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Clinical Evaluation of Chlorotoxin-redirected Chimeric Antigen Receptor (CAR) T cells for Treatment of Glioblastoma

氯毒素重定向嵌合抗原受体 (CAR) T 细胞治疗胶质母细胞瘤的临床评价

基本信息

批准号：
10614932
负责人：
CHRISTINE BROWN
金额：
$ 73.42万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614932
关键词：
Address Adoptive Transfer Amino Acids Antibodies Antigens Autologous B lymphoid malignancy Binding Blood Brain Brain Neoplasms CAR T cell therapy CD19 gene Catheters Cells Central Nervous System Cerebrospinal Fluid Characteristics Chlorotoxin Cities Clinic Clinical Clinical Research Clinical Trials Coupled Cyst Fluid Data Disease Disease remission Evolution Future Gene Expression Glioblastoma Goals Hematologic Neoplasms Heterogeneity Human Image Immune Immunologic Monitoring Immunologics Immunotherapy Individual Inflammatory Investigational New Drug Application Letters Ligands Maximum Tolerated Dose Mediating Medical Modality Monitor Nature Non-Malignant Normal tissue morphology Organ Outcome Participant Pathway interactions Patient-Focused Outcomes Patients Peptides Phase I Clinical Trials Phenotype Population Positioning Attribute Prognosis Property Radiation therapy Recurrence Recurrent tumor Research Resistance Safety Sampling Scorpion Venoms Scorpions Solid Neoplasm Surface Antigens Surrogate Markers T-Lymphocyte Testing Therapeutic Time Tumor Antigens Tumor Expansion antitumor effect cancer cell chimeric antigen receptor chimeric antigen receptor T cells clinical outcome assessment clinical translation cross reactivity cytokine design early phase clinical trial experience first-in-human improved improved outcome in vitro activity in vivo innovation mouse model neoplasm immunotherapy neoplastic cell novel novel therapeutics patient prognosis patient response phase I trial preclinical study pressure programs protein expression research clinical testing response standard of care success therapy resistant treatment response tumor tumor eradication

项目摘要

PROJECT SUMMARY Despite increasingly aggressive standard of care treatments, patients with glioblastoma (GBM) have a poor prognosis that has remained unchanged for decades, and this represents a fundamental unmet medical need. Progress in immunotherapy across a broad range of tumor types provides hope that immunological approaches, including CAR T cell therapy, may improve outcomes for patients with GBM. This is supported by the ability of CD19-targeted CAR T cells to eliminate B cell malignancies in the central nervous system (CNS), as well as early clinical experiences showing safety and disease-modifying activity of CAR T cells in GBM. One major challenge for GBM immunotherapies is the phenotypic heterogeneity of GBM tumors coupled with the scarcity of targetable tumor-associated antigens. As an approach to address this challenge we have developed a novel CAR that exploits the selective and broad GBM-binding properties of chlorotoxin (CLTX). CLTX is a 36-amino acid peptide component of scorpion venom that binds specifically to GBM and other tumors with minimal cross- reactivity to non-malignant cells. Previous early phase clinical trials have established safety of CLTX when used as a GBM-targeting peptide for imaging and radiotherapy. Our preclinical studies demonstrate that CLTX-CAR T cells mediate potent antitumor activity in vitro and in vivo, with no observable effector activity against normal human cells or when adoptively transferred into cross-reactive mouse models. We now aim, in this proposal, to clinically test the hypothesis that CLTX-CAR T cells will be safe and mediate antitumor effects when locoregionally delivered to the CNS in patients with GBM. Aim 1 will evaluate the feasibility, safety and response rates of CLTX-CAR T cells in patients with recurrent GBM in a phase 1 clinical trial. CLTX-CAR T cells will be delivered locoregionally via intratumoral [ICT] and intracerebroventricular [ICV] catheters. Aim 2 will assess CAR-mediated immunological changes associated with response and resistance. Taking advantage of our catheter-based locoregional delivery strategy that allows sampling of the CSF throughout treatment, we will monitor surrogate markers of CAR T cell activity, including CAR T cell persistence and changes in inflammatory cytokines and endogenous immune subsets. We will also compare the intrinsic characteristics across different autologous CAR T cell products with clinical response. Aim 3 will investigate pathways of GBM tumor resistance and CAR-induced tumor evolution pre- and post-therapy, investigating antigen escape pathways and adaptive immunosuppressive mechanisms to CAR T treatment. The innovative use of scorpion-derived CLTX for tumor targeting would be the first example of a natural peptide−based CAR in the clinic, potentially expanding CAR designs beyond antibody- and ligand-based targeting domains. CLTX-CAR T cell targeting of a wide range of GBM cells within individual tumors is significant in that it will expand our armamentarium and potentially help to limit antigen escape and enhance tumor eradication, thereby improving outcomes for patients with GBM.

