Optimizing Dual-Targeted and Dual-Armored CAR T Cells for Small Cell LungCancer

优化用于小细胞肺癌的双靶点和双装甲 CAR T 细胞

基本信息

批准号：
10523835
负责人：
Renier Joseph Brentjens
金额：
$ 58.5万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10523835
关键词：
Acute Address Anti-CD47 Antibodies Antigen Targeting Antigens Biological Models Biology CD19 gene CD47 gene Cancer Biology Cell Therapy Cell physiology Cell surface Cells Clinical Clinical Trials Data Development Disease Down-Regulation Eating Extensive Stage FDA approved Failure Funding Ganglioside GD3 Generations Genetic Genetic Engineering Goals Hematologic Neoplasms Hepatitis delta Antigens Heterogeneity Human Immune Immune system Immunocompetent Immunoglobulin Fragments Immunotherapy In Vitro Interleukin-12 Interleukin-18 Investigational New Drug Application Ligands Malignant neoplasm of ovary Mediating Methods Modality Molecular Mutation Patients Persons Phagocytosis Phase I Clinical Trials Pre-Clinical Model Preclinical Testing Preparation Prognosis Proteins Refractory Relapse Resistance Signal Transduction Solid Neoplasm System T-Lymphocyte Technology Testing Therapeutic Treatment Failure Tumor Antigens Work anti-PD-1 anti-tumor immune response cancer cell cancer therapy checkpoint receptors chimeric antigen receptor chimeric antigen receptor T cells clinical translation clinically relevant cytokine design gene therapy genetically modified cells immune checkpoint improved in vivo in vivo Model lung cancer cell lung small cell carcinoma macrophage molecular targeted therapies mouse model neoplastic cell neuroendocrine cancer notch protein novel novel therapeutic intervention novel therapeutics patient derived xenograft model pre-clinical programmed cell death protein 1 receptor response tool tumor tumor microenvironment

项目摘要

ABSTRACT A patient's own T cells can be modified using gene therapy technology to express receptors, termed chimeric antigen receptors or CARs, which allow these immune T cells to recognize proteins on the tumor cell surface, and in turn allow these CAR modified T cells to recognize and kill the patient's own tumor cells. This approach has been successful in some hematological malignancies, however, it has not been successful to date in solid tumors including small cell lung cancer (SCLC). Two mechanisms by which SCLC may evade T cell-mediated killing are loss of expression of antigens, and suppression of T cell function in the tumor microenvironment. In this proposal, we will attempt to overcome these barriers by designing CAR T cells that target two SCLC antigens simultaneously, and that produce multiple factors (“armors”) that enhance T cell activity in solid tumors. We hypothesize that these dual-armored, dual targeted (DADT) CAR T cells will be more effective against SCLC than previous T cell-mediated and immune therapies. We have previously shown that CAR T cells targeted to either the antigen GD3 or to the antigen DLL3, both of which are expressed on the majority of small cell lung cancers, are capable of killing SCLC cells in preclinical systems. Additionally, we have developed multiple armored CAR T cells that secrete factors such as IL-18, or an antibody-derived single-chain variable fragment (scFv) that blocks the immune checkpoint receptor PD-1, or an scFv blocking the phagocytosis-inhibitory signal CD47 on tumor cells. All of these armors enhance CAR T cell activity in our in vivo model systems through different mechanisms. In Aim 1 of this proposal, we will generate CAR T cells targeting DLL3 and GD3 simultaneously, to overcome antigen heterogeneity and antigen loss in tumors as a means of escape from T cell-mediated killing. Simultaneously, in Aim 2, we will test pairs of armors to identify the pair that is the most effective at enhancing the activity of single antigen-targeted CAR T cells against SCLC in vivo in immunocompetent systems. We then analyze the immune cells in the SCLC tumor microenvironment following CAR T cell treatment to assess changes mediated by the armored CAR T cells. Ultimately, in Aim 3, we will combine these approaches to generate CAR T cells that recognize GD3 and DLL3 and produce multiple armors. These DADT CAR T cells for SCLC may be suitable for further preclinical testing in preparation for clinical trials beyond the scope of this proposal, representing a novel therapeutic approach to SCLC. Given our robust track record in CAR T cell clinical translation, we fully anticipate having new CAR T cells suitable for clinical trials at the conclusion of funding. Additionally, these novel CAR T cells may be used as tools to explore the interactions between T cells and the SCLC microenvironment. The analysis of changes in SCLC tumors induced by the armored CAR T cells proposed here may reveal novel aspects of SCLC biology and illuminate mechanisms of immune escape and treatment failure in SCLC.

抽象的可以使用基因治疗技术修饰患者自身的 T 细胞来表达受体，称为嵌合抗原受体或 CAR，使这些免疫 T 细胞能够识别肿瘤细胞表面的蛋白质，进而让这些CAR修饰的T细胞识别并杀死患者自身的肿瘤细胞。已在某些血液系统恶性肿瘤中取得成功，但迄今为止在实体瘤方面尚未取得成功。肿瘤，包括小细胞肺癌 (SCLC)，SCLC 可能通过两种机制逃避 T 细胞介导。杀伤是抗原表达的丧失以及肿瘤微环境中T细胞功能的抑制。在此提案中，我们将尝试通过设计针对两种 SCLC 抗原的 CAR T 细胞来克服这些障碍同时，产生增强实体瘤中 T 细胞活性的多种因子（“装甲”）。追求这些双装甲、双靶向 (DADT) CAR T 细胞将更有效地对抗 SCLC 与之前的 T 细胞介导的免疫疗法相比，我们之前已经证明 CAR T 细胞靶向抗原 GD3 或抗原 DLL3，两者均在大多数小细胞肺上表达此外，我们还开发了多种在临床前系统中杀死 SCLC 细胞的药物。分泌 IL-18 或抗体衍生的单链可变片段等因子的装甲 CAR T 细胞 (scFv) 阻断免疫检查点受体 PD-1，或阻断吞噬抑制信号的 scFv 肿瘤细胞上的 CD47 通过增强体内模型系统中的 CAR T 细胞活性。在该提案的目标 1 中，我们将生成针对 DLL3 和 GD3 的 CAR T 细胞。同时，克服肿瘤中的抗原异质性和抗原丢失，作为逃避 T 的手段同时，在目标 2 中，我们将测试成对的盔甲，以确定最重要的一对。有效增强单抗原靶向 CAR T 细胞体内抗 SCLC 的活性然后我们分析 SCLC 肿瘤微环境中的免疫细胞。最终，在目标 3 中，我们将通过 CAR T 细胞治疗来评估装甲 CAR T 细胞介导的变化。结合这些方法来生成识别 GD3 和 DLL3 并产生多种装甲的 CAR T 细胞。这些用于 SCLC 的 DADT CAR T 细胞可能适合进一步的临床前测试，为临床试验做准备鉴于我们的稳健进展，这超出了本提案的范围，代表了一种新的 SCLC 治疗方法。 CAR T细胞临床转化记录，我们完全期待有适合临床试验的新CAR T细胞此外，这些新型 CAR T 细胞可用作探索相互作用的工具。 T细胞和SCLC微环境之间的变化分析。这里提出的装甲 CAR T 细胞可能会揭示 SCLC 生物学的新方面并阐明其机制 SCLC 的免疫逃逸和治疗失败。