Retroviral Immunotoxins for Leukemia

白血病的逆转录病毒免疫毒素

• 批准号: 7227710
• 负责人: Daniel A Vallera
• 金额: $ 29.78万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7227710
• 关键词: Address; Animal Model; Antibodies; Antigens; Appendix; Binding; Biological; Biological Models; CD8B1 gene; Cancer Center; Cell Line; Cells; Cellular Structures; Class; Clone Cells; Collaborations; Data; Disadvantaged; Dose; Failure; Flow Cytometry; Foundations; Funding; Future; Gene Targeting; Genes; Genome; Grant; Homing; Human; Immune system; Immunotoxins; In Vitro; Interleukin-2; Interleukin-3; Journals; Laboratories; Lead; Learning; Ligands; Link; Localized; Malignant Neoplasms; Measures; Modeling; Monoclonal Antibodies; Mus; Normal tissue morphology; Numbers; Organ; Peer Review; Process; Production; Property; Proviruses; Publishing; Purpose; RNA Splicing; Reagent; Recombinants; Refit; Research Personnel; Role; Site; Solutions; Spleen; T-Cell Leukemia; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; Toxin; Work; anticancer research; cancer cell; cancer site; cell type; cellular transduction; chemotherapy; clinical application; cytokine; experience; gene therapy; improved; in vivo; killings; leukemia; lymph nodes; migration; programs; research study; response; single molecule; tumor; vector

DESCRIPTION (provided by applicant): Immunotoxins (IT) are experimental pharmacologic agents that are made by linking antibodies or cytokines that specifically bind to cancer cells to potent catalytic toxins of which a single molecule can kill a cell. Their major purpose is to deliver therapy selectively to cancer cells instead of non-target organs, as does conventional chemotherapy. Although these agents selectively bind and kill cancer cells, clinically they have been limited by their 1) failure to penetrate and localize in adequate concentrations in cancer target tissue 2) localization in nontarget organs limiting the tolerated dose and collapsing the therapeutic window. In this proposal, we will explore a solution to this problem. Cells of the immune system such as T cells are the most prominent cell types which penetrate, attack, and destroy cancer cells and are naturally suited for the expression and production of cytokines in response to antigenic challenge. Therefore, in the first cycle of funding we took advantage of the a well-known property of T cells which is their ability to migrate to tumors and provided proof that they could be used to deliver immunotoxin to leukemia in vivo using gene therapy. We showed that T cells could deliver retroviral IT (retlT) consisting of IL-3 spliced to genetically modified toxin locally at the site of the leukemia and produce a significant anti-leukemia effect. Our studies have now generated several important questions concerning this new class of agent, and in this proposal, we will attempt to determine how they work. We have established a new model of retlT therapy which we will use as a foundation for future attempts to modify and improve retlT. The model takes advantage of the use of antigen specific T cell clones. We will use this to test the usefulness of retlT leukemia therapy. Previous studies focused us on a single ligand (IL-3). Now, in aim 1 we will characterize the role of T cells in this established model, determining whether it is better to use CD4+ or CD8+ T cell clones for delivery. Then in aims 2, 3, and 4 we will determine just how and why our approach works. Aim 2 will focus on the T cell component of the model and we will ask how many T cells localize to the tumor in vivo as compared to other extratumoral sites. Will the localization of T these retlT secreting T cells cause toxicity? Aim 3 focuses on the IT moiety and we will determine the role of secreted IT and how much is necessary. Finally in aim 4, we will determine if retlT can reduce toxicity compared to conventional IT and whether they have effects on components of the host immune system.

