Use of Genetically Engineered T cells Targeting Tumor Stroma to Treat Lung Cancer

使用靶向肿瘤基质的基因工程 T 细胞治疗肺癌

• 批准号: 8578578
• 负责人: Steven Mark Albelda
• 金额: $ 35.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-23 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578578
• 关键词: Ablation; Adoptive Transfer; Adult; Animal Model; Antibodies; Antigen Receptors; Antigen Targeting; Area; Back; Blood; Blood Vessels; CD19 gene; Cancer Model; Cancer Patient; Cell Surface Proteins; Cells; Chronic; Clinical; Clinical Trials; Data; Diploidy; Epithelial; Fc Receptor; Fibroblasts; Funding; Genetic; Genetic Engineering; Goals; Grant; Growth; Human; Immune; Immune response; Immune system; Immunodeficient Mouse; Immunotherapy; Incidence; Inflammatory; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mesothelioma; Messenger RNA; Modeling; Mus; Neoplasm Metastasis; Normal tissue morphology; Patients; Production; Reagent; Receptor Gene; Research; Research Infrastructure; Role; Scientist; Specificity; Stromal Cells; Supporting Cell; Surface Antigens; Survival Rate; T cell therapy; T-Cell Lymphoma; T-Lymphocyte; Testing; Tissues; Toxic effect; United States; Work; Wound Healing; cancer cell; chemotherapy; chimeric antibody; experience; fibroblast-activating factor; improved; killings; lentivirally transduced; mesothelin; neoplastic cell; novel strategies; novel therapeutic intervention; pre-clinical; programs; public health relevance; success; tumor; tumor growth; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): One especially promising area of immunotherapy has been adoptive transfer of genetically programmed, patient-derived blood lymphocytes transfected with chimeric antigen receptor genes (CARs) to combine the effector functions of T lymphocytes with the ability of antibodies to recognize pre-defined surface antigens with high specificity in a non-MHC restricted manner. The success of CAR-T cell therapy depends on targeting an antigen that is highly expressed in tumors, but at minimal levels in normal tissues. To date, only cancer cells have been targeted, however, it is well established that beyond a minimal size, cancer progression is dependent on a stroma that contains blood vessels, inflammatory cells, and fibroblasts. The underlying hypothesis of this proposal is that destruction of stromal cells using CAR-T cells will alter the tumor microenvironment leading to inhibition of tumor growth in lung cancer. Because stromal cells are diploid and genetically stable, this could reduce the incidence of immune evasion. To test this hypothesis, we will target fibroblast activation protein (FAP), a stromal cell-surface protein highly expressed on cancer-associated fibroblasts in most human epithelial cancers, including lung cancers, but present at very low levels on normal adult tissues, except healing wounds and in some chronic inflammatory conditions. We propose the following specific aims: Aim 1. Evaluate the efficacy of retrovirally-transduced murine FAP-CAR T cells to inhibit the growth of lung cancers (using three mouse lung cancer models). Aim 2. Evaluate the mechanisms by which retrovirally-transduced murine FAP-CAR T cells inhibit the growth of tumors. Aim 3. Evaluate the combination of FAP-CAR T cells with chemotherapy (Aim 3A) and with a tumor-cell targeted CAR (mesothelin-CAR) (Aim 3B). Aim 4. Evaluate the efficacy and mechanisms of lentivirally-transduced human FAP-CAR T cells to inhibit the growth of human lung cancers in immunodeficient mice. In addition to obtaining answers to the scientific questions described above, completion of these aims will provide the preclinical data needed to implement a clinical trial for lung cancer. Funding for a potential FAP-CAR clinical trial is not requested in this proposal, but will be obtained through other support. If our strategy proves effective, this project will likely have additional significace beyond lung cancer, since FAP could be targeted in many tumors.

描述（由申请人提供）：免疫治疗的一个特别有前景的领域是过继转移用嵌合抗原受体基因（汽车）转染的遗传编程的患者来源的血液淋巴细胞，以将T淋巴细胞的效应子功能与抗体以非MHC限制性方式以高特异性识别预定义表面抗原的能力联合收割机结合。 CAR-T细胞疗法的成功取决于靶向在肿瘤中高度表达，但在正常组织中水平最低的抗原。迄今为止，只有癌细胞被靶向，然而，已经确定的是，超过最小尺寸，癌症进展取决于含有血管、炎性细胞和成纤维细胞的基质。这一提议的基本假设是， 使用CAR-T细胞的基质细胞将改变肿瘤微环境，从而抑制肺癌中的肿瘤生长。由于基质细胞是二倍体且遗传稳定，这可以降低免疫逃避的发生率。为了验证这一假设，我们将靶向成纤维细胞活化蛋白（FAP），这是一种基质细胞表面蛋白，在大多数人类上皮癌（包括肺癌）中的癌症相关成纤维细胞上高度表达，但在正常成人组织中的水平非常低，除了愈合伤口和一些慢性炎症条件。我们提出以下具体目标：目标1。评估逆转录病毒转导的鼠FAP-CAR T细胞抑制肺癌生长的功效（使用三种小鼠肺癌模型）。目标二。评估逆转录病毒转导的鼠FAP-CAR T细胞抑制肿瘤生长的机制。目标3。评估FAP-CAR T细胞与化疗（Aim 3A）和与肿瘤细胞靶向CAR（间皮素-CAR）（Aim 3B）的组合。目标4。评估慢病毒转导的人FAP-CAR T细胞抑制免疫缺陷小鼠中人肺癌生长的功效和机制。 除了获得上述科学问题的答案外，这些目标的完成将提供实施肺癌临床试验所需的临床前数据。本提案不要求为潜在的FAP-CAR临床试验提供资金，但将通过其他支持获得资金。如果我们的策略被证明是有效的，这个项目可能会有额外的意义超越肺癌，因为FAP可以在许多肿瘤中靶向。