项目概要尽管护理治疗标准越来越积极，但胶质母细胞瘤 (GBM) 患者的病情仍然很差几十年来预后一直保持不变，这代表了基本的未满足的医疗需求。多种肿瘤类型的免疫疗法的进展为免疫学方法带来了希望，包括 CAR T 细胞疗法可能会改善 GBM 患者的预后。这是由以下能力支持的 CD19 靶向 CAR T 细胞可消除中枢神经系统 (CNS) 以及 B 细胞恶性肿瘤早期临床经验显示 CAR T 细胞在 GBM 中的安全性和疾病缓解活性。一个专业 GBM 免疫疗法面临的挑战是 GBM 肿瘤的表型异质性以及稀缺性可靶向的肿瘤相关抗原。作为应对这一挑战的方法，我们开发了一种新颖的方法利用氯毒素 (CLTX) 的选择性和广泛 GBM 结合特性的 CAR。 CLTX是36个氨基蝎毒的酸性肽成分，与 GBM 和其他肿瘤特异性结合，交叉作用最小对非恶性细胞的反应性。先前的早期临床试验已确定 CLTX 使用时的安全性作为用于成像和放射治疗的 GBM 靶向肽。我们的临床前研究表明 CLTX-CAR T 细胞在体外和体内介导有效的抗肿瘤活性，但没有观察到针对正常细胞的效应活性人类细胞或过继转移到交叉反应小鼠模型中时。我们现在的目标是，在本提案中临床测试 CLTX-CAR T 细胞在以下情况下是安全的并介导抗肿瘤作用的假设：局部递送至 GBM 患者的 CNS。目标 1 将评估可行性、安全性和响应在一项 1 期临床试验中，CLTX-CAR T 细胞在复发性 GBM 患者中的比率。 CLTX-CAR T细胞将通过瘤内 [ICT] 和脑室内 [ICV] 导管进行局部递送。目标 2 将评估 CAR 介导的与反应和耐药相关的免疫变化。利用我们的基于导管的局部递送策略，允许在整个治疗过程中对脑脊液进行采样，我们将监测 CAR T 细胞活性的替代标记，包括 CAR T 细胞持久性和炎症变化细胞因子和内源性免疫亚群。我们还将比较不同类型的内在特征具有临床反应的自体CAR T细胞产品。目标 3 将研究 GBM 肿瘤抵抗途径和 CAR 诱导的治疗前和治疗后的肿瘤进化，研究抗原逃逸途径和适应性 CAR T 治疗的免疫抑制机制。蝎子来源的 CLTX 治疗肿瘤的创新用途靶向将是临床上基于天然肽的 CAR 的第一个例子，有可能扩展 CAR 超越基于抗体和配体的靶向域的设计。 CLTX-CAR T细胞靶向多种单个肿瘤内的 GBM 细胞意义重大，因为它将扩大我们的军备库，并可能有助于限制抗原逃逸并增强肿瘤根除，从而改善 GBM 患者的预后。