Autoantibodies to tumor-derived neoepitopes as biomarkers and immunoPET agents for the early detection of small cell lung cancer

肿瘤衍生新表位的自身抗体作为生物标志物和免疫 PET 试剂用于小细胞肺癌的早期检测

• 批准号: 10715807
• 负责人: Delphine L Chen
• 金额: $ 58.2万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715807
• 关键词: Address; American; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Benefits and Risks; Binding; Biodistribution; Biological Assay; Biological Markers; Blood; Blood Tests; Cancer Patient; Cell Line; Cell membrane; Cell surface; Cessation of life; Chelating Agents; Clinic; Clinical; Complex; Data; Detection; Development; Diagnosis; Disease; Early Diagnosis; Early Intervention; Eligibility Determination; Ensure; Epitopes; Excision; Future; Guidelines; Human; Image; Immunoconjugates; Label; Limited Stage; Location; Lung; Malignant Neoplasms; Mediastinal; Mediating; Monoclonal Antibodies; Nerve Tissue; Neuroendocrine Cell; Neurologic; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Performance; Persons; Plasma; Population; Positron-Emission Tomography; Post-Translational Protein Processing; Pre-Clinical Model; Primary Neoplasm; Production; Proteins; Protocols documentation; Radioimmunoconjugate; Radioisotopes; Recombinant Antibody; Recommendation; Reproducibility; Resected; Risk Factors; Role; SPINK1 gene; Sensitivity and Specificity; Site; Smoker; Smoking; Survival Rate; Syndrome; TFRC gene; TIMP2 gene; Testing; Therapeutic Intervention; Translating; Translations; Tumor stage; Tumor-Derived; United States Preventative Services Task Force; Woman; Xenograft Model; cell immortalization; circulating biomarkers; cohort; computed tomography screening; density; diagnostic biomarker; diagnostic platform; early detection biomarkers; early screening; experimental study; expression vector; first-in-human; fluorodeoxyglucose; fluorophore; high risk; high risk population; human monoclonal antibodies; human tissue; humanized monoclonal antibodies; imaging agent; imaging modality; immune imaging; improved; in vivo; low dose computed tomography; lung cancer screening; men; mortality; mouse model; neoantigens; non-invasive imaging; novel; patient derived xenograft model; preclinical study; protein expression; risk stratification; small cell lung carcinoma; standard of care; subcutaneous; targeted imaging; therapy resistant; tumor

Project Summary/Abstract Small-cell lung cancer (SCLC) kills over 30,000 Americans every year and has a dismal 5-year overall survival rate of less than 7%. However, SCLC outcomes are greatly improved by early detection and intervention, with a nearly 50% 5-year survival rate for patients diagnosed at an early stage. These discrepant outcomes indicate that, by far, the majority of SCLC cases are diagnosed at later stages at which tumors rapidly become resistant to therapy, with death quickly following. Thus, an effective early detection strategy is necessary that both identifies cancer in people at high risk and facilitates non-invasive imaging that can confirm and delineate small tumors to guide surgical resection and treatment. We have found that autoantibodies (AAb) are present in the plasma of essentially all SCLC patients (much more common than in other major cancers) and have validated at least 7 AAb-identified neoantigens expressed by SCLC tumors that can be exploited as highly cancer-specific early detection biomarkers and/or imaging targets. We envision an early detection/diagnosis platform performed during the recommended annual low-dose computed tomography (LD-CT) lung cancer screenings for heavy smokers. However, LD-CT and all current imaging modalities are not suitable for SCLC early detection even in smoking enriched populations due to lower than required sensitivity/specificity and risk/benefit analyses. Here, we propose a two-tiered approach, with a blood test that detects the presence of AAb specific for SCLC that would trigger immuno-positron emission tomography (immunoPET) imaging utilizing a radioimmunoconjugate that specifically targets the autoantigenic proteins expressed only on SCLC tumors. The blood test ensures that only high-risk individuals are screened and the immunoPET confirms and localizes the tumor for future treatment. Thus, in Aim 1, we propose to define the role of SCLC-specific autoantigens (AAg), isolate human B cells specific to the AAg, test the AAg as highly sensitive and specific early detection biomarkers, and sequence the AAb variable regions and clone them into expression vectors to produce human monoclonal recombinant antibodies for imaging purposes. In Aim 2, we propose to perform immunoimaging of SCLC tumors using fluorophore- and radionuclide-labeled AAb immunoconjugates specific for these cancer targeted neoantigens/epitopes. Preliminary data for the 2 antibodies that we have tested so far show that they specifically bind to SCLC tumors in preclinical models, underscoring the feasibility of the entire pipeline. In summary, we will combine AAb-AAg early detection for risk stratification with immunoPET imaging to confirm and localize tumors, thereby establishing an early detection pathway capable of reducing the mortality of this highly aggressive cancer.

项目摘要/摘要 小细胞肺癌（SCLC）每年杀死30,000多名美国人，整体5年惨淡 生存率小于7％。但是，通过早期检测和干预，SCLC的结果大大改善 早期诊断出的患者的5年生存率接近50％。这些差异结果 表明迄今 对治疗有抵抗力，迅速死亡。因此，有效的早期检测策略必须 两者都识别出高风险的人的癌症，并促进可以确认和描述的非侵入性成像 小肿瘤可指导外科切除和治疗。我们发现自身抗体（AAB）存在于 本质上所有SCLC患者的血浆（比其他主要癌症更为普遍），并且已经验证 至少7种由SCLC肿瘤表达的AAB鉴定的新抗原，可以被用作高度癌症特异性 早期检测生物标志物和/或成像靶标。我们设想执行的早期检测/诊断平台 在建议的年度低剂量计算机断层扫描（LD-CT）肺癌筛查中 吸烟者。但是，即使在 吸烟富集的人群由于所需的敏感性/特异性和风险/收益分析而少。这里， 我们提出了一种两层方法，并进行了血液测试，该方法检测到SCLC的AAB的存在， 将触发免疫峰值发射断层扫描（Immunopet），利用放射免疫共轭物进行成像 该专门针对仅在SCLC肿瘤上表达的自身抗原蛋白。血液检查确保 只有筛查高风险的个体，并且免疫集证实并将肿瘤定位为未来的治疗。 因此，在AIM 1中，我们建议定义SCLC特异性自身抗原（AAG），分离人B细胞的作用 在AAG上，将AAG测试为高度敏感和特定的早期检测生物标志物，然后对AAB进行测序 可变区域并将其克隆到表达载体中，以产生人类单克隆重组抗体 用于成像目的。在AIM 2中，我们建议使用荧光团和 放射性核素标记的AAB免疫偶联物针对这些癌症的新抗原/表位。 到目前为止我们已经测试的两种抗体的初步数据表明它们专门与SCLC肿瘤结合 在临床前模型中，强调了整个管道的可行性。总而言之，我们将结合AAB-AAG 通过免疫图成像进行风险分层的早期检测以确认和定位肿瘤，从而确定 早期检测途径，能够降低这种高度侵略性癌症的死亡率。