ADOPTIVE CELL THERAPY OF SOFT TISSUE SARCOMAS USING AUTOLOGOUS TUMOR VACCINATION

最近有研究表明，人类肉瘤表达肿瘤- 有可能被T细胞识别的相关抗原。 尽管有这些观察，但很明显，这些问题的弱点 抗原和/或肿瘤诱导抑制的存在会导致 癌症患者的免疫反应无效。我们假设 对肉瘤的免疫反应可以被调节以诱导T细胞 这种反应可能对治疗有用。我们 建议产生疫苗免疫的T细胞用于免疫治疗 IV期肉瘤患者使用源自广泛的 临床前研究。这些研究已经证明，淋巴球 来自肿瘤疫苗接种的淋巴结内有T细胞，可以 对免疫原性低的肿瘤产生特异性抗肿瘤反应性 体外激活后。此外，动物数据表明，使用 由转基因GM-CSF基因的肿瘤细胞组成的疫苗 更有效的治疗，并可能克服系统性 T细胞的免疫抑制。在此提出的研究将产生 对激发T细胞反应的要求的重要见解 抗肉瘤相关肿瘤抗原，并将使我们能够研究 肿瘤是否诱导抑制T细胞信号转导 TCR-分子存在于肉瘤患者体内。

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. We hypothesize that the immune response to sarcoma can be modulated to elicit T cells reactivity, and that this response may be useful for therapy. We 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 demonstraed that lympohocytes from lymph nodes primed by tumor vaccination harbor T cells which can develop specific antitumor reactivity against poorly immunogenic tumors after in vitro activation. Furthermore, animal data suggests 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 will 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- is present in sarcoma patients.