TUMOR VACCINES

肿瘤疫苗

• 批准号: 6344687
• 负责人: GEORGIA B VOGELSANG
• 金额: $ 22.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-27 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6344687
• 关键词: B lymphocyte; CD8 molecule; SDS polyacrylamide gel electrophoresis; T cell receptor; antigen presenting cell; autologous transplantation; bone marrow transplantation; cellular immunity; clinical research; clinical trials; colony stimulating factor; combination cancer therapy; cyclophosphamide; cytotoxic T lymphocyte; cytotoxicity; disease /disorder model; enzyme linked immunosorbent assay; flow cytometry; genetically modified animals; graft versus host disease; hematopoietic stem cells; human subject; human therapy evaluation; human tissue; humoral immunity; immunoglobulin genes; laboratory mouse; leukemia; leukocytes; lymphoma; monoclonal antibody; multiple myeloma; natural killer cells; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer radiation therapy; neoplasm /cancer relapse /recurrence; neoplasm /cancer vaccine; nonhuman therapy evaluation; radionuclides; tissue /cell culture; tumor antigens

Recently there has been renewed interest in strategies aimed at generating active antitumor immune responses in patients with cancer. In most instances, the identity of the relevant tumor associated antigens is not known. Consequently, autologous or allogeneic tumor cells have been used as a source of antigen for vaccination. This approach has taken advantage of the recent identification of factors that regulate the priming of systemic immunity. Tumor cells genetically modified in vitro to secrete cytokines or express co-stimulatory molecules have been studied for the ability to activate systemic antitumor immunity when used as a vaccine. Such studies in animal models demonstrate that vaccination with a number of genetically modified tumor cell vaccine constructs results in protection against a subsequent systemic tumor challenge, or eradication of a small pre-established systemic tumor burden. These studies form the basis for several on going phase I clinical trials exploring this approach in patients with solid tumors. While these early studies have been promising, there is evidence to suggest that the systemic immunity primed by tumor vaccination has limited efficacy against more advanced tumor burdens. We and others have shown that with time, tolerance to tumor antigens develops, and with further tumor progression, a more global tumor-induced immunosuppression occurs. Consequently, tumor cell vaccination may hold the greatest promise if preceded by a significant reduction in tumor burden. For many malignancies, autologous bone marrow transplantation offers the greatest opportunity to achieve a state of minimal residual disease. Furthermore, the reconstitution of the immune system following transplantation may restore the capacity to respond to tumor associated antigens to which tolerance had been established. The major focus of this project is to explore the integration of tumor-specific active immunotherapy with myeloablative chemotherapy and autologous peripheral blood stem-cell (PBSC) transplantation. This strategy will be studied in an animal model of B cell lymphoma, as well as in patients with indolent lymphoma and multiple myeloma. Targeting these initial studies to the therapy of two B-cell lineage malignancies will enable an analysis of immunity raised to a defined tumor-specific antigen, i.e. immunoglobulin idiotype protein. in this way, we seek to address unambiguously the ability to generate tumor specific immunity in the transplant setting.

最近，人们对针对的战略有了重新兴趣 在患者中产生主动抗肿瘤免疫反应 癌症。在大多数情况下，相关肿瘤的身份 相关的抗原尚不清楚。因此，自体或 同种异性肿瘤细胞已被用作抗原的来源 疫苗接种。这种方法利用了最近的 识别调节全身性启动的因素 免疫。肿瘤细胞在体外基因修饰以分泌 已经研究了细胞因子或快递共刺激分子的 当用作当用作系统性抗肿瘤免疫力的能力 疫苗。动物模型中的此类研究表明疫苗接种 具有许多转基因肿瘤细胞疫苗构建体 导致防止随后的系统性肿瘤挑战， 或根除一个小的预先建立的全身性肿瘤负担。 这些研究构成了在进行I期临床上的几个基础 在实体瘤患者中探索这种方法的试验。尽管 这些早期研究很有希望，有证据表明 表明肿瘤疫苗接种启动的全身免疫力已有 对更高级肿瘤负担的有限疗效。我们和其他人 已经表明，随着时间的流逝，对肿瘤抗原的耐受性会发展出来，并且 随着肿瘤进展的进一步，全球肿瘤诱导的 免疫抑制发生。因此，肿瘤细胞接种可能 如果在之前大幅减少之前，请保持最大的承诺 肿瘤负担。对于许多恶性肿瘤，自体骨髓 移植提供了实现国家的最大机会 最小残留疾病。此外，重组 移植后免疫系统可能会恢复 响应与肿瘤相关的抗原的耐受性 已确立的。该项目的主要重点是探索 与肿瘤特异性活动免疫疗法的整合 脊髓含量的化学疗法和自体外周血干细胞 （PBSC）移植。该策略将在动物中研究 B细胞淋巴瘤的模型以及懒惰的患者 淋巴瘤和多发性骨髓瘤。针对这些初步研究 两个B细胞谱系恶性肿瘤的治疗将使 分析对定义的肿瘤特异性抗原的免疫力分析 即免疫球蛋白的白痴型蛋白质。这样，我们试图 明确地解决特定肿瘤的能力 在移植设置中的免疫力。