Molecular engineering and systematic evaluation of bispecific aptamers to develop potent and efficacious therapies for the immunomodulation of Non-Small Cell Lung Cancer

双特异性适体的分子工程和系统评估，以开发有效的非小细胞肺癌免疫调节疗法

• 批准号: 10751309
• 负责人: Brian J Thomas
• 金额: $ 3.34万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2027-08-20
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751309
• 关键词: Address; Adenocarcinoma; Adjuvant; Adverse event; Affect; Affinity; Antibodies; Antigen Presentation; Antitumor Response; Aptamer Technology; Attention; Automobile Driving; Binding; Biodistribution; Biological Products; Bispecific Antibodies; Bypass; Cancer Biology; Cancer Patient; Cardiovascular Diseases; Categories; Cause of Death; Cell Cycle; Cells; Clinical; Clinical Trials; Development; Disease; Disease Progression; Dose Limiting; Drug Kinetics; Effectiveness; Emotional; Engineering; Epidermal Growth Factor Receptor; Evaluation; Excision; Exclusion; Exercise; Family; Financial Hardship; Future; Generations; Goals; Hematologic Neoplasms; Heterogeneous-Nuclear Ribonucleoproteins; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune system; In Vitro; Intercellular Junctions; Kinetics; Length; Life; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Memory; Mentors; Methods; Modeling; Modification; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Nucleic Acids; Oligonucleotides; Oncogenes; PTPRC gene; Patients; Peptide/MHC Complex; Phenotype; Phosphoric Monoester Hydrolases; Play; Prevalence; Process; Productivity; Property; Psyche structure; Pulmonary Inflammation; Radiation; Radon; Rationalization; Reagent; Recurrence; Relapse; Research; Resistance; Role; Signal Transduction; Smoker; Solid; Specificity; Squamous cell carcinoma; Synapses; T-Cell Activation; T-Lymphocyte; Techniques; Therapeutic; Therapeutic Index; Training; Tumor Antigens; Tumor-Infiltrating Lymphocytes; Tyrosine Kinase Inhibitor; United States; anti-cancer; anti-tumor immune response; aptamer; burden of illness; cancer cell; cancer subtypes; cancer therapy; cell type; chemotherapy; chimeric antigen receptor T cells; clinical translation; conventional therapy; defined contribution; design; efficacious treatment; exhaustion; humanized mouse; immune activation; immune-related adverse events; immunogenicity; immunological synapse; immunomodulatory therapies; immunoregulation; improved; in vivo; long term memory; lung cancer cell; mouse model; non-smoker; novel; novel therapeutics; patient derived xenograft model; pre-clinical; prevent; rational design; resistance mechanism; response; segregation; side effect; small molecule inhibitor; statistics; targeted treatment; transcriptomics; tumor; tumor heterogeneity

PROJECT SUMMARY Cancer is set to bypass cardiovascular disease as the number one cause of death in United States and it is a leading cause of death worldwide. Non-Small Cell Lung Cancer (NSCLC) is a major contributing factor to this statistic. Recent advancements in chemotherapeutic delivery and the development small molecule inhibitors, such as tyrosine kinase inhibitors, have been indispensable in decreasing disease prevalence and burden. Additionally, the recent FDA approvals of immunomodulating therapies, such as immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) T cells, and bispecific antibodies, emphasizes the importance that immune system evasion plays in disease progression and relapse. Unfortunately, administration of these targeted and immunomodulating therapies is often met with tumor acquired resistance (e.g., secondary mutations; T cell exhaustion) and incites non-specific or on-target/off tumor side effects (e.g., immune related adverse events). This suggests a need for alternative or adjuvant NSCLC therapies that are not only potent and efficacious but exercise a wide therapeutic index. We propose to exploit aptamer technology as one potential way to address this need. Aptamers are single strand oligonucleotides that bind to their targets with high specificity and affinity and their relative lack of immunogenicity as a foreign substance, compared to antibodies, make them ideal reagents to modulate the immune system. Furthermore, their ease of manipulation makes molecular engineering to design and optimize such reagents relatively straightforward. Our goal is to develop novel immunomodulating bispecific aptamers (bsApts) that dually bind to immune cell CD3ε and NSCLC tumor associated antigens (TAAs) to induce formation of effective immune synapses. We propose to use molecular engineering techniques to rationally design bsApts and systematically evaluate specific bsApt properties, such as (i) valency, (ii) affinity, and (iii) linker length/type in their ability to induce artificial immune cell activation in vitro and anti-tumor responses in vivo. We also propose to take a transcriptomics approach to better understand how designs/targets affect tumor heterogeneity, tumor infiltrating lymphocyte phenotypes, and off-target immune cell activation. Secondary goals look at improving pharmacokinetic properties that limit bsApt clinical translatability while long-term goals look to generalize our findings on these properties to current and future bispecific therapies that target a wide range of solid and hematological cancers.

项目总结