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

摘要 以T细胞为基础的疗法最近已成为治疗癌症的重要疗法。抵抗力 这些细胞的活性、复发、毒性和死亡仍然是其 取得成功，并强烈呼吁建立机制以增强效力，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)将选择性地 体内的癌细胞，然后在癌细胞处合成和释放抗肿瘤药物 细胞表面或进入肿瘤微环境。PERPONCE的选择性和地方性阐述 肿瘤部位或癌细胞上的抗肿瘤药物应该同时：1)减少 相对于传统癌症药物治疗的毒性；2)克服免疫介导的耐药性 从肿瘤中的调节细胞和细胞因子到传统的CAR T细胞治疗 微环境(因为制造的细胞毒药物不会受到影响)3)克服抗原 丧失不同的耐药机制(因为药物将在没有抗原的情况下杀死癌细胞 4)相对于传统CAR T细胞的毒性降低，因为前药 输液可以是药理学规定的、预定的或停止的。此外，这种酶 表达式可以设置为有条件的。拟议战略的组成部分包括：1) 前体药物/药物对，其中前体药物对正常细胞或组织无毒，所产生的 这种药物可以有效地杀死癌细胞。几种类型的前药系统将被开发用于不同的 功能和属性(目标1)。2)CAR T细胞通过一种途径导向肿瘤特异性抗原 特定于谱系的单链抗体(如CD19或MUC16)或更特定的基于TCRm的单链抗体(如 WT1或PRAME，)3)一种通过基因工程进入CAR T细胞的酶，能够 在当地将前药转化为活性药物。我们称这些细胞为“合成酶” 武装杀手“细胞或Seaker细胞。这些细胞将在体外进行设计和测试(目标2)。 以及动物模型(目标3)。这项工作将通过多PI、多学科进行 David A.Scheinberg(Pi)、Derek S.Tan(Co-Pi)和Renier的实验室之间的合作 Brentjens(联合调查员)，由合成和医药方面的广泛专业知识组成 化学、生物化学、药理学、细胞生物学和癌症免疫学 领导15年以上的工作经验。

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.