Translating Autoantibodies Into Chimeric Antigen Receptor-T cell Therapy for Small Cell Lung Cancer

将自身抗体转化为嵌合抗原受体 T 细胞疗法治疗小细胞肺癌

• 批准号: 10689108
• 负责人: Kristin J Lastwika
• 金额: $ 59.15万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689108
• 关键词: Address; Antibodies; Antigen Targeting; Antigens; Autoantibodies; Autoantigens; B-Lymphocytes; Binding; Biological Markers; Biological Models; Blood; CAR T cell therapy; Cancer Model; Cancer Patient; Cancer cell line; Cell surface; Cells; Clinical; Complex; Data Set; Development; Diagnosis; Discrimination; Disease; Dose; Down-Regulation; Engineering; Epitopes; Failure; Genetically Engineered Mouse; Hand; High Prevalence; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; Immunobiology; Immunocompetent; Immunology; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Libraries; Ligand Binding Domain; Liquid substance; Lymphoma; Major Histocompatibility Complex; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Molecular; Multiple Myeloma; Neurologic; Normal tissue morphology; Paraneoplastic Syndromes; Patients; Phenotype; Plasma; Post-Translational Protein Processing; Pre-Clinical Model; Prevalence; Production; Sensitivity and Specificity; Signal Transduction; Smoking; Solid Neoplasm; Surface Antigens; Surrogate Markers; Survival Rate; Symptoms; Syndrome; T cell therapy; T-Cell Activation; TFRC gene; TP53 gene; Testing; Therapeutic; Tissues; Toxic effect; Translating; Tumor Antigens; Tumor Tissue; antigen binding; blood-based biomarker; cancer immunotherapy; cancer survival; cancer therapy; chimeric antigen receptor T cells; clinically relevant; cytokine; design; effective therapy; engineered T cells; exhaustion; immune cell infiltrate; immunogenic; immunogenicity; in vivo; in vivo evaluation; innovation; insight; leukemia; mouse model; neoantigens; neoplastic cell; novel; novel strategies; patient derived xenograft model; pre-clinical; preclinical study; programmed cell death ligand 1; protein complex; receptor; response; small cell lung carcinoma; success; trafficking; tumor; tumorigenesis

Abstract For the last 30 years, the 5-year survival rate of small cell lung cancer (SCLC) has been less than 7% despite the addition of immune checkpoint inhibitors as treatment options. Therapies like immune checkpoint inhibitors that aim to reengage an immune response may not succeed for SCLC as previous studies have shown downregulation of MHC molecules, low PD-L1 expression and limited immune infiltration. However, SCLC is often associated with autoantibody-driven Paraneoplastic Syndromes, providing evidence for the immunogenicity of SCLC. We propose that chimeric antigen receptor T cells (CAR-Ts) as a novel approach for SCLC immunotherapy that overcomes impediments to endogenous immunity. CAR-Ts are synthetically engineered to fuse antibody ligand binding domains with costimulatory components that activate T cells after engagement of cell surface antigens, and have had considerable success in leukemia, lymphoma, and multiple myeloma. The microenvironment of SCLC is phenotypically closer to CAR-T responsive lymphoma than many solid tumors where CAR-Ts have thus far had limited success. A challenge for CAR-T cells in many solid tumors is the identification of target antigens that are tumor-specific. We have identified 13 novel cell surface antigen and here will prioritize 3 with high prevalence in SCLC. Each of these antigens have post-translational modifications that act as neoantigens and lead to autoantibody production in a high percentage of SCLC cases. We will capture these neoantigen-autoantibodies from SCLC patient-derived B cells, sequence the tumor specific binding sequences, and design and test CARs constructed from the single chain variable fragments (scFvs). The benefit of isolating autoantibodies from SCLC patients to detect tumor-specific neoantigens is three-fold: 1. The antigens identified have already proven to be immunogenic; 2. The variable regions of these human autoantibodies can be directly engineered into ligand binding domains of CAR-T cells; and 3. Autoantibodies can be detected in the blood of patients and serve as tissue surrogate biomarkers to guide CAR-T cell target selection. The CAR-T cells we develop will be rigorously tested in multiple preclinical models that address complementary but non-overlapping therapeutic barriers. These include testing CAR-T cell tumor infiltration, efficacy and toxicity in a library of genetically diverse SCLC patient derived xenografts and identifying, then overcoming, immunosuppressive mechanisms in the immune competent Rb/p53 genetically engineered mouse model. Our team of experts in lung cancer, autoantibody biomarkers, immunology and CAR-T cells is well equipped to execute the development of novel immunotherapies that are desperately needed in SCLC.

摘要 在过去的30年里，尽管小细胞肺癌（SCLC）的5年生存率低于7%， 增加免疫检查点抑制剂作为治疗选择。免疫检查点抑制剂等疗法 如先前研究所示，旨在重新启动免疫反应的方法可能不会成功治疗小细胞肺癌 MHC分子下调、低PD-L1表达和有限的免疫浸润。然而，SCLC 通常与自身抗体驱动的副肿瘤综合征有关，为 SCLC的免疫原性。我们提出嵌合抗原受体T细胞（CAR-Ts）作为一种新的方法， 克服内源性免疫障碍的SCLC免疫疗法。CAR-T是合成的， 工程化以将抗体配体结合结构域与共刺激组分融合，所述共刺激组分在免疫后激活T细胞。 细胞表面抗原的参与，并在白血病，淋巴瘤和多发性骨髓瘤中取得了相当大的成功。 骨髓瘤SCLC的微环境在表型上比许多人更接近CAR-T反应性淋巴瘤。 迄今为止，CAR-T在实体瘤中的成功有限。CAR-T细胞在许多实体瘤中面临的挑战 是识别肿瘤特异性的靶抗原。我们鉴定了13种新的细胞表面抗原 在此将优先考虑在SCLC中具有高患病率的3种。这些抗原中的每一种都具有翻译后 这些修饰充当新抗原并在高百分比的SCLC病例中导致自身抗体产生。 我们将从SCLC患者来源的B细胞中捕获这些新抗原-自身抗体，对肿瘤特异性抗体进行测序， 结合序列，以及设计和测试由单链可变片段（scFv）构建的汽车。 从SCLC患者中分离自身抗体以检测肿瘤特异性新抗原的益处有三方面：1. 鉴定的抗原已经被证明是免疫原性的; 2.这些人的可变区 自身抗体可以直接工程化到CAR-T细胞的配体结合结构域中;和3.自身抗体 可以在患者血液中检测到，并作为组织替代生物标志物指导CAR-T细胞靶向 选择.我们开发的CAR-T细胞将在多个临床前模型中进行严格测试， 互补但不重叠的治疗障碍。这些包括测试CAR-T细胞肿瘤浸润， 在遗传多样性SCLC患者来源的异种移植物的文库中进行有效性和毒性研究， 免疫活性Rb/p53基因工程小鼠的免疫抑制机制 模型我们的肺癌、自身抗体生物标志物、免疫学和CAR-T细胞专家团队 配备执行开发新的免疫疗法，迫切需要在小细胞肺癌。