T Cell Immunotherapy of Pediatric Brain Tumors

描述(申请人提供)：已激活的体外收养转移 淋巴引流自体肿瘤细胞来源的T淋巴细胞 疫苗的毒性很低，在一些成年人中可以介导肿瘤消退。 恶性胶质瘤或肾细胞癌患者在我们以前的治疗中 临床研究。这项以研究为导向的提案的第一个目标是 确定儿童过继免疫治疗的可行性和毒性 以脑肿瘤为重点的复发性实体瘤患者。短期 手术时将建立自体肿瘤细胞系 切除手术。一种混合辐照自体肿瘤细胞的疫苗 将在皮内注射GM-CSF以刺激免疫反应 抽干了国民警局。增生性引流的淋巴结将被手术切除，并 T细胞将在体外被葡萄球菌肠毒素A(SEA)和 IL-2诱导分化为效应器功能并快速增殖。 激活的T细胞将在增殖反应的高峰期被收获 并对患者进行静脉注射。毒性和反应将是 量过了。第二个目标是分析T细胞和血清学反应 与自体肿瘤抗原(AGS)有关。CD_4、CD_8 T细胞前体频率的研究 对树突状细胞(DC)呈递的肿瘤裂解物有反应的细胞将是 在疫苗引流的LN中测定并与治疗前和治疗后进行比较 PBMC。第三个目标将探索肿瘤免疫学中的一个基本问题， 也就是说，免疫优势T细胞反应是否与 类似组织学类型的同种异体肿瘤中存在的抗原。 对自体肿瘤裂解物有反应的疫苗耗尽的LN T细胞将是 同种异体来源的裂解物冲击的自体DC刺激 神经胶质瘤细胞系。如果没有观察到交叉反应，这将表明 在这种疫苗接种方法中，私人肿瘤抗原在免疫上占主导地位 支持自体肿瘤疫苗战略。或者，如果交叉 -反应性胶质瘤AGS被发现，这将刺激未来的研究 抗原的分子特征，并提供了 一种统一的胶质瘤疫苗的开发。

DESCRIPTION (PROVIDED BY APPLICANT): The adoptive transfer of ex vivo activated T lymphocytes derived from lymph nodes (LNs) draining autologous tumor cell vaccines had very low toxicity and mediated tumor regression in some adult patients with malignant gliomas or renal cell carcinoma treated on our previous clinical studies. The first objective of this research-driven proposal is to determine the feasibility and toxicity of adoptive immunotherapy in pediatric patients with recurrent solid tumors with emphasis on brain tumors. Short-term autologous tumor cell lines will be established at the time of surgical resection. A vaccine consisting of irradiated autologous tumor cells admixed with GM-CSF will be injected intradermally to stimulate an immune response in draining LNs. The hyperplastic draining LNs will be surgically removed and the T cells will be activated ex vivo with staphylococcal enterotoxin A (SEA) and IL-2 to induce differentiation to effector function and rapid proliferation. Activated T cells will be harvested at the peak of the proliferative response and administered intravenously to patients. Toxicity and response will be measured. The second objective is to analyze the T cell and serologic response to autologous tumor antigens (Ags). The precursor frequency of CD4+ and CD8+ T cells that respond to tumor lysate presented by dendritic cells (DC) will be determined in the vaccine-draining LN and compared with pre and post treatment PBMC. The third objective will explore a basic question in tumor immunology, namely, whether immunodominant T cell responses are cross-reactive with antigens present in allogeneic tumors of similar histologic type. Vaccine-draining LN T cells that respond to autologous tumor lysate will be stimulated using autologous DC pulsed with lysate derived from allogeneic glioma lines. If cross-reactivity is not observed it would indicate that private tumor antigens are immunodominant in this vaccination method and support the strategy of autologous tumor vaccines. Alternatively if cross -reactive glioma Ags are identified it would stimulate future studies for molecular characterization of the antigens and provide the rationale for development of a uniform glioma vaccine.