ENHANCING TUMOR IMMUNITY BY CLASS II GENE TRANSFECTION

通过II类基因转染增强肿瘤免疫力

• 批准号: 6340561
• 负责人: SUZANNE OSTRAND-ROSENBERG
• 金额: $ 4万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6340561
• 关键词: CD antigens; MHC class II antigen; antigen presentation; cell migration; cytokine; gene therapy; helper T lymphocyte; laboratory mouse; melanoma; metastasis; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; sarcoma; surface antigens; tissue /cell culture; transfection

Our long-term goal is to induce immunity and long-term immunological memory against autologous tumor in the tumor-bearing host. CD8+ T cells can be effective agents in tumor rejection, however, they usually require "help," from specifically activated CD4+ Th cells. In many cases immunity is not effective because CD4+ Th cells are not activated to tumor antigen. We have therefore hypothesized that tumor immune responses could be significantly improved if stimulation of tumor-specific CD4+ Th cells was more effective. Our strategy to improve presentation of tumor antigen has focussed on genetically modifying tumor cells so that they directly present tumor peptides to CD4+ Th cells, bypassing the need for professional antigen presenting cells (APC). During the first 4.5 years of this grant, we have used gene transfer to express syngeneic MHC class II genes in sarcoma and melanoma cells such that the genetically modified tumor cells directly present class II/tumor peptide to the responding CD4+ T cells. These transfectants are very effective immunogens for inducing long-term, specific immunity against wild type tumor. Tumor cell expression of the costimulatory molecule B7 along with syngeneic MHC class II yields cells that are potent immunotherapeutic agents for the treatment of established sarcomas. During the next 5 years, our goals are two-fold: l) Develop the future therapeutic use of these transfectants for treatment of established tumor and the prevention of metastatic disease. 2) Ascertain the mechanism by which th transfectants induce immunity. These goals will be accomplished.through the following specific aims: l) Enhance the ability of class II transfected tumor to activate CD4+ T cells by transfecting them with genes encoding molecules specific to professional APC (B7-2, CD48, heat stable antigen, ICAM-1), and genes encoding cytokines that stimulate CD4+ T cell differentiation (IL-12, IL- 1beta). 2) Determine if the transfectants can "rescue" mice carrying established wild type tumor. 3) Determine if the transfectants can be immunizing and/or immunotherapeutic agents for the prevention and/or treatment of metastatic disease. Determine if recurrence of primary tumor can be blocked by immunization with transfectants. 4) Ascertain how the transfectants stimulate tumor-specific immunity. We assume that if we understand the mechanism(s) by which the transfectants stimulate the immune response, we will be better able to manipulate them as therapeutic agents. Completion of these studies will therefore provide a strong foundation for future translational research employing this novel immunotherapeutic strategy.

我们的长期目标是诱导免疫和长期免疫 对荷瘤宿主自体肿瘤的记忆。cd 8 + T细胞 可以是肿瘤排斥的有效药物，然而，它们通常需要 “帮助”，来自特异性激活的CD 4 + Th细胞。在许多情况下， 因为CD 4 + Th细胞不被肿瘤抗原激活，所以没有效果。 因此，我们假设肿瘤免疫反应可能是 如果刺激肿瘤特异性CD 4 + Th细胞， 更有效地 我们改善肿瘤抗原呈递的策略 专注于基因修饰肿瘤细胞， 将肿瘤肽提呈给CD 4 + Th细胞，绕过了免疫调节的需要 专职抗原呈递细胞（APC）。在最初的4.5年里， 在这项资助下，我们利用基因转移来表达同源的MHC II类分子， 肉瘤和黑素瘤细胞中的基因， 肿瘤细胞直接将II类/肿瘤肽呈递给应答的CD 4 + T细胞。 这些转染子是非常有效的免疫原， 对野生型肿瘤的长期特异性免疫。肿瘤细胞 共刺激分子B7沿着同基因MHC类的表达 II产生的细胞是用于治疗的有效免疫剂 已经形成的肉瘤。未来五年，我们的目标有两个： l）开发这些转染子用于治疗的未来治疗用途 和预防转移性疾病。 （二） 确定转染子诱导免疫的机制。这些 将通过以下具体目标实现这些目标： l）增强II类转染的肿瘤活化CD 4 + T细胞的能力 细胞，用编码特定于 专职APC（B7-2、CD 48、热稳定抗原、ICAM-1）和基因 编码刺激CD 4 + T细胞分化的细胞因子（IL-12，IL-14，IL-15，IL-16，IL-17）。 1beta）。2)确定转染子是否可以“拯救”携带 建立野生型肿瘤。3)确定转染子是否可以 用于预防和/或治疗癌症的免疫和/或免疫增强剂， 转移性疾病的治疗。确定原发肿瘤是否复发 可以通过用转染子免疫来阻断。4)确定如何 转染子刺激肿瘤特异性免疫。我们假设如果我们 了解转染子刺激细胞增殖的机制。 免疫反应，我们将能够更好地操纵它们作为治疗 剂.因此，完成这些研究将提供一个强有力的 为今后采用这本小说的翻译研究奠定了基础 免疫策略