ENHANCING TUMOR IMMUNITY BY CLASS II GENE TRANSFECTION

我们的长期目标是诱导免疫力和长期免疫力 荷瘤宿主对自体肿瘤的记忆。CD8+T细胞 可以是治疗肿瘤排斥反应的有效药物，然而，它们通常需要 “帮助”，来自特殊激活的CD4+Th细胞。在许多情况下享有豁免权 是无效的，因为CD4+Th细胞不会被肿瘤抗原激活。 因此，我们假设肿瘤免疫反应可能是 如果对肿瘤特异性CD4+Th细胞的刺激 更有效。我们改进肿瘤抗原呈递的策略已经 专注于对肿瘤细胞进行基因改造，以便它们直接 将肿瘤多肽呈现给CD4+Th细胞，绕过了 专业抗原提呈细胞(APC)。在最初的4.5年里 这项资助，我们使用基因转移来表达同基因的MHC II类 肉瘤和黑色素瘤细胞中的基因 肿瘤细胞直接向应答的CD4+递送II类/肿瘤多肽 T细胞。这些转染体是非常有效的免疫原，用于诱导 针对野生型肿瘤的长期、特异性免疫。肿瘤细胞 共刺激分子B7与同源MHC类分子的表达 Ii产生的细胞是治疗的有效免疫治疗剂。 已经建立的肉瘤。未来5年，我们的目标是双重的： L)开发了这些转染体用于治疗的未来治疗用途 对已建立的肿瘤和转移疾病的预防。2) 确定TH基因转染体诱导免疫的机制。这些 将通过以下具体目标实现目标： L)增强II类转染瘤激活CD_4~+T细胞的能力 通过将编码特异性分子的基因导入细胞 专业APC(B7-2、CD48、热稳定抗原、ICAM-1)和基因 编码刺激CD4+T细胞分化的细胞因子(IL-12、IL-2 1测试版)。2)确定转基因小鼠是否能“拯救”携带 已建立的野生型肿瘤。3)确定转染体是否可以 免疫和/或免疫治疗剂，用于预防和/或 治疗转移性疾病。确定原发肿瘤是否复发 可通过转染体免疫阻断。4)确定 转染体可刺激肿瘤特异性免疫。我们假设如果我们 了解转染者刺激细胞生长的机制(S) 免疫反应，我们将能够更好地操纵它们作为治疗 探员们。因此，这些研究的完成将提供强有力的 为未来利用这部小说进行翻译研究奠定基础 免疫治疗策略。

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.