) to patients suffering from NHHR-PC. Based on our recent findings that human serum kallikrein-2 (hK2) levels correlate with overall survival in patients suffering from HRPC, we will determine the role of hK2 as a survival predictor in HRPC patients treated with immunotherapy. 2) To identify and characterize the type, extent, and duration of the immune response in patients treated in Arm I and Arm II. We will enroll 30 patients to each arm of this open-label phase 2 trial. Metastasis-free survival is the primary endpoint, while vaccine toxicity and tolerability, PSA-based progression-free survival, change in PSA velocity and duration of PSA response, changes in the predictive survival score and changes of immune function are among secondary endpoints. The proposed trial combines the advantages of APCCs as a source of tumor antigens with DCs that present antigens both to CD4+ and CD8+ T cells. The applicants are fully equipped, trained and experienced in clinical grade manufacturing of APCCs and DCs and have tested them in earlier separate clinical trials assuring timely initiation and technical success of the study.

对于非转移性难治性（NMHR）前列腺癌的男性，目前尚无治疗方法。 （PC）中指定。对于这些患者，免疫治疗可能是有益的。这项建议旨在加强临床 针对PC的治疗性疫苗接种的有效性，并在NMHR阶段的患者中进行测试， 转移性难治性前列腺癌（HRPC）的进展可能会延迟。该研究旨在 联合收割机结合两种迄今为止分别应用的免疫治疗模式： 细胞和用同种异体PC细胞（APCC）接种。最近，我们的合作者报告说， 仅由APCCs组成，42%的患者的PSA速度降低， 与26周的历史对照相比，患有NMHR-PC的男性进展至58周 （Michael等人，Clin Cancer Res，11：4469-4478; 2005）。我们假设这种APCC的临床疗效 通过与完全成熟的自体骨髓树突状细胞（amDC）组合， 被工程化以分泌IL-6和IL-12;这些细胞因子预期刺激细胞毒性T细胞的扩增， 抑制性T调节细胞。本研究的具体目的是：1）进行两组 APCC疫苗单独给药（I组）或与 amDC（II组）治疗NHHR-PC患者。根据我们最近的发现人类血清 激肽释放酶-2（hK 2）水平与HRPC患者的总生存期相关，我们将确定 hK 2作为免疫治疗HRPC患者生存预测因子的作用2)识别和 描述I组和II组治疗患者的免疫应答类型、程度和持续时间。 我们将在这项开放标签2期试验的每个组招募30名患者。无转移生存率是 终点，而疫苗毒性和耐受性、基于PSA的无进展生存期、PSA变化 PSA反应的速度和持续时间，预测生存评分的变化和免疫功能的变化。 功能是次要终点。拟议的试验结合了亚太经合组织的优势， 肿瘤抗原的来源，具有向CD 4+和CD 8 + T细胞呈递抗原的DC。申请人 在APCC和DC的临床级制造方面设备齐全、训练有素且经验丰富，并经过测试 他们在早期单独的临床试验中确保及时启动和研究的技术成功。