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：
10705578
负责人：
Gianpietro Dotti
金额：
$ 48.37万
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/10705578
关键词：
Address Adverse event Antibodies Antibody Specificity Antigen Targeting Antigens B lymphoid malignancy B-Lymphocytes Biological Availability CD19 Antigens CD276 gene Caspase Cell Therapy Cell physiology Cell surface Cells Clinical Clinical Research Cross Reactions Data Desmoplastic Dose Limiting Endoplasmic Reticulum Engineering Enzymes Epitopes Evaluable Disease Evaluation Extracellular Matrix Family Genetic Goals Growth Heat-Shock Proteins 90 Hematologic Neoplasms Heparan Sulfate Proteoglycan Human Immune Immune checkpoint inhibitor Immunocompetent Immunotherapy In Vitro Infiltration Infusion procedures Integral Membrane Protein Invaded Macrophage Malignant lymphoid neoplasm Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Molecular Chaperones Molecular Conformation Mus Myelogenous Myeloid-derived suppressor cells Nature Normal tissue morphology North Carolina Oral PD-1 blockade PD-1/PD-L1 PDL1 pathway Pancreatic Ductal Adenocarcinoma Patients Penetration Phase Phase I Clinical Trials Pre-Clinical Model Prognosis Proteins Reaction Receptor Protein-Tyrosine Kinases Refractory Reporting Safety Shapes Signal Transduction Solid Neoplasm T cell therapy T-Lymphocyte Testing Therapeutic Time Tissues Toxic effect Tumor Escape Tumor Promotion Universities cancer cell cancer type chimeric antigen receptor chimeric antigen receptor T cells effector T cell extracellular first-in-human glucose-regulated protein 94 heparanase immune cell infiltrate immunosuppressive macrophages in vivo inhibitor leukemia malignant breast neoplasm melanoma member mouse model neoplastic cell novel pancreatic cancer cells pancreatic ductal adenocarcinoma model patient prognosis phase 1 study pre-clinical preclinical study prevent programs receptor expression response safety assessment 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：摘要据报道，通过 T 细胞过继转移在 B 细胞恶性肿瘤中取得了显着的临床反应用针对 CD19 抗原的嵌合抗原受体 (CAR) 进行重定向。然而，开发 CAR-T 治疗包括胰腺导管腺癌 (PDAC) 在内的实体瘤具有挑战性，因为： (1) CAR-T 可靶向的 PDAC 相关抗原有限，通常不完全表达由 PDAC 产生，并充当乘客，而不是肿瘤发生的驱动因素，从而允许抗原漂移； (2) CAR-T 是侵袭富含基质的肿瘤（例如 PDAC）的能力有缺陷； (3)PDAC肿瘤微环境 (TME) 具有高度免疫抑制作用。在本提案中，我们旨在解决这些关键问题。我们已经确定 B7-H3 (CD276) 作为 PDAC 中嵌合抗原受体 (CAR) T 细胞的合适靶标。 B7-H3是一种肿瘤- 促进跨膜蛋白在 60% 至 93% 的 PDAC、黑色素瘤、白血病、乳腺癌、前列腺癌和卵巢癌，而在正常健康组织中表达有限。我们开发了并在 PDAC 的异种和免疫活性小鼠模型中测试了 B7-H3.CAR-T，显示出抗肿瘤作用活动和安全。因此，在目标 1 中，我们建议在 PDAC 患者中开展一项 I 期临床研究，以评估 B7-H3.CAR-T 的安全性和抗肿瘤活性，其中还包括诱导型 caspase9 (iC9) 作为安全开关可在出现毒性时终止 B7-H3.CAR-T 的活性。在目标 2 中，我们建议发展临床前模型 CAR-T，其中 T 细胞不仅通过 CAR 获得肿瘤特异性表达，但也有能力克服 PDAC 的促纤维增生性质。具体来说，B7-H3.CAR-Ts 将被进一步改造以重新表达 CAR-T 中存在缺陷的乙酰肝素酶 (HPSE) 生成供临床使用。此外，我们将探讨 94 kDa 的葡萄糖调节蛋白（gp96 或 Grp94) 是热休克蛋白 (HSP) 90 家族 (HSP90B1) 的成员，也可用作 PDAC 中的额外靶点可防止当靶向单一抗原时由于抗原丢失而引起的肿瘤逃逸。在目标 3 我们建议将巨噬细胞和骨髓源性抑制细胞 (MDSC) 重新编程为非通过使用有效的口服生物可利用的 TAM RTK 小分子抑制剂来达到免疫抑制状态由北卡罗来纳大学开发（IND #128236）。因此，我们将进行临床前研究来评估巨噬细胞和 MDSC 中的 TAM RTK 信号传导抑制是否有利于 B7- 的抗肿瘤活性 H3.CAR-Ts。如果成功，该策略将被纳入拟议的 I 期临床的第二阶段使用 B7-H3.CAR-T 进行研究。