THERAPY OF SARCOMAS WITH VACCINE-PRIMED LYMPHOCYTES

用疫苗引发的淋巴细胞治疗肉瘤

• 批准号: 2517754
• 负责人: VERNON K. SONDAK
• 金额: $ 15.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-11 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2517754
• 关键词: T cell receptor; T lymphocyte; clinical research; clinical trials; colony stimulating factor; cytotoxicity; disease /disorder model; enzyme linked immunosorbent assay; human subject; human therapy evaluation; immunologic assay /test; interferon gamma; interleukin 2; interleukin 4; kidney neoplasms; laboratory mouse; leukocyte activation /transformation; melanoma; neoplasm /cancer immunotherapy; neoplastic cell; receptor expression; sarcoma; tissue /cell culture; tumor necrosis factor alpha; vaccines

DESCRIPTION: It has recently been demonstrated that human sarcomas express tumor-associated antigens potentially capable of being recognized by T cells. Despite these observations, it is evident that the weakness of these antigens and/or the presence of tumor-induced suppression results in an ineffective immune response in cancer patients. The applicants hypothesize that the immune response to sarcoma can be modulated to elicit T cell reactivity, and that this response may be useful for therapy. They propose to generate vaccine-primed T cells for the immunotherapy of stage IV sarcoma patients utilizing methods derived from extensive preclinical studies. These studies have demonstrated that lymphocytes from lymph nodes primed by tumor vaccination harbor T cells which can develop specific anti-tumor reactivity against poorly immunogenic tumors after in vitro activation. Furthermore, animal data suggest that using vaccines composed of tumor cells transfected with the GM-CSF gene are more therapeutically efficacious and may overcome systemic immunosuppression of T cells. The studies proposed herein may yield important insights into the requirements for eliciting T cell responses against sarcoma-associated tumor antigens, and will allow us to study whether tumor-induced suppression of the T cell signal transduction molecule TCR-z is present in sarcoma patients. The specific aims of this application are: 1. To assess the in vivo immune response to lymph node lymphocytes primed with autologous tumor plus BCG and activated in vitro in the adoptive immunotherapy of metastatic sarcoma. To assess the in vivo immune response of lymph node lymphocytes primed with GM-CSF gene-modified tumor in the adoptive immunotherapy of metastatic sarcoma. 3. To examine the in vitro immunologic reactivity of in vitro activated vaccine-primed lymph node lymphocytes with respect to autologous tumor. 4. To examine the expression of TCR-z in the peripheral blood and vaccine-primed lymph node lymphocytes of sarcoma patients, and to determine whether TCR-z expression is upregulated after in vitro activation.

描述：最近已经证明了人类肉瘤Express 肿瘤相关的抗原可能能够被T识别 细胞。 尽管有这些观察，但很明显这些弱点 抗原和/或存在肿瘤诱导的抑制导致 癌症患者的免疫反应无效。 申请人假设 可以调节对肉瘤的免疫反应以引起T细胞 反应性，这种反应可能对治疗有用。 他们建议 生成疫苗生化的T细胞进行IV期肉瘤的免疫疗法 利用从广泛的临床前研究中得出的方法的患者。 这些研究表明，来自淋巴结的淋巴细胞 肿瘤疫苗接种携带T细胞，该细胞可以开发特定的抗肿瘤 体外激活后对免疫原性肿瘤的反应性。 此外，动物数据表明使用由肿瘤细胞组成的疫苗 用GM-CSF基因转染更有效，并且 可以克服T细胞的全身免疫抑制。 研究提出 此处可能会对引起的要求产生重要的见解 针对与肉瘤相关的肿瘤抗原的细胞反应，将使我们 研究肿瘤诱导的T细胞信号转导的抑制是否 分子TCR-Z存在于肉瘤患者中。 这个特定的目的 应用是：1。评估体内免疫反应对淋巴结 淋巴细胞用自体肿瘤加上BCG并在体外激活 转移性肉瘤的收养免疫疗法。 评估体内 用GM-CSF基因修饰的淋巴结淋巴细胞的免疫反应 转移性肉瘤的收养免疫疗法中的肿瘤。 3。检查 体外的体外免疫反应性，体外活化疫苗引发的 淋巴结相对于自体肿瘤。 4。检查 TCR-Z在外周血和疫苗引发的淋巴结中的表达 肉瘤患者的淋巴细胞，并确定TCR-Z表达是否 体外激活后被上调。