CAR T cells targeting mesothelin and secreting bispecific antibodies targeting fibroblasts in pancreatic cancer

CAR T 细胞靶向间皮素并分泌靶向胰腺癌成纤维细胞的双特异性抗体

基本信息

批准号：
10731635
负责人：
Marcela Valderrama Maus
金额：
$ 141.35万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-09 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10731635
关键词：
Achievement Address Antibodies Antigen Targeting Antigens Binding Biological Assay Biology Bispecific Antibodies Blood Bone Marrow CAR T cell therapy CD3 Antigens Cell Therapy Cell physiology Cells Clinical Trials Correlative Study Data Dose Drug Combinations Drug Targeting Effectiveness Engineering Engraftment Extracellular Matrix Fibroblasts Genetic Markers Hematologic Neoplasms Immune Immune response Immune system In Vitro Infiltration Infusion procedures Injections Intravenous Intravenous infusion procedures Knowledge Lentivirus Vector Malignant Neoplasms Malignant neoplasm of pancreas Methods Modeling Monitor Neoplasm Metastasis Normal Cell PD-1 inhibitors Pancreatic Ductal Adenocarcinoma Pathway interactions Patient Monitoring Patient-Focused Outcomes Patients Peripheral Pharmaceutical Preparations Phase Phase I Clinical Trials Phenotype Plasmids Pre-Clinical Model Preclinical Testing Protocols documentation Recommendation Resistance Role Route Safety Solid Solid Neoplasm Supporting Cell T cell infiltration T-Lymphocyte Testing Time Tissues Toxic effect Tumor Antigens Tumor Promotion Tumor Suppression Work advanced disease advanced pancreatic cancer adverse event monitoring antigen binding antitumor effect cancer cell cell killing cell type chimeric antigen receptor chimeric antigen receptor T cells combinatorial cytokine density design detection assay disease prognosis fibroblast-activating factor improved in vivo inhibitor manufacture mesothelin mouse model neoplastic cell neurotoxicity novel pancreatic cancer cells pancreatic cancer patients pancreatic ductal adenocarcinoma model pancreatic neoplasm pembrolizumab peripheral blood phase I trial pre-clinical prevent programmed cell death protein 1 programs protein expression response synergism treatment optimization trial design tumor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY CAR T cell therapy for solid tumors is hindered by a lack of tumor-specific antigens that are safe to target and homogenously expressed throughout the tumor, difficulty infiltrating the tumor due to dense tumor stroma, and suppression of CAR T cell function by the tumor microenvironment (TME). We plan to address these issues using novel meso-FAP CAR-TEAM cells that simultaneously target mesothelin, a solid tumor antigen that has already been proven safe to target in patients, and cancer-associated fibroblasts (CAFs), which inhibit T cell infiltration and suppress T cell function in the TME. The CAFs are targeted with T cell-engaging antibody molecules (TEAMs) secreted from the CAR T cells that bind to CD3 and fibroblast activation protein (FAP), which is highly expressed on CAFs. The TEAM allows for CAF elimination by CAR and non-CAR T cells in the tumor. We have already demonstrated that meso-FAP CAR-TEAM cells kill pancreatic cancer cells and CAFs in vitro, in vivo, and in patient-derived ex vivo models and have superior anti-tumor function compared to meso-CAR T cells alone. For the UG3 phase of this project, we will further optimize meso-FAP CAR-TEAM cells by determining the best mesothelin binder to use (SS1 vs. a novel binder developed by our lab), optimal route of injection (IV vs. IP) for targeting pancreatic tumors, and rationale drug combinations that address CAR T cell limitations in solid tumors. We will improve antigen density using an ADAM17 inhibitor (INCB7839) to prevent mesothelin cleavage from pancreatic cancer cells, optimize CAR T cell killing and persistence using ibrutinib to polarize meso-FAP CAR T cells to a Th1/Th17 phenotype, and further prevent suppression by the tumor microenvironment using a PD1 inhibitor (pembrolizumab). These drugs will be singly combined with meso-FAP CAR-TEAM cells to determine which best promotes efficacy in our preclinical models. Collectively, these results will inform the design of a phase I clinical trial for pancreatic cancer patients with advanced disease. During the UH3 phase, we will determine the safety and tolerability of meso-FAP CAR-TEAM cells. We have chosen pancreatic cancer as our first solid tumor target due to the dismal prognosis of the disease, the high percentage of patients with mesothelin-expressing tumors, and the known role of CAFs in promoting tumor growth. While our primary objective will be to determine safety, we will also monitor patient outcomes (progression and survival) while performing correlative studies to determine CAR T cell phenotype and function. We will also monitor the tumor and tumor microenvironment for mechanisms of response or resistance, such as changes in antigen expression and immunosuppressive cells. Overall, this project will develop a novel CAR-TEAM design to target a solid tumor and its microenvironment while optimizing the trial design through rigorous preclinical testing. If successful, the meso-FAP CAR T cell product could be directly applied to other mesothelin-expressing solid tumors and the knowledge gained from the UG3 phase will inform on the critical aspects of CAR T cell function to optimize prior to initiating a clinical trial.