描述（由申请人提供）：免疫毒素（IT）是实验性药物制剂，通过将特异性结合癌细胞的抗体或细胞因子与单分子可杀死细胞的有效催化毒素连接而制成。它们的主要目的是选择性地向癌细胞而不是非靶器官提供治疗，就像传统化疗一样。尽管这些药物选择性地结合并杀死癌细胞，但在临床上它们受到以下因素的限制：1) 无法渗透并在癌症靶组织中以足够的浓度定位；2) 在非靶器官中的定位限制了耐受剂量并缩小了治疗窗。在这个提案中，我们将探索解决这个问题的方法。免疫系统细胞（例如 T 细胞）是最主要的细胞类型，可以穿透、攻击和破坏癌细胞，并且天然适合表达和产生细胞因子以应对抗原挑战。因此，在第一个资助周期中，我们利用了 T 细胞众所周知的特性，即它们迁移到肿瘤的能力，并提供了证据，证明它们可以通过基因疗法在体内向白血病输送免疫毒素。我们发现，T 细胞可以在白血病部位局部递送由 IL-3 与转基因毒素剪接组成的逆转录病毒 IT (retlT)，并产生显着的抗白血病作用。我们的研究现已产生了有关此类新型代理的几个重要问题，在本提案中，我们将尝试确定它们的工作原理。我们建立了一种新的 retlT 治疗模型，我们将以此作为未来尝试修改和改进 retlT 的基础。该模型利用了抗原特异性 T 细胞克隆的优势。我们将用它来测试 retlT 白血病治疗的有效性。之前的研究主要集中在单一配体（IL-3）上。现在，在目标 1 中，我们将描述 T 细胞在该已建立模型中的作用，确定使用 CD4+ 或 CD8+ T 细胞克隆进行递送是否更好。然后，在目标 2、3 和 4 中，我们将确定我们的方法如何以及为何发挥作用。目标 2 将重点关注模型的 T 细胞成分，我们将询问与其他肿瘤外部位相比，体内有多少 T 细胞定位于肿瘤。这些retlT分泌T细胞的定位会引起毒性吗？目标 3 重点关注 IT 部分，我们将确定秘密 IT 的作用以及必要程度。最后，在目标 4 中，我们将确定与传统 IT 相比，retlT 是否可以降低毒性，以及它们是否对宿主免疫系统的组成部分有影响。

项目成果

Design and modification of EGF4KDEL 7Mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity.

• DOI: 10.1038/sj.bjc.6605297
• 发表时间: 2009-10-06
• 期刊: British journal of cancer
• 影响因子: 8.8

A novel bispecific ligand-directed toxin designed to simultaneously target EGFR on human glioblastoma cells and uPAR on tumor neovasculature.

• DOI: 10.1007/s11060-010-0392-5
• 发表时间: 2011-06
• 期刊: JOURNAL OF NEURO-ONCOLOGY
• 影响因子: 3.9
• 作者: Tsai, Alexander K.;Oh, Seunguk;Chen, Hua;Shu, Yanqun;Ohlfest, John R.;Vallera, Daniel A.
• 通讯作者: Vallera, Daniel A.

Genetic alteration of a bispecific ligand-directed toxin targeting human CD19 and CD22 receptors resulting in improved efficacy against systemic B cell malignancy.

• DOI: 10.1016/j.leukres.2009.02.006
• 发表时间: 2009-09
• 期刊: Leukemia research
• 影响因子: 2.7
• 作者: Vallera DA;Chen H;Sicheneder AR;Panoskaltsis-Mortari A;Taras EP
• 通讯作者: Taras EP

A new drug delivery method of bispecific ligand-directed toxins, which reduces toxicity and promotes efficacy in a model of orthotopic pancreatic cancer.

• DOI: 10.1097/mpa.0b013e3181cbd908
• 发表时间: 2010-08
• 期刊: Pancreas
• 影响因子: 2.9
• 作者: Oh S;Stish BJ;Vickers SM;Buchsbaum DJ;Saluja AK;Vallera DA
• 通讯作者: Vallera DA

Retroviral immunotoxin gene therapy of leukemia in mice using leukemia-specific T cells transduced with an interleukin-3/Bax fusion protein gene.

使用转染白细胞介素 3/Bax 融合蛋白基因的白血病特异性 T 细胞对小鼠白血病进行逆转录病毒免疫毒素基因治疗。

• DOI: 10.1089/104303403322611791
• 发表时间: 2003
• 期刊: Human gene therapy.
• 作者: Vallera,DanielA;Jin,Ni;Shu,Yanqun;Panoskaltsis-Mortari,Angela;Kelekar,Ameeta;Chen,Wei
• 通讯作者: Chen,Wei