Project 4: Using Synthetic Immunology to Improve Activity and Specificity, and Overcome Resistance, in Cellular Therapy

项目 4:利用合成免疫学提高细胞治疗的活性和特异性,并克服耐药性

基本信息

  • 批准号:
    10210210
  • 负责人:
  • 金额:
    $ 42.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1997
  • 资助国家:
    美国
  • 起止时间:
    1997-09-30 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

Abstract T cell-based therapies have emerged recently as important therapies for cancer. Resistance to the activity of these cells, relapse, toxicities and deaths are still important hurdles to their success and strongly call for mechanisms to potentiate efficacy, while at the same time, to better control the safety of cell therapies. The goal of this project is to create a new generation of synthetic, tumor-specific T cells (based on CAR and TCRm technology) that will selectively home to cancer cells in vivo and then synthesize and release anti-neoplastic drugs at the cancer cell surface or into the tumor microenvironment. The selective and local elaboration of potent anti-neoplastic drugs at the tumor site, or on the cancer cells, should simultaneously: 1) reduce toxicity relative to conventional cancer drug therapy; 2) overcome immune mediated resistance to conventional CAR T cell therapy from regulatory cells and cytokines in the tumor microenvironment (because the cytotoxic drugs made will not be affected;) 3) overcome antigen loss variant mechanisms of resistance (because the drugs will kill cancer cells without antigen on the cell surface;) 4) reduce toxicity relative to conventional CAR T cells because the prodrug infusions can be pharmacologically regulated, scheduled, or stopped. In addition, the enzyme expression can be made conditional. The components of the proposed strategy are: 1) prodrug/drug pair in which the prodrug is not toxic to normal cells or tissues and the resulting drug potently kills cancer cells. Several types of prodrug systems will be developed for various functions and properties (Aim 1). 2) A CAR T cell directed to a tumor specific antigen via a lineage specific scFv (such as CD19 or MUC16) or a more specific TCRm-based scFv (such as to WT1 or PRAME,) 3) An enzyme genetically engineered into the CAR T cell capable of converting the prodrug into the active drug locally. We term these cells “Synthetic Enzyme Armed KillER” cells or SEAKER cells. These cells will be designed and tested in vitro (Aim 2) and in animal models (Aim 3.) This work will be carried out through a multi-PI, multidisciplinary collaboration between the labs of David A. Scheinberg (PI), Derek S. Tan (Co-PI), and Renier Brentjens (Co-Investigator), comprising extensive expertise in synthetic and medicinal chemistry, biochemistry, pharmacology, cell biology, and cancer immunology, that builds on prior work from the leaders over 15 years.
摘要 基于T细胞的疗法最近已经成为癌症的重要疗法。抗 这些细胞活性、复发、毒性和死亡仍然是其治疗的重要障碍, 成功,并强烈呼吁建立机制,以加强功效,同时, 更好地控制细胞疗法的安全性。这个项目的目标是创造新一代 合成的肿瘤特异性T细胞(基于CAR和TCRm技术), 在体内找到癌细胞的家,然后在癌细胞处合成并释放抗肿瘤药物。 细胞表面或进入肿瘤微环境。选择性的和局部的阐述 在肿瘤部位或癌细胞上的抗肿瘤药物应同时:1)减少 相对于常规癌症药物疗法的毒性; 2)克服免疫介导的抗性 从肿瘤中的调节细胞和细胞因子到传统的CAR T细胞疗法 微环境(因为制成的细胞毒性药物不会受到影响;)3)克服抗原 丧失变异耐药机制(因为药物会杀死没有抗原的癌细胞 4)相对于常规CAR T细胞降低毒性,因为前药 输注可以被自动调节、预定或停止。此外,酶 表达式可以是有条件的。拟议战略的组成部分是:1) 前体药物/药物对,其中前体药物对正常细胞或组织无毒, 这种药能有效地杀死癌细胞。将开发几种类型的前药系统用于各种用途。 功能和属性(目标1)。2)一种CAR T细胞,其通过免疫组织化学方法针对肿瘤特异性抗原。 谱系特异性scFv(如CD 19或MUC 16)或更特异性的基于TCR m的scFv(如 3)基因工程化到CAR T细胞中的酶,其能够 将前药局部转化为活性药物。我们称这些细胞为“合成酶 武装杀手”细胞或搜索细胞。这些细胞将在体外设计和测试(目标2) 和在动物模型中(目标3.)这项工作将通过多PI,多学科 大卫A. Scheinberg(PI),Derek S. Tan(Co-PI)和Renier Brentjens(共同研究者),包括在合成和药物方面的广泛专业知识 化学、生物化学、药理学、细胞生物学和癌症免疫学, 15年来领导人的工作。

