Redirected T Cell Therapy to Cure Invasive Fungal Infections

重定向 T 细胞疗法治愈侵袭性真菌感染

基本信息

批准号：
10396163
负责人：
DIMITRIOS P KONTOYIANNIS
金额：
$ 5.3万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-05 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396163
关键词：
Address Adjuvant Therapy Anabolism Animals Antifungal Agents Antifungal Therapy Apoptosis Aspergillosis Aspergillus B lymphoid malignancy Bacteria Biomedical Engineering Blood Circulation CAR T cell therapy CD28 gene CD3 Antigens CD4 Positive T Lymphocytes Candida Caspofungin Cell Aging Cell Wall Cells Clinical Clinical Trials Coculture Techniques Collection Communicable Diseases Cytoplasmic Granules Cytoplasmic Tail DNA Sequence Alteration Development Disease Dose Drug resistance Exocytosis Extracellular Domain Extracellular Space Family Firefly Luciferases Flow Cytometry Fusarium Future Generations Genetic Recombination Germination Glycosaminoglycans Granzyme Growth HIV Hour Image Immune response Immunocompromised Host Immunologic Adjuvants Immunologic Deficiency Syndromes Immunosuppressive Agents Industrial fungicide Infection Infectious Agent Interferon Type II Interferons Laboratories Length Lung Malignant Neoplasms Masks Mediating Memory Methodology Modeling Molds Mucor Mucorales Multi-Drug Resistance Mus Mycoses Natural Immunity Natural Killer Cells Organism Pathway interactions Patients Pattern recognition receptor Peripheral Blood Mononuclear Cell Pharmacology Pharmacotherapy Phase Phenotype Plasmids Production Recombinants Rhizopus Scedosporium Signal Transduction Sleeping Beauty System T cell therapy T memory cell T-Cell Activation T-Cell Immunologic Specificity T-Lymphocyte Therapeutic Time TimeLine Tissues Transplant Recipients Transplantation Treatment Efficacy Validation Virus Virus Diseases Yeasts beta-Glucans cancer therapy cell killing chimeric antigen receptor chimeric antigen receptor T cells clinical application combat congenital immunodeficiency cytokine dectin 1 design engineered T cells fungus genetically modified cells granulysin imaging system improved in vivo inhibitor/antagonist microscopic imaging novel pathogen perforin real-time images receptor receptor binding screening

项目摘要

Project Summary Chimeric antigen receptor (CAR) T-cell therapy give new hope to patients suffering from drug-resistant infectious organisms such as Aspergillus, Candida, or Mucor. This is the first time that a pattern-recognition receptor (Dectin-1) has been adapted to redirect T-cell specificity to control fungal infection. Dectin-1 CAR (D-CAR) can activate the cytolytic machinery, and likely the perforin/granzyme and granulysin pathway, of genetically modified T-cells. The production of IFN- from the D-CAR+ T-cells may further augment innate immunity to invasive fungal infections if recombinant IFN-γ is administered pharmacologically or derived from CD4+ helper T-cells or natural killer cells. In the R21 phase, 2 major factors that limit immediate clinical applications of CAR T-cell therapy will be addressed: (1) generation of rapidly proliferative β-glucan-specific D-CAR+ T-cells and (2) long-term in vivo persistence to control invasive fungal infection. Several types of CARs are currently used in clinical trials to control B-cell malignancy. Because it is not yet apparent which CAR design provides fully competent T-cell activation for a given patient, we have developed an approach for screening multiple CAR molecules. Our team has developed the EZ-CAR platform for generating multiple CARs by mixing and matching components derived from known T-cell activating receptors while keeping the targeting domain intact. Using this approach, we will generate about 21 D-CARs with the Dectin-1 fungal targeting domain. Rapid production (within 10 days of PBMC collection from donor) may improve the therapeutic potential of the manufactured T-cells because it avoids the replication-mediated T-cell senescence and terminal differentiation that is associated with loss of in vivo persistence. In the R33 phase, the study will be expanded to target a wide variety of clinically important opportunistic molds (Mucor, Scedosporium) and yeasts (Candida). Drug-resistant isolates identified in MD Anderson clinical laboratories will be used for validating the therapeutic efficacy of the D-CAR+ T cells. In some fungi, such as Rhizopus (Mucorales family), the β-glucan layer is masked by the glycosaminoglycans (GAG) layer. D-CAR+ T- cell therapy will be used in combination with fungal cell wall biosynthesis inhibitors such as caspofungin to disrupt the glycosaminoglycans layer, which will allow better recognition and activation of the D-CAR+ T-cell therapy. In summary, patients suffering from invasive fungal infections due to primary immunodeficiencies such as genetic mutations and secondary immunodeficiencies such as human immunodeficiency virus infection, cancer, and transplantation are highly likely to benefit from immune adjuvant therapy. Development of single-engineered T- cells that can target various pathogens, such as D-CAR+ T-cells cells, which redirect T-cell specificity to Aspergillus, Candida, and Mucor species, is highly warranted to combat invasive fungal infections in immunocompromised patients.

项目摘要嵌合抗原受体（CAR）T细胞疗法为患有抗药性感染性的患者带来了新的希望曲霉，念珠菌或粘膜等生物。（Dectin-1）已改编成重定向T细胞特异性以控制功能。激活基因修饰的细胞溶解机器，可能是培养素/颗粒酶和颗粒素途径 T细胞。感染如果重组IFN-γ是在药理学上施用或源自CD4+辅助T细胞或天然的杀手细胞。在R21阶段，限制了限制汽车T细胞治疗的IMEDITAITE诊所临床临床的2个主要因素将是解决：（1）生成快速增殖的β-葡萄化D-car+ t-cells和（2）长期体内控制侵入性真菌感染的持久性。目前，在临床试验中使用了几种类型的汽车来控制B细胞恶性肿瘤。明显哪种汽车设计为给定患者提供了完全胜任的T细胞激活，我们已经开发了筛选多个汽车分子的方法。通过混合和匹配组件从已知的T细胞激活受体得出的多辆汽车，同时保持目标域完整。靶向域的快速生产（在捐赠者收集的PBMC之内）可能会改善治疗制成的T细胞的潜力是因为它避免了复制细胞衰老和末端与体内持久性丧失有关的区分。在R33阶段，该研究将扩展到针对各种临床重要的霉菌（粘液，SC孢子）和酵母（念珠菌）。实验室将用于验证某些真菌的D型+ T细胞的治疗方法根瘤菌（粘膜家族），β-葡聚糖层被糖胺聚糖（GAG）掩盖。细胞疗法将与真菌细胞生物合成抑制剂（例如Aspofungin）结合使用以破坏糖胺聚糖层，该层会更好地识别和激活D-CAR+ T细胞疗法。总而言之，由于原发性免疫缺陷，诸如遗传的患者突变和继发性免疫缺陷，例如人类免疫缺陷病毒感染，癌症移植很可能受益于免疫辅助治疗。可以靶向各种病原体的细胞，例如D-CAR+ T细胞细胞，这些细胞将T-Cell特异性重定向到曲霉，念珠菌和粘液物种是高度保证的免疫功能低下的患者。