T Cell Immunotherapy of Pediatric Brain Tumors

描述（由申请人提供）：过继转移的离体激活 来自引流自体肿瘤细胞的淋巴结（LN）的T淋巴细胞 疫苗的毒性非常低，在一些成人中介导肿瘤消退， 恶性胶质瘤或肾细胞癌患者接受过我们的既往治疗 临床研究。这项研究驱动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 复发性实体瘤患者，重点是脑肿瘤。短期 自体肿瘤细胞系将在手术时建立， 切除术一种由经过辐照的自体肿瘤细胞混合而成的疫苗 将皮内注射GM-CSF以刺激免疫反应， 排出淋巴结。增生的引流淋巴结将通过手术切除， T细胞将用葡萄球菌肠毒素A（SEA）离体活化， IL-2诱导分化为效应子功能和快速增殖。 活化的T细胞将在增殖反应的峰值时收获 并通过静脉注射给患者。毒性和反应将 测定了第二个目的是分析T细胞和血清学反应 自体肿瘤抗原（Ags）。CD 4+和CD 8 + T细胞前体频率 对树突状细胞（DC）递呈的肿瘤裂解物产生反应的细胞将被 在疫苗引流LN中测定，并与治疗前后进行比较 PBMC。第三个目标将探讨肿瘤免疫学中的一个基本问题， 即，免疫显性T细胞应答是否与 存在于相似组织学类型的同种异体肿瘤中的抗原。 对自体肿瘤裂解物有反应的疫苗引流LN T细胞将被免疫。 用来自同种异体的裂解物脉冲的自体DC刺激 胶质瘤细胞系。如果未观察到交叉反应性，则表明 在该疫苗接种方法中，特异性肿瘤抗原是免疫显性的， 支持自体肿瘤疫苗的策略。或者，如果交叉 - 反应性胶质瘤Ag被鉴定，这将刺激未来的研究， 抗原的分子表征，并提供 开发统一的胶质瘤疫苗。

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.