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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.

项目总结