项目摘要缺乏靶向靶标的肿瘤特异性抗原，阻碍了实体瘤的CAR T细胞疗法在整个肿瘤中均匀表达，难以渗透由于密集的肿瘤基质引起的肿瘤，并且通过肿瘤微环境（TME）抑制CAR T细胞功能。我们计划解决这些问题使用同时靶向间皮素的新型中型驾驶汽车团细胞，一种具有的实体肿瘤抗原已经被证明可以安全地靶向患者，并且与癌症相关的成纤维细胞（CAF）抑制了T细胞浸润和抑制TME中的T细胞功能。 CAF用T细胞抗体靶向与CD3和成纤维细胞激活蛋白（FAP）结合的CAR T细胞分泌的分子（团队），该细胞分泌在CAF上高度表达。该团队允许在肿瘤中消除汽车和非车T细胞的CAF。我们已经证明，在体外杀死胰腺癌细胞和CAF，体内和患者来源的离体模型，与中型t t相比具有优越的抗肿瘤功能单独使用细胞。对于该项目的UG3阶段，我们将通过确定最佳使用中皮粘合剂（SS1与我们实验室开发的新型粘合剂），最佳途径针对胰腺肿瘤的注射（IV与IP），以及针对CAR T细胞的基本原理药物组合实体瘤的局限性。我们将使用ADAM17抑制剂（INCB7839）提高抗原密度以防止间皮素从胰腺癌细胞裂解，使用ibrutinib优化CAR T细胞杀死和持久性将Meso-Fap Car T细胞偏振至TH1/TH17表型，并进一步防止肿瘤抑制使用PD1抑制剂（Pembrolizumab）的微环境。这些药物将与Meso-fap单独合并 CAR-Team细胞确定哪种最能促进我们的临床前模型中的功效。总的来说，这些结果将为患有晚期疾病的胰腺癌患者进行I期临床试验的设计。在 UH3阶段，我们将确定中型驾驶员团队的安全性和耐受性。我们选择了胰腺癌是由于疾病的惨淡预后，胰腺癌是我们的第一个实体瘤靶标表达间皮素的肿瘤患者，以及CAF在促进肿瘤生长中的已知作用。尽管我们的主要目标是确定安全性，我们还将监测患者的结果（进展和生存）同时进行相关研究以确定CAR T细胞表型和功能。我们还将监视肿瘤和肿瘤微环境的反应机制或抗性机制，例如抗原的变化表达和免疫抑制细胞。总体而言，该项目将开发出一种新颖的汽车团队设计实体瘤及其微环境，同时通过严格的临床前测试优化试验设计。如果成功的，中率的汽车T细胞产品可以直接应用于其他表达间皮的固体肿瘤和从UG3阶段获得的知识将告知CAR T细胞功能的关键方面在启动临床试验之前进行优化。