Project 2: Combined CAR-T cell therapy

项目2：联合CAR-T细胞疗法

基本信息

批准号：
10334084
负责人：
Gianpietro Dotti
金额：
$ 43.38万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-16 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10334084
关键词：
Address Adverse event Antibodies Antibody Specificity Antigen Targeting Antigens Attenuated B lymphoid malignancy B-Lymphocytes CD19 Antigens CD276 gene Cell Therapy Cell physiology Cell surface Cells Clinical Clinical Research Data Desmoplastic Dose-Limiting Endoplasmic Reticulum Engineering Enzymes Epitopes Evaluable Disease Evaluation Extracellular Matrix Family Genetic Goals Growth Heat-Shock Proteins 90 Hematologic Neoplasms Heparitin Sulfate Human Immune Immune checkpoint inhibitor Immunocompetent Immunotherapy In Vitro Infiltration Infusion procedures Integral Membrane Protein Invaded Lung Lymphoid Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Molecular Chaperones Molecular Conformation Mus Myelogenous Myeloid-derived suppressor cells Nature North Carolina Oral PD-1 blockade PD-1/PD-L1 Pancreatic Ductal Adenocarcinoma Patients Phase Phase I Clinical Trials Pre-Clinical Model Prognosis Proteins Reaction Receptor Protein-Tyrosine Kinases Refractory Reporting Safety Shapes Signal Transduction Solid Solid Neoplasm T cell therapy T-Lymphocyte Testing Time Tissues Toxic effect Tumor Escape Tumor-infiltrating immune cells Universities base cancer cell cancer type chimeric antigen receptor chimeric antigen receptor T cells extracellular first-in-human glucose-regulated protein 94 heparanase immunosuppressive macrophages in vivo inhibitor leukemia macrophage malignant breast neoplasm melanoma member mouse model neoplastic cell novel pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model patient prognosis phase 1 study pre-clinical preclinical study prevent receptor expression response small molecule inhibitor success suicide gene tumor tumor microenvironment tumorigenesis tumorigenic

项目摘要

PROJECT 2: ABSTRACT Remarkable clinical responses have been reported in B-cell malignancies by adoptive transfer of T cells redirected with a chimeric antigen receptor (CAR) specific for the CD19 antigen. However, developing CAR-Ts for the treatment of solid tumors including pancreatic ductal adenocarcinoma (PDAC) is challenging because: (1) PDAC-associated antigens that are targetable by CAR-Ts are limited, generally not exclusively expressed by PDAC, and act as passengers, not as drivers of tumorigenesis, allowing for antigenic drift; (2) CAR-Ts are defective in their capacity to invade stroma-rich tumors such as PDAC; (3) PDAC tumor microenvironment (TME) is highly immunosuppressive. In this proposal we aim at solving these critical issues. We have identified B7-H3 (CD276) as a suitable target for chimeric antigen receptor (CAR) T cells in PDAC. B7-H3 is a tumor- promoting transmembrane protein aberrantly expressed in 60% to 93% of PDAC, melanoma, leukemia, breast, prostate and ovarian cancer, while limited expression is seen on normal healthy tissues. We have developed and tested B7-H3.CAR-Ts in xenogeneic and immunocompetent mouse models of PDAC showing antitumor activity and safety. Thus in Aim 1 we propose to develop a phase I clinical study in patients with PDAC to assess safety and antitumor activity of B7-H3.CAR-Ts that also include the inducible caspase9 (iC9) as a safety switch to terminate the activity of B7-H3.CAR-Ts in case of toxicity. In Aim 2 we propose to develop in preclinical models CAR-Ts in which T cells are not be only rendered tumor specific through the CAR expression, but are also equipped to overcome the desmoplastic nature of PDAC. Specifically, B7-H3.CAR-Ts will be further engineered to re-express the enzyme heparanase (HPSE), which is defective in CAR-Ts generated for clinical use. Furthermore, we will explore if the glucose-regulated protein of 94 kDa (gp96 or Grp94), which is a member of the heat shock protein (HSP) 90 family (HSP90B1) can also be used as additional target in PDAC to prevent tumor escape due to antigen loss when one single antigen is targeted. In Aim 3 we propose to reprogram macrophages and myeloid derived suppressor cells (MDSC) to a non- immunosuppressive state by using potent and orally bioavailable TAM RTK small molecule inhibitors developed at University of North Carolina (IND #128236). We will thus perform preclinical studies to evaluate whether TAM RTK signaling inhibition in macrophages and MDSC would favor the antitumor activity of B7- H3.CAR-Ts. If successful, this strategy will be included into a second phase of the proposed Phase I clinical study with B7-H3.CAR-Ts.

项目2：摘要 B细胞恶性肿瘤已通过T细胞的过继转移报告了显着的临床反应用针对CD19抗原的嵌合抗原受体（CAR）重定向。但是，开发汽车-TS 为了治疗包括胰腺导管腺癌（PDAC）在内的实体瘤，这是具有挑战性的，因为：（1）由CAR-TS靶向的PDAC相关抗原受到限制，通常不完全表达 PDAC由PDAC充当乘客，而不是肿瘤发生的驱动因素，允许抗原漂移；（2）CAR-TS是侵入富基质的肿瘤（如PDAC）的能力有缺陷；（3）PDAC肿瘤微环境（TME）高度免疫抑制。在此提案中，我们旨在解决这些关键问题。我们已经确定了 B7-H3（CD276）是PDAC中嵌合抗原受体（CAR）T细胞的合适靶标。 B7-H3是肿瘤在60％至93％的PDAC，黑素瘤，白血病，乳房，前列腺癌和卵巢癌，而在正常健康组织上的表达有限。我们已经发展了并测试了抗肿瘤的异构和免疫能力的小鼠模型中的B7-H3.CAR-TS 活动和安全。因此，在AIM 1中，我们建议在PDAC患者中开发I期临床研究评估B7-H3.CAR-TS的安全性和抗肿瘤活性，其中还包括诱导型caspase9（IC9）在毒性的情况下，安全转换以终止B7-H3.CAR-TS的活性。在AIM 2中，我们建议在临床前模型CAR-TS不仅可以通过汽车对T细胞进行特异性肿瘤表达，但也有能力克服PDAC的脱糖性质。具体来说，B7-H3.CAR-TS 将进一步设计以重新表达乙酰肝素酶（HPSE），该酶在CAR-TS中有缺陷生成临床用途。此外，我们将探索是否为94 kDa的葡萄糖调节蛋白（gp96或 GRP94），这是热休克蛋白（HSP）90家族（HSP90B1）的成员 PDAC中的其他靶标可防止一种单个抗原靶向时由于抗原损失而导致的肿瘤逃逸。在 AIM 3我们建议将巨噬细胞和髓样衍生抑制细胞（MDSC）重新编程为非 - 免疫抑制状态通过使用有效的和口服的可生物利用TAM RTK小分子抑制剂在北卡罗来纳大学（IND＃128236）开发。因此，我们将进行临床前研究以评估巨噬细胞和MDSC中的TAM RTK信号传导是否有利于B7-的抗肿瘤活性 H3.CAR-TS。如果成功，此策略将被包括在拟议的I期临床的第二阶段中使用B7-H3.CAR-TS进行研究。