ADOPTIVE CELL THERAPY OF SOFT TISSUE SARCOMAS USING AUTOLOGOUS TUMOR VACCINATION

最近已经证明，人肉瘤表达可能能够被T细胞识别的肿瘤相关抗原。 尽管有这些观察结果，但很明显，这些抗原的弱点和/或肿瘤诱导的抑制的存在导致癌症患者中无效的免疫应答。 我们推测，肉瘤的免疫反应可以被调节，以引起T细胞的反应，这种反应可能是有用的治疗。 我们建议利用来自广泛的临床前研究的方法产生用于IV期肉瘤患者的免疫治疗的疫苗引发的T细胞。 这些研究已经证明，来自通过肿瘤疫苗接种引发的淋巴结的嗜酸性红细胞携带T细胞，其在体外活化后可以针对免疫原性差的肿瘤产生特异性抗肿瘤反应性。 此外，动物数据表明，使用由转染有GM-CSF基因的肿瘤细胞组成的疫苗在治疗上更有效，并且可以克服T细胞的全身性免疫抑制。 本文提出的研究将产生重要的见解的要求引发T细胞对肉瘤相关的肿瘤抗原的反应，并将使我们能够研究肿瘤诱导的抑制T细胞信号转导分子TCR-是否存在于肉瘤患者。

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. Furthermaor, 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.