项目成果

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DAVID A SCHEINBERG其他文献

DAVID A SCHEINBERG的其他文献

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{{ truncateString('DAVID A SCHEINBERG', 18)}}的其他基金

Understanding and Mimicking TCR Recognition with Therapeutic Monoclonal Antibodies.
使用治疗性单克隆抗体理解和模拟 TCR 识别。
  • 批准号:
    10238855
  • 财政年份:
    2020
  • 资助金额:
    $ 42.64万
  • 项目类别:
Understanding and Mimicking TCR Recognition with Therapeutic Monoclonal Antibodies.
使用治疗性单克隆抗体理解和模拟 TCR 识别。
  • 批准号:
    10462737
  • 财政年份:
    2020
  • 资助金额:
    $ 42.64万
  • 项目类别:
Understanding and Mimicking TCR Recognition with Therapeutic Monoclonal Antibodies.
使用治疗性单克隆抗体理解和模拟 TCR 识别。
  • 批准号:
    10674741
  • 财政年份:
    2020
  • 资助金额:
    $ 42.64万
  • 项目类别:
Understanding and Mimicking TCR Recognition with Therapeutic Monoclonal Antibodies.
使用治疗性单克隆抗体理解和模拟 TCR 识别。
  • 批准号:
    10046963
  • 财政年份:
    2020
  • 资助金额:
    $ 42.64万
  • 项目类别:
Targeted Alpha-particle Therapy
靶向α粒子治疗
  • 批准号:
    7728786
  • 财政年份:
    2008
  • 资助金额:
    $ 42.64万
  • 项目类别:
POTENTIATING & FOCUSING THE IMMUNE RESPONSE TO CANCER BY USE OF PEPTIDE ANTIGENS
增效
  • 批准号:
    7318392
  • 财政年份:
    2007
  • 资助金额:
    $ 42.64万
  • 项目类别:
RADIOIMMUNOTHERAPY WITH ALPHA AND BETA EMITTERS
使用 α 和 β 发射器进行放射免疫治疗
  • 批准号:
    6563802
  • 财政年份:
    2002
  • 资助金额:
    $ 42.64万
  • 项目类别:
RADIOIMMUNOTHERAPY WITH ALPHA AND BETA EMITTERS
使用 α 和 β 发射器进行放射免疫治疗
  • 批准号:
    6423087
  • 财政年份:
    2001
  • 资助金额:
    $ 42.64万
  • 项目类别:
POTENTIATION OF LEUKEMIA RESISTANCE CONFERRED BY MARROW ALLOGRAFT
同种异体骨髓移植增强白血病抵抗力
  • 批准号:
    6336336
  • 财政年份:
    2000
  • 资助金额:
    $ 42.64万
  • 项目类别:
POTENTIATION OF LEUKEMIA RESISTANCE CONFERRED BY MARROW ALLOGRAFT
同种异体骨髓移植增强白血病抵抗力
  • 批准号:
    6203042
  • 财政年份:
    1999
  • 资助金额:
    $ 42.64万
  • 项目类别:
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