EpoxySEAKER and onSEAKER: CAR T-Cell Systems for Targeted Local Biosynthesis of Therapeutic Warheads

EpoxySEAKER 和 onSEAKER：用于治疗性弹头局部靶向生物合成的 CAR T 细胞系统

基本信息

批准号：
10634571
负责人：
Broderick C Corless
金额：
$ 2.7万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-28 至 2023-09-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10634571
关键词：
Acids Adverse effects Anabolism Antigens Antineoplastic Agents B-Lymphocytes Binding Biochemical Biological Assay CAR T cell therapy Cancerous Carboxylic Acids Cell Survival Cells Classification Clinical Treatment Clinical Trials Cytotoxic agent Decarboxylation Development Disease Dose Engineering Environment Enzyme Activation Enzymes FDA approved Generations Histone Deacetylase Histone Deacetylase Inhibitor Immune response Immunologics Immunosuppression In Situ In Vitro Keto Acids Killer Cells Kinetics Mediating Modeling Multiple Myeloma Mus Patients Pharmaceutical Preparations Pharmacy facility Phase Prodrugs Property Proteasome Inhibitor Recombinants Site Streptomyces System T-Cell Proliferation T-Lymphocyte Therapeutic Therapeutic Effect Threonine Toxic effect Treatment Effectiveness Trichostatin A Variant Vorinostat Zinc analog cancer cell chelation chimeric antigen receptor chimeric antigen receptor T cells covalent bond cytokine release syndrome cytotoxic dehydrogenation design enzyme activity exhaust exhaustion hydroxamate immunoengineering in vitro activity in vitro testing in vivo in vivo evaluation inhibitor interest multicatalytic endopeptidase complex novel novel therapeutic intervention off-target site pharmacologic small molecule synthetic enzyme tumor

项目摘要

EPOXYSEAKER AND ONSEAKER: CAR T-CELL SYSTEMS FOR TARGETED LOCAL BIOSYNTHESIS OF THERAPEUTIC WARHEADS Our labs have developed novel SEAKER (Synthetic Enzyme-Armed KillER) CAR T-cells that express enzymes that cleave masking groups from systemically administered non-toxic prodrugs. The localization of SEAKER cells to tumors allows for specific conversion of the prodrug to anticancer agent at the site of interest. These SEAKER cells overcome limitations of CAR T-cell therapy such as T-cell exhaustion, immunosuppression and antigen variance by creating a cascade effect through proliferation of T-cells, constitutive secretion of enzymes and catalytic generation of the active drugs. The enzymes continue to produce cytotoxic compounds at the tumor site even after the T-cells functionally exhaust. We will engineer this system to produce novel “epoxySEAKER” and “onSEAKER” cells that express bacterial biosynthetic enzymes and convert non- toxic prodrug substrates into cytotoxic compounds through an enzyme-mediated therapeutic warhead installation. Limiting the bulkiness of the prodrug by eliminating the need for masking moieties we expect greater pharmacological properties of the prodrugs. Installing the warhead moiety onto the prodrug rather than cleaving a masking group will eliminate the non-specific activation of cytotoxic agents and reduce the on-target, off-site toxicity associated with the target compounds. We plan to use our two novel SEAKER systems to target the tumor environment, elicit immunologic responses, and subsequently secrete EpnF or TsnB9 which will enzymatically activate prodrug variants of FDA approved drugs in situ. We will generate multiple prodrugs for the two SEAKER systems and evaluate their conversion to the active compounds using recombinant enzymes in vitro. Compounds such as carfilzomib and panobinostat are associated with on-target off-site toxicity when administered for the treatment of multiple myeloma. Tumor targeting “epoxySEAKER” or “onSEAKER” cells will localize the secretion of synthetic enzyme to the tumor site, allowing systemic administration of non-toxic prodrug, subsequent in situ compound synthesis and reduced off-site toxicity demonstrated by the target compounds. The additive therapeutic effect of the CAR-T cells and small-molecules will increase the effectiveness of treatment and may expand the target scope of CAR-T cell therapy.

环氧化鞋和Onseaker：用于靶向局部生物合成的汽车T细胞系统治疗弹头我们的实验室开发了表达酶的新型Seaker（合成酶杀手）T细胞T细胞从系统地施用的无毒前药中明确的掩蔽组。 Seaker的本地化细胞到肿瘤可以在感兴趣的部位将前药转化为抗癌剂。这些 Seaker细胞克服了CAR T细胞疗法的局限性，例如T细胞耗尽，免疫抑制和抗原方差通过T细胞的扩散，酶的构成分泌来产生级联反应。和活性药物的催化产生。这些酶继续在肿瘤上产生细胞毒性化合物站点即使在T细胞功能上排气之后。我们将设计该系统生产新颖表达细菌生物合成酶并转化非 - 通过酶介导的治疗弹头，有毒前药底物成细胞毒性化合物安装。通过消除掩盖部分的需求，我们期望更大前药的药理特性。将弹头部分安装到前瞻性上而不是切割掩膜组将消除细胞毒性剂的非特异性激活，并减少靶标的异地与靶化合物相关的毒性。我们计划使用我们的两个新型的Seaker系统来针对肿瘤环境，引起免疫反应，随后分泌EPNF或TSNB9，该EPNF或TSNB9将酶激活FDA批准的前药变体原位毒品。我们将为两个Seaker系统生成多个前药，并评估它们的转换为活性化合物在体外使用重组酶。 Carfilzomib和Panobinostat等化合物当给予多发性骨髓瘤治疗时，与靶向的异地毒性有关。瘤靶向“环氧基牛排”或“ Onseaker”细胞将将合成酶的分泌定位于肿瘤部位，允许全身施用无毒前药，随后原位化合物靶化合物证明的合成和降低的异地毒性。添加剂疗法 CAR-T细胞和小分子的影响将提高治疗的有效性，并可能扩大 CAR-T细胞疗法的目标范围。