THERAPY OF SARCOMAS WITH VACCINE-PRIMED LYMPHOCYTES

描述：最近已经证明，人类肉瘤表达 肿瘤相关抗原可能被T细胞识别， 细胞 尽管有这些意见，但很明显，这些弱点 抗原和/或肿瘤诱导的抑制的存在导致 癌症患者的免疫反应无效。 申请人假设 对肉瘤的免疫反应可以被调节， 反应性，并且这种反应可能对治疗有用。 他们提出 产生疫苗引发的T细胞用于IV期肉瘤的免疫治疗 患者使用来自广泛临床前研究的方法。 这些研究已经证明，来自淋巴结的淋巴细胞被 肿瘤疫苗携带可产生特异性抗肿瘤的T细胞 体外活化后对免疫原性差的肿瘤的反应性。 此外，动物数据表明，使用由肿瘤细胞组成的疫苗， 用GM-CSF基因转染的细胞在治疗上更有效， 可以克服T细胞的系统性免疫抑制。 建议的研究 本文可能会产生重要的见解的要求，引发T 细胞对肉瘤相关肿瘤抗原的反应， 研究肿瘤诱导的T细胞信号转导抑制是否 分子TCR-z存在于肉瘤患者中。 具体目标是 应用是：1. 评估对淋巴结的体内免疫应答 用自体肿瘤加BCG致敏的淋巴细胞在体外活化， 转移性肉瘤的过继免疫治疗。 为了评估体内 GM-CSF基因修饰淋巴结淋巴细胞的免疫应答 转移性肉瘤过继免疫治疗中的肿瘤。 3. 审查 体外活化疫苗致敏的体外免疫反应性 淋巴结淋巴细胞相对于自体肿瘤。 4. 审查 外周血和疫苗致敏淋巴结中TCR-z的表达 淋巴细胞的肉瘤患者，并确定是否TCR-z表达 在体外活化后上调。

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.