CELL BASED TUMOR VACCINES TARGETING CD4+ T LUMPHOCYTES

针对 CD4 T 淋巴细胞的细胞肿瘤疫苗

• 批准号: 6377670
• 负责人: SUZANNE OSTRAND-ROSENBERG
• 金额: $ 24.68万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377670
• 关键词: CD antigens; MHC class II antigen; antigen presentation; cell line; clinical research; eye neoplasms; helper T lymphocyte; human subject; human therapy evaluation; immune tolerance /unresponsiveness; laboratory mouse; melanoma; metastasis; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; superantigens; tetanus toxin; transfection; vaccine development

We are developing vaccine strategies for inducing immunity to ocular melanoma, the most common malignancy of the eye. Although primary tumor can be treated, 50% of patients develop metastatic disease for which there is no successful therapy. We hypothesize that the generation of tumor-specific, long-term immunity may be a useful therapy for established primary and metastatic disease. During the past 8 years we have developed a unique immunization therapy using genetically modified tumor cell-based vaccines for enhancing antigen presentation of tumor antigens. Our strategy focuses on activating tumor-specific CD4+ T helper lymphocytes. CD4+ T cells are particularly important in anti- tumor immunity because they provide the requisite "help" for optimal CD8+ activity, and because they are critical for long-term memory. We have shown in 3 mouse models that tumor cells transfected with syngeneic MHC class II, CD80 and superantigen genes are potent immunotherapeutic agents. Given the promising animal results, we would like to test our approaches in patients. The animal studies used autologous tumor cells for the "base" vaccine. Autologous human tumor material, however, is not always available, and customization for individual patients is neither cost effective nor feasible. As an alternative approach we will use established human ocular melanoma tumor cell lines as the "base" vaccine. We believe that optimal vaccine efficacy can be achieved if we understand the mechanism by which the vaccines stimulate anti- tumor immunity. We will, therefore, not only assess vaccine efficacy, but also test several hypothesis on which the vaccine strategy is based by performing the following Specific Aims: 1) Identify human ocular melanoma cell lines are the "base" lines for the vaccine, and transfect them with CD80, HLA-DR, and superantigen genes. 2) Determine the ability of the transfectants to stimulate tumor-specific HLA-DR restricted CD4+ T cell responses. 3) Determine if the stage or extent of disease affects patients' ability to respond to the vaccine. 4) Determine if individuals with tumor are "tolerant" to their tumor antigens and hence less likely to respond; and 5) Determine if the vaccines function as antigen presenting cells for tumor-encoded endogenously synthesized antigens. Completion of these studies will provide the framework for conducting a clinical trial, and will provide mechanistic information for further improvement of the vaccines.

我们正在开发疫苗策略，以诱导对眼部黑色素瘤（最常见的眼部恶性肿瘤）的免疫力。尽管原发性肿瘤可以治疗，但 50% 的患者会出现转移性疾病，且没有成功的治疗方法。我们假设肿瘤特异性的长期免疫的产生可能是治疗已确定的原发性疾病和转移性疾病的有效疗法。在过去的 8 年里，我们开发了一种独特的免疫疗法，使用基于转基因肿瘤细胞的疫苗来增强肿瘤抗原的抗原呈递。我们的策略重点是激活肿瘤特异性 CD4+ T 辅助淋巴细胞。 CD4+ T 细胞在抗肿瘤免疫中特别重要，因为它们为最佳 CD8+ 活性提供必要的“帮助”，并且对于长期记忆至关重要。我们在 3 个小鼠模型中证明，用同基因 MHC II 类、CD80 和超抗原基因转染的肿瘤细胞是有效的免疫治疗剂。鉴于有希望的动物实验结果，我们希望在患者身上测试我们的方法。动物研究使用自体肿瘤细胞作为“基础”疫苗。然而，自体人类肿瘤材料并不总是可用，并且针对个体患者的定制既不具有成本效益也不可行。作为替代方法，我们将使用已建立的人眼黑色素瘤肿瘤细胞系作为“基础”疫苗。我们相信，如果我们了解疫苗刺激抗肿瘤免疫的机制，就可以实现最佳的疫苗功效。因此，我们不仅要评估疫苗的功效，还要通过执行以下具体目标来测试疫苗策略所依据的几个假设：1) 确定人眼部黑色素瘤细胞系是疫苗的“基础”细胞系，并转染它们带有 CD80、HLA-DR 和超抗原基因。 2) 确定转染子刺激肿瘤特异性 HLA-DR 限制性 CD4+ T 细胞反应的能力。 3) 确定疾病的阶段或程度是否影响患者对疫苗的反应能力。 4) 确定患有肿瘤的个体是否对其肿瘤抗原“耐受”，从而不太可能做出反应； 5) 确定疫苗是否充当肿瘤编码内源合成抗原的抗原呈递细胞。这些研究的完成将为进行临床试验提供框架，并将为进一步改进疫苗提供机制信息。