Retroviral Immunotoxins for Leukemia

白血病的逆转录病毒免疫毒素

基本信息

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
项目类别：
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

项目摘要

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）是实验性药理学剂，它们是通过将特异性结合到癌细胞与有效催化毒素的抗体或细胞因子联系起来制成的，单个分子可以杀死细胞。他们的主要目的是像常规化疗一样，选择性地将治疗选择性地提供给癌细胞，而不是非目标器官。尽管这些药物有选择地结合并杀死癌细胞，但在临床上，它们受到其1）未能穿透和定位在癌症靶组织中的足够浓度的限制。在此提案中，我们将探讨解决此问题的解决方案。免疫系统（例如T细胞）的细胞是渗透，攻击和破坏癌细胞的最突出的细胞类型，并且自然适合于响应抗原性挑战而表达和生产细胞因子。因此，在资金的第一个周期中，我们利用了T细胞的众所周知的特性，这是它们迁移到肿瘤的能力，并提供了证据证明它们可以使用基因治疗在体内将免疫毒素用于体内白血病。我们表明，T细胞可以递送逆转录病毒（RETLT），这些IL-3在白血病部位局部局部修饰的IL-3组成，并产生明显的抗白血病作用。现在，我们的研究已经提出了有关这种新的代理类别的几个重要问题，在此提案中，我们将尝试确定它们的工作方式。我们已经建立了一种新的Retlt疗法模型，我们将用作未来修改和改善Retlt的尝试的基础。该模型利用使用抗原特异性T细胞克隆。我们将使用它来测试RETLT白血病疗法的有用性。先前的研究将我们集中在单个配体（IL-3）上。现在，在AIM 1中，我们将表征T细胞在这个已建立的模型中的作用，确定是否更好地使用CD4+或CD8+ T细胞克隆进行输送。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什么起作用。 AIM 2将集中在模型的T细胞成分上，我们将询问与其他肿瘤外部位相比，有多少T细胞定位于体内肿瘤。 T这些RETLT分泌T细胞的定位会引起毒性吗？ AIM 3专注于IT部分，我们将确定分泌的作用以及需要多少。最终，在AIM 4中，我们将确定与常规的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成分产生影响。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
作者：
通讯作者：

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

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.
影响因子：
0
作者：
Vallera,DanielA;Jin,Ni;Shu,Yanqun;Panoskaltsis-Mortari,Angela;Kelekar,Ameeta;Chen,Wei
通讯作者：
Chen,Wei

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