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，以诱导对眼黑色素瘤（眼睛最常见的恶性肿瘤）的免疫力。虽然原发性肿瘤可以治疗，但50%的患者发展为转移性疾病，对此没有成功的治疗方法。我们推测，产生肿瘤特异性的长期免疫可能是一种有效的治疗原发性和转移性疾病的方法。在过去的8年中，我们已经开发出一种独特的免疫疗法，使用基于基因修饰的肿瘤细胞的疫苗来增强肿瘤抗原的抗原呈递。我们的策略集中在激活肿瘤特异性CD 4 + T辅助淋巴细胞。CD 4 + T细胞在抗肿瘤免疫中特别重要，因为它们为最佳CD 8+活性提供必要的“帮助”，并且因为它们对长期记忆至关重要。我们已经在3个小鼠模型中表明，转染了同系MHC II类、CD 80和超抗原基因的肿瘤细胞是有效的免疫抑制剂。鉴于动物实验结果令人鼓舞，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，自体的人类肿瘤材料并不总是可用的，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，就可以获得最佳的疫苗功效。因此，我们将不仅评估疫苗功效，而且通过执行以下特定目的来测试疫苗策略所基于的几个假设：1）鉴定人眼黑素瘤细胞系是疫苗的“基础”系，并用CD 80、HLA-DR和超抗原基因对它们进行转染。2)确定转染子刺激肿瘤特异性HLA-DR限制性CD 4 + T细胞应答的能力。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具有“耐受性”并因此不太可能应答;和5）确定疫苗是否充当肿瘤编码的内源性合成抗原的抗原呈递细胞。这些研究的完成将为开展临床试验提供框架，并将为进一步改进疫苗提供机制信息。