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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：
10380107
负责人：
Renier Joseph Brentjens
金额：
$ 63.07万
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/10380107
关键词：
Acute Lymphocytic Leukemia Address Anti-CD47 Antibodies Antigen Targeting Antigens Biological Models Biology CD19 gene CD47 gene Cancer Biology Cell physiology Cell secretion 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 IL18 gene Immune Immune checkpoint inhibitor Immune system Immunocompetent Immunoglobulin Fragments Immunotherapy In Vitro Interleukin-12 Investigational New Drug Application Ligands Lymphoma Macrophage 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 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 small cell lung carcinoma 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.

